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Sample records for leukaemia gene tel

  1. Gene duplication within the Green Lineage: the case of TEL genes.

    PubMed

    Charon, Céline; Bruggeman, Quentin; Thareau, Vincent; Henry, Yves

    2012-09-01

    Recent years have witnessed a breathtaking increase in the availability of genome sequence data, providing evidence of the highly duplicate nature of eukaryotic genomes. Plants are exceptional among eukaryotic organisms in that duplicate loci compose a large fraction of their genomes, partly because of the frequent occurrence of polyploidy (or whole-genome duplication) events. Tandem gene duplication and transposition have also contributed to the large number of duplicated genes in plant genomes. Evolutionary analyses allowed the dynamics of duplicate gene evolution to be studied and several models were proposed. It seems that, over time, many duplicated genes were lost and some of those that were retained gained new functions and/or expression patterns (neofunctionalization) or subdivided their functions and/or expression patterns between them (subfunctionalization). Recent studies have provided examples of genes that originated by duplication with successive diversification within plants. In this review, we focused on the TEL (TERMINAL EAR1-like) genes to illustrate such mechanisms. Emerged from the mei2 gene family, these TEL genes are likely to be land plant-specific. Phylogenetic analyses revealed one or two TEL copies per diploid genome. TEL gene degeneration and loss in several Angiosperm species such as in poplar and maize seem to have occurred. In Arabidopsis thaliana, whose genome experienced at least three polyploidy events followed by massive gene loss and genomic reorganization, two TEL genes were retained and two new shorter TEL-like (MCT) genes emerged. Molecular and expression analyses suggest for these genes sub- and neofunctionalization events, but confirmation will come from their functional characterization.

  2. Expression patterns of TEL genes in Poaceae suggest a conserved association with cell differentiation.

    PubMed

    Paquet, Nicolas; Bernadet, Marie; Morin, Halima; Traas, Jan; Dron, Michel; Charon, Celine

    2005-06-01

    Poaceae species present a conserved distichous phyllotaxy (leaf position along the stem) and share common properties with respect to leaf initiation. The goal of this work was to determine if these common traits imply common genes. Therefore, homologues of the maize TERMINAL EAR1 gene in Poaceae were studied. This gene encodes an RNA-binding motif (RRM) protein, that is suggested to regulate leaf initiation. Using degenerate primers, one unique tel (terminal ear1-like) gene from seven Poaceae members, covering almost all the phylogenetic tree of the family, was identified by PCR. These genes present a very high degree of similarity, a much conserved exon-intron structure, and the three RRMs and TEL characteristic motifs. The evolution of tel sequences in Poaceae strongly correlates with the known phylogenetic tree of this family. RT-PCR gene expression analyses show conserved tel expression in the shoot apex in all species, suggesting functional orthology between these genes. In addition, in situ hybridization experiments with specific antisense probes show tel transcript accumulation in all differentiating cells of the leaf, from the recruitment of leaf founder cells to leaf margins cells. Tel expression is not restricted to initiating leaves as it is also found in pro-vascular tissues, root meristems, and immature inflorescences. Therefore, these results suggest that TEL is not only associated with leaf initiation but more generally with cell differentiation in Poaceae.

  3. TEL/AML-1 fusion gene. its frequency and prognostic significance in childhood acute lymphoblastic leukemia.

    PubMed

    Jamil, A; Theil, K S; Kahwash, S; Ruymann, F B; Klopfenstein, K J

    2000-10-15

    TEL gene rearrangement due to the 12;21 chromosome translocation is believed to be the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL). A study was conducted to investigate the frequency and prognostic significance of TEL/AML-1 fusion gene resulting from a cryptic t(12;21)(p13;q22). Bone marrow samples from 86 patients diagnosed over the past 5 years at Columbus Children's Hospital were analyzed by fluorescence in situ hybridization (FISH) technique for TEL/AML-1 fusion gene, using LSI((R)) DNA probes. The positive cases were analyzed for clinical outcome. Patients in this study received treatment according to Children's Cancer Group (CCG) protocols. Fifteen of the 86 cases (17%) were positive for the fusion gene. All were B-cell lineage and except for one, all were CD10 positive. TEL/AML-1 was not found in any T-cell ALL. The mean overall survival (OS) following diagnosis for the TEL/AML-1-positive group was significantly longer than for the TEL/AML-1-negative group by log-rank = 7.84, P = 0.005. Similarly, the event-free survival (EFS) after remission for the positive group (median 94.5 months) was longer than the negative group (median 57 months) by log-rank = 7.19, P = 0.007. This study confirms that the TEL/AML-1 fusion gene may be the most common genetic event in childhood ALL, occurring in 17% of the patients. It appears restricted to the B-cell lineage. In this study, the presence of a TEL/AML-1 fusion gene was statistically significant in predicting both OS and EFS, indicating a favorable clinical outcome for these patients. Screening for TEL/AML-1 should become routine at diagnosis and a useful biological variable for risk stratification in future clinical trials.

  4. Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients.

    PubMed

    Ali, Mohamed A E; Naka, Kazuhito; Yoshida, Akiyo; Fuse, Kyoko; Kasada, Atsuo; Hoshii, Takayuki; Tadokoro, Yuko; Ueno, Masaya; Ohta, Kumiko; Kobayashi, Masahiko; Takahashi, Chiaki; Hirao, Atsushi

    2014-07-18

    Acute myeloid leukaemia (AML) is a heterogeneous neoplastic disorder in which a subset of cells function as leukaemia-initiating cells (LICs). In this study, we prospectively evaluated the leukaemia-initiating capacity of AML cells fractionated according to the expression of a nucleolar GTP binding protein, nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model in which green fluorescent protein (GFP) is expressed under the control of a region of the NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukaemia colonies in vitro, and exhibited the highest leukaemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukaemia-initiating capacity that we termed the 'leukaemia stem cell gene signature'. This gene signature stratified human AML patients into distinct clusters that reflected prognosis, demonstrating that the mouse leukaemia stem cell gene signature is significantly associated with the malignant properties of human AML. Further analyses of gene regulation in leukaemia stem cells could provide novel insights into diagnostic and therapeutic approaches to AML.

  5. Current status of gene expression profiling in the diagnosis and management of acute leukaemia.

    PubMed

    Bacher, Ulrike; Kohlmann, Alexander; Haferlach, Torsten

    2009-06-01

    Gene expression profiling (GEP) enables the simultaneous investigation of the expression of tens of thousands of genes and was successfully introduced in leukaemia research a decade ago. Aiming to better understand the diversity of genetic aberrations in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), pioneer studies investigated and confirmed the predictability of many cytogenetic and molecular subclasses in AML and ALL. In addition, GEP can define new prognostic subclasses within distinct leukaemia subgroups, as illustrated in AML with normal karyotype. Another approach is the development of treatment-specific sensitivity assays, which might contribute to targeted therapy studies. Finally, GEP might enable the detection of new molecular targets for therapy in patients with acute leukaemia. Meanwhile, large multicentre studies, e.g. the Microarray Innovations in LEukaemia (MILE) study, prepare for a standardised introduction of GEP in leukaemia diagnostic algorithms, aiming to translate this novel methodology into clinical routine for the benefit of patients with the complex disorders of AML and ALL.

  6. The clinical implications of gene mutations in chronic lymphocytic leukaemia

    PubMed Central

    Rossi, Davide; Gaidano, Gianluca

    2016-01-01

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  7. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia.

    PubMed

    Wan, Liling; Wen, Hong; Li, Yuanyuan; Lyu, Jie; Xi, Yuanxin; Hoshii, Takayuki; Joseph, Julia K; Wang, Xiaolu; Loh, Yong-Hwee E; Erb, Michael A; Souza, Amanda L; Bradner, James E; Shen, Li; Li, Wei; Li, Haitao; Allis, C David; Armstrong, Scott A; Shi, Xiaobing

    2017-03-09

    Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.

  8. Comprehensive Analysis of MILE Gene Expression Data Set Advances Discovery of Leukaemia Type and Subtype Biomarkers.

    PubMed

    Labaj, Wojciech; Papiez, Anna; Polanski, Andrzej; Polanska, Joanna

    2017-03-01

    Large collections of data in studies on cancer such as leukaemia provoke the necessity of applying tailored analysis algorithms to ensure supreme information extraction. In this work, a custom-fit pipeline is demonstrated for thorough investigation of the voluminous MILE gene expression data set. Three analyses are accomplished, each for gaining a deeper understanding of the processes underlying leukaemia types and subtypes. First, the main disease groups are tested for differential expression against the healthy control as in a standard case-control study. Here, the basic knowledge on molecular mechanisms is confirmed quantitatively and by literature references. Second, pairwise comparison testing is performed for juxtaposing the main leukaemia types among each other. In this case by means of the Dice coefficient similarity measure the general relations are pointed out. Moreover, lists of candidate main leukaemia group biomarkers are proposed. Finally, with this approach being successful, the third analysis provides insight into all of the studied subtypes, followed by the emergence of four leukaemia subtype biomarkers. In addition, the class enhanced DEG signature obtained on the basis of novel pipeline processing leads to significantly better classification power of multi-class data classifiers. The developed methodology consisting of batch effect adjustment, adaptive noise and feature filtration coupled with adequate statistical testing and biomarker definition proves to be an effective approach towards knowledge discovery in high-throughput molecular biology experiments.

  9. A 17-gene stemness score for rapid determination of risk in acute leukaemia.

    PubMed

    Ng, Stanley W K; Mitchell, Amanda; Kennedy, James A; Chen, Weihsu C; McLeod, Jessica; Ibrahimova, Narmin; Arruda, Andrea; Popescu, Andreea; Gupta, Vikas; Schimmer, Aaron D; Schuh, Andre C; Yee, Karen W; Bullinger, Lars; Herold, Tobias; Görlich, Dennis; Büchner, Thomas; Hiddemann, Wolfgang; Berdel, Wolfgang E; Wörmann, Bernhard; Cheok, Meyling; Preudhomme, Claude; Dombret, Herve; Metzeler, Klaus; Buske, Christian; Löwenberg, Bob; Valk, Peter J M; Zandstra, Peter W; Minden, Mark D; Dick, John E; Wang, Jean C Y

    2016-12-15

    Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC(+) and 89 LSC(-) cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.

  10. Etiology of leukaemias

    PubMed Central

    Law, L. W.

    1962-01-01

    A critical review is made of the present knowledge of the etiology of neoplasms of the haematopoietic system in experimental animals and man. Genetic factors play a dominant role in the origin of leukaemias in mice. A Mendelian interpretation of the data is excluded and several genes appear to be involved in susceptibility. The data available on leukaemias in man are equivocal so far as the role of genetic factors is involved. The author discusses the value of family and twin studies—which suggest the operation of rare, highly penetrant, recessive genes—and of cytogenetic studies in contributing to a fuller understanding of the nature and etiology of leukaemia. PMID:14462960

  11. Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.

    PubMed

    Curtis, Claire E; Grand, Francis H; Musto, Pellegrino; Clark, Andrew; Murphy, John; Perla, Gianni; Minervini, Maria M; Stewart, Janet; Reiter, Andreas; Cross, Nicholas C P

    2007-07-01

    We identified two patients with a t(2;4)(p24;q12) and a t(4;12)(q2?3;p1?2), respectively, in association with BCR-ABL and FIP1L1-PDGFRA negative chronic eosinophilic leukaemia. Molecular analysis revealed a novel STRN-PDGFRA fusion for the t(2;4) and ETV6-PDGFRA for the t(4;12). The fusions were confirmed by specific amplification of the genomic breakpoints, reverse transcription polymerase chain reaction and fluorescence in situ hybridisation. Both patients were treated with imatinib and, following a rapid haematological response, achieved cytogenetic remission and a major molecular response. In conclusion, PDGFRA fuses to diverse partner genes in myeloid disorders. Identification of these fusions is important as they are particularly sensitive to imatinib.

  12. Real-time quantification of TEL-AML1 fusion transcripts for MRD detection in relapsed childhood acute lymphoblastic leukaemia. Comparison with antigen receptor-based MRD quantification methods.

    PubMed

    Taube, Tillmann; Eckert, Cornelia; Körner, Gabriele; Henze, Günter; Seeger, Karlheinz

    2004-07-01

    Response to therapy of ALL assessed by molecular methods has been proved to be a predictor of outcome. Alternatively to established but very labour-intensive DNA-based PCR-techniques the TEL-AML1 fusion transcript can serve as a marker for MRD monitoring. MRD quantification using TEL-AML1 is of particular interest if the results are directly comparable to data obtained by established DNA-based assays. Investigation of the potential of MRD monitoring using LightCycler technology for TEL-AML1 real-time quantification and comparison to results from established DNA-based MRD assays revealed corresponding results. Accordingly, TEL-AML1 MRD quantification is a sensitive, specific and rapid method that can supplement clone-specific MRD detection.

  13. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia

    SciTech Connect

    Barker, G.F.; Golub, T.R.; Gilliland, D.G.; Bohlander, S.K.; Rowley, J.D.; Heibert, S.W.; Raimondi, S.C.; Ward, D.C.; Bray-Ward, P.; Morgan, E.

    1995-05-23

    Chromosomal rearrangements involving band 12p13 are found in a wide variety of human leukemias but are particularly common in childhood acute lymphoblastic leukemia. The genes involved in these rearrangements, however, have not been identified. We now report the cloning of a t(12;21) translocation breakpoint involving 12p13 and 21q22 in two cases of childhood pre-B acute lymphoblastic leukemia, in which t(12;21) rearrangements were not initially apparent. The consequence of the translocation is fusion of the helix-loop-helix domain of TEL, an ETS-like putative transcription factor, to the DNA-binding and transactivation domains of the transcription factor AML1. These data show that TEL, previously shown to be fused to the platelet-derived growth factor receptor {beta} in chronic myelomonocytic leukemia, can be implicated in the pathogenesis of leukemia through its fusion to either a receptor tyrosine kinase or a transcription factor. The TEL-AML1 fusion also indicates that translocations affecting the AML1 gene can be associated with lymphoid, as well as myeloid, malignancy. 23 refs., 5 figs.

  14. Association between leukaemia inhibitory factor gene polymorphism and pregnancy outcomes after assisted reproduction techniques.

    PubMed

    Oliveira, Joao Batista A; Vagnini, Laura D; Petersen, Claudia G; Renzi, Adriana; Oliveira-Pelegrin, Gabriela R; Mauri, Ana L; Ricci, Juliana; Massaro, Fabiana C; Dieamant, Felipe; Cavagna, Mario; Baruffi, Ricardo L R; Franco, Jose G

    2016-01-01

    Certain gene polymorphisms are associated with implantation failure and pregnancy loss. Studies of leukaemia inhibitory factor (LIF) gene polymorphisms are scarce. The LIF single nucleotide polymorphism (SNP) thymine (T)/guanine (G) (rs929271) was studied in women to determine whether an association existed with pregnancy outcomes after intracytoplasmic sperm injection (ICSI); 411 women who underwent ICSI were recruited. DNA was extracted from the peripheral blood, and the LIF gene SNP T/G (rs929271) was genotyped using real-time polymerase chain reaction. Participants were divided into three groups according to their LIF genotype: T/T (n = 168), T/G (n = 202) and G/G (n = 41). All IVF and ICSI procedures were carried out under the same clinical and laboratory conditions. The ICSI cumulative results (from fresh plus frozen cycles) of each genotype group were analysed. The G/G genotype in women was associated with a higher implantation rate (T/T: 15.9%, T/G: 16.2%, G/G: 27.0%; P < 0.05), ongoing pregnancy rate/patient (T/T: 31.5%, T/G: 36.1%, G/G: 53.7%; P < 0.05) and ongoing pregnancy rate/transfer (T/T: 18.5%, T/G: 20.2%, G/G: 36.7%; P < 0.05). LIF SNP T/G (rs929271) seems to be a susceptibility biomarker capable of predicting implantation efficiency and pregnancy outcomes.

  15. Fusion of platelet-derived growth receptor {beta} to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation

    SciTech Connect

    Golub, T.; Barker, G.; Gilliland, D.G.

    1994-09-01

    Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome characterized by abnormal clonal myeloid proliferation, and by progression to acute myelogenous leukemia (AML). A recently recognized subgroup of CMML has a t(5;12) (q33;p13) balanced translocation. Fluorescence in situ hybridization (FISH) localized the translocation breakpoint near the CSF1 receptor (CSF1R) locus on chromosome 5q. Pulsed-field gel electrophoresis confirmed rearrangements near CSF1R, but involvement of CSF1R itself was excluded. Southern blotting showed a rearrangement within the closely linked PDGF receptor {beta} (PDGFR{beta}) gene. Ribonuclease protection assays localized the translocation breakpoint to nucleotide 1766 in PDGFR{beta} RNA. Anchored PCR was used to identify the chromosome 12 fusion partner, a novel ets-like protein, tel. Tel contains a highly conserved carboxy terminal ets-like DNA-binding domain, and an amino terminal domain with a predicted helix-loop-helix (HLH) secondary structure. The consequence of the t(5;12) translocation is fusion of the tel HLH domain to the PDGFR{beta} transmembrane and tyrosine kinase domains. The tel HLH domain may contribute a dimerization motif which serves to constitutively activate PDGFR{beta} tyrosine kinase activity. The tel-PDGFR{beta} fusion demonstrates the oncogenic potential of PDGFR{beta}, and may provide a paradigm for early events in the pathogenesis of AML.

  16. Diagnosis and management of neonatal leukaemia.

    PubMed

    van der Linden, Marieke H; Creemers, Sara; Pieters, Rob

    2012-08-01

    Leukaemia in neonates (infants <1 month) is rare, whereby neonatal acute myeloid leukaemia (AML) is more frequent than neonatal acute lymphoblastic leukaemia (ALL). High mortality rates are observed, though AML has a better prognosis than ALL. Neonatal leukaemia is typically presented with hepatosplenomegaly, leukaemia cutis and/or hyperleucocytosis. Congenital infections should be ruled out before diagnosis. Rearrangement of the MLL gene is the most frequently occurring genetic aberration. Treatment includes intensive multi-agent chemotherapy, usually with age-related dose adjustments next to supportive care. Treatment intensification for ALL could be indicated in the future as the dismal prognosis is subject to high relapse rates in ALL.

  17. Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children.

    PubMed

    Chan, Jason Yong-Sheng; Ugrasena, Dewa G; Lum, Danny Wai-Kiong; Lu, Yi; Yeoh, Allen Eng-Juh

    2011-09-01

    Xenobiotic and folate metabolic pathways are important for the maintenance of genetic stability and may influence susceptibility to the development of childhood acute lymphoblastic leukaemia (ALL). In this study, we investigated 10 polymorphisms in 6 genes (GSTM1-present/null, GSTT1-present/null, GSTP1 1578A > G, NQO1 609C > T, MTHFR 677C > T, MTHFR 1298A > C, MTHFD1 1958G > A, 3'-TYMS 1494 6bp-deletion/insertion, 5'-TYMS 28bp-tandem repeats, and SLC19A1 80G > A) in a cohort of 185 Javanese children with ALL and 177 healthy controls. In ALL patients, none of the polymorphisms demonstrated a statistically significant association with ALL after correcting for multiple comparisons. Gender-stratified analysis showed that in girls, GSTT1-null genotype was associated with increased ALL risk (OR = 2.20; p = 0.027), while GSTP1 1578AG genotype was associated with reduced risk (OR = 0.43; p = 0.031). Strong linkage disequilibrium between the MTHFR 677C > T and 1298A > C polymorphisms was observed (D' = 1.0; r(2) = 0.072). The haplotypes 677C-1298C and 677T-1298A were associated with a reduced risk of ALL (OR = 0.68 and 0.64, respectively; gender-adjusted global p = 0.028). Classification and regression tree (CART) analysis was employed to identify potential high-order gene-gene interactions and cluster subjects into susceptibility groups. SLC19A1 80G > A emerged as the predominant polymorphism associated with risk of ALL. Individuals simultaneously carrying MTHFR 1298AA, 3'-TYMS 6bp deletion(s) and SLC19A1 80A-allele(s) were at higher disease risk (OR = 2.21; p < 0.001). On the contrary, simultaneous possession of MTHFR 1298CC, 3'-TYMS 6bp homozygosity and SLC19A1 80A-allele(s) conferred lower risk (OR = 0.25; p = 0.004). Carriage of NQO1 609C-allele amongst SLC19A1 80GG genotype was associated with lower risk (OR = 0.47; p = 0.003). In conclusion, our study has demonstrated the importance of gender and gene-gene interaction within the xenobiotic and folate pathways in

  18. The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line.

    PubMed Central

    Longhurst, T. J.; O'Neill, G. M.; Harvie, R. M.; Davey, R. A.

    1996-01-01

    Multidrug resistance (MDR) in cancer cells is a major contributor to the failure of chemotherapy treatment. This paper describes a novel protein named the anthracycline resistance associated (ARA) protein. The ara gene is amplified in the MDR leukaemia line CCRF-CEM/E1000 and its mRNA is overexpressed. ARA belongs to the ATP binding cassette (ABC) family of proteins. Another ABC protein, the multidrug resistance-associated protein (MRP), has previously been reported to be overexpressed in the CEM/E1000 subline. The primary amino acid sequence of ARA indicates that it is 49.5 kDa without glycosylation, and that it has one potential glycosylation site. ARA has one ATP binding site and associated transmembrane regions. This is in contrast to MRP (190 kDa, 172 kDa deglycosylated) and most other higher eukaryote ABC proteins, which consist of two similar halves, each having one ATP binding site. In addition to ARA being coexpressed with MRP, comparison of amino acid sequences showed that, among known proteins, ARA is most similar to the C-terminal half of MRP. Images Figure 1 Figure 2 PMID:8912525

  19. Methylation of tumour suppressor gene promoters in the presence and absence of transcriptional silencing in high hyperdiploid acute lymphoblastic leukaemia.

    PubMed

    Paulsson, Kajsa; An, Qian; Moorman, Anthony V; Parker, Helen; Molloy, Gael; Davies, Teresa; Griffiths, Mike; Ross, Fiona M; Irving, Julie; Harrison, Christine J; Young, Bryan D; Strefford, Jon C

    2009-03-01

    Promoter methylation is a common phenomenon in tumours, including haematological malignancies. In the present study, we investigated 36 cases of high hyperdiploid (>50 chromosomes) acute lymphoblastic leukaemia (ALL) with methylation-specific multiplex ligase-dependent probe amplification to determine the extent of aberrant methylation in this subgroup. The analysis, which comprised the promoters of 35 known tumour suppressor genes, showed that 16 genes displayed abnormal methylation in at least one case each. The highest number of methylated gene promoters seen in a single case was thirteen, with all but one case displaying methylation for at least one gene. The most common targets were ESR1 (29/36 cases; 81%), CADM1 (IGSF4, TSLC1; 25/36 cases; 69%), FHIT (24/36 cases; 67%) and RARB (22/36 cases; 61%). Interestingly, quantitative reverse transcription-polymerase chain reaction showed that although methylation of the CADM1 and RARB promoters resulted in the expected pattern of downregulation of the respective genes, no difference could be detected in FHIT expression between methylation-positive and -negative cases. Furthermore, TIMP3 was not expressed regardless of methylation status, showing that aberrant methylation does not always lead to gene expression changes. Taken together, our findings suggest that aberrant methylation of tumour suppressor gene promoters is a common phenomenon in high hyperdiploid ALL.

  20. Hypomethylation of the CTGF gene locus is a common feature of paediatric pre-B acute lymphoblastic leukaemia.

    PubMed

    Welch, Mathew D; Greene, Wayne K; Kees, Ursula R

    2013-08-01

    The connective tissue growth factor gene (CTGF) is aberrantly expressed in 75% of precursor B-cell acute lymphoblastic leukaemias (pre-B ALL) and is associated with poor outcome. We identified consistent hypomethylation of the CTGF locus in primary pre-B ALL specimens regardless of CTGF expression. By contrast, primary T-cell ALL specimens, which do not express CTGF, exhibited distinctive patterns of hypermethylation. Furthermore, we confirmed that global changes in DNA methylation and histone acetylation can both functionally modulate CTGF expression in pre-B ALL cell lines. These data suggest that hypomethylation of the CTGF locus is an essential prerequisite for aberrant CTGF expression in pre-B ALL.

  1. The gene expression signature of relapse in paediatric acute lymphoblastic leukaemia: implications for mechanisms of therapy failure.

    PubMed

    Beesley, Alex H; Cummings, Aaron J; Freitas, Joseph R; Hoffmann, Katrin; Firth, Martin J; Ford, Jette; de Klerk, Nicolas H; Kees, Ursula R

    2005-11-01

    Despite significant improvements in the treatment of childhood acute lymphoblastic leukaemia (ALL), the prognosis for relapsing patients remains poor. The aim of this study was to generate a transcriptional profile of relapsed ALL to increase our understanding of the mechanisms involved in therapy failure. RNA was extracted from 11 pairs of cryopreserved pre-B ALL bone marrow specimens taken from the same patients at diagnosis and relapse, and analysed using HG-U133A microarrays. Relapse specimens overexpressed genes that are involved with cell growth and proliferation, in keeping with their aggressive phenotype. When tested in 72 independent specimens of pre-B ALL and T-ALL, the identified genes could successfully differentiate between diagnosis and relapse in either lineage, indicating the existence of relapse mechanisms common to both. These genes have functions relevant for oncogenesis, drug resistance and metastasis, but are not related to classical multidrug-resistance pathways. Increased expression of the top-ranked gene (BSG) at diagnosis was significantly associated with adverse outcome. Several chromosomal loci, including 19p13, were identified as potential hotspots for aberrant gene expression in relapsed ALL. Our results provide evidence for a link between drug resistance and the microenvironment that has previously only been considered in the context of solid tumour biology.

  2. Prediction of relapse in paediatric pre-B acute lymphoblastic leukaemia using a three-gene risk index.

    PubMed

    Hoffmann, Katrin; Firth, Martin J; Beesley, Alex H; Freitas, Joseph R; Ford, Jette; Senanayake, Saranga; de Klerk, Nicholas H; Baker, David L; Kees, Ursula R

    2008-03-01

    Despite high cure rates 25% of children with acute lymphoblastic leukaemia (ALL) relapse and have dismal outcome. Crucially, many are currently stratified as standard risk (SR) and additional markers to improve patient stratification are required. Here we have used diagnostic bone marrow specimens from 101 children with pre-B ALL to examine the use of gene expression profiles (GEP) as predictors of long-term clinical outcome. Patients were divided into two cohorts for model development and validation based on availability of specimen material. Initially, GEP from 55 patients with sufficient material were analysed using HG-U133A microarrays, identifying an 18-gene classifier (GC) that was more predictive of outcome than conventional prognostic parameters. After feature selection and validation of expression levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR), a three-gene qRT-PCR risk index [glutamine synthetase (GLUL), ornithine decarboxylase antizyme inhibitor (AZIN), immunoglobulin J chain (IGJ)] was developed that predicted outcome with an accuracy of 89% in the array cohort and 87% in the independent validation cohort. The data demonstrate the feasibility of using GEP to improve risk stratification in childhood ALL. This is particularly important for the identification of patients destined to relapse despite their current stratification as SR, as more intensive front-line treatment options for these individuals are already available.

  3. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.

    PubMed

    Law, Philip J; Berndt, Sonja I; Speedy, Helen E; Camp, Nicola J; Sava, Georgina P; Skibola, Christine F; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R; Clot, Guillem; Teras, Lauren R; Quintela, Inés; Birmann, Brenda M; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R; Hall, Andrew G; Purdue, Mark P; Mainou-Fowler, Tryfonia; Vajdic, Claire M; Jackson, Graham H; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G; Lawrence, Charles; Call, Timothy G; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W Ryan; Link, Brian K; Conde, Lucia; Bracci, Paige M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C H; Southey, Melissa C; Milne, Roger L; Clavel, Jacqueline; Topka, Sabine; Spinelli, John J; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M; Harris, Robert J; Miligi, Lucia; Pettitt, Andrew R; North, Kari E; Allsup, David J; Fraumeni, Joseph F; Bailey, James R; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J; Fegan, Chris; Rosenquist, Richard; de Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J S; Catovsky, Daniel; Campo, Elias; Cerhan, James R; Allan, James M; Rothman, Nathanial; Houlston, Richard; Slager, Susan

    2017-02-06

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10(-13)), 1q42.13 (rs41271473, P=1.06 × 10(-10)), 4q24 (rs71597109, P=1.37 × 10(-10)), 4q35.1 (rs57214277, P=3.69 × 10(-8)), 6p21.31 (rs3800461, P=1.97 × 10(-8)), 11q23.2 (rs61904987, P=2.64 × 10(-11)), 18q21.1 (rs1036935, P=3.27 × 10(-8)), 19p13.3 (rs7254272, P=4.67 × 10(-8)) and 22q13.33 (rs140522, P=2.70 × 10(-9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

  4. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

    PubMed Central

    Law, Philip J.; Berndt, Sonja I.; Speedy, Helen E.; Camp, Nicola J.; Sava, Georgina P.; Skibola, Christine F.; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J.; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R.; Clot, Guillem; Teras, Lauren R.; Quintela, Inés; Birmann, Brenda M.; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E.; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R.; Hall, Andrew G.; Purdue, Mark P.; Mainou-Fowler, Tryfonia; Vajdic, Claire M.; Jackson, Graham H.; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G.; Lawrence, Charles; Call, Timothy G.; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W Ryan; Link, Brian K.; Conde, Lucia; Bracci, Paige M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C. H.; Southey, Melissa C.; Milne, Roger L.; Clavel, Jacqueline; Topka, Sabine; Spinelli, John J.; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M.; Harris, Robert J.; Miligi, Lucia; Pettitt, Andrew R.; North, Kari E.; Allsup, David J.; Fraumeni, Joseph F.; Bailey, James R.; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J.; Fegan, Chris; Rosenquist, Richard; de Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J. S.; Catovsky, Daniel; Campo, Elias; Cerhan, James R.; Allan, James M.; Rothman, Nathanial; Houlston, Richard; Slager, Susan

    2017-01-01

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response. PMID:28165464

  5. Association between the MDR1 gene variant C3435T and risk of leukaemia: a meta-analysis.

    PubMed

    Zhang, B-B; Xuan, C; Deng, K-F; Wu, N; Lun, L-M

    2013-09-01

    Although a number of genetic studies have attempted to link the multidrug resistance (MDR1) C3435T polymorphism to risk of leukaemia, the results were often inconsistent. The present study aimed at investigating the pooled association using a meta-analysis on the published studies. 1933 cases and 2215 controls of 11 published studies in English before June 2012 were involved in the updated meta-analysis. Furthermore, subgroup analysis was performed in different ethnic and leukaemia subtype groups. This meta-analysis suggests that the MDR1 C3435T polymorphism associate with risk of leukaemia. The effect of the variant on the expression levels and the possible functional role of the variant in leukaemia should be addressed in further studies.

  6. Myristicin from nutmeg induces apoptosis via the mitochondrial pathway and down regulates genes of the DNA damage response pathways in human leukaemia K562 cells.

    PubMed

    Martins, Célia; Doran, Carolina; Silva, Inês C; Miranda, Claudia; Rueff, José; Rodrigues, António S

    2014-07-25

    Myristicin, an allylbenzene, is a major active component of various spices, such as nutmeg and cinnamon, plants from the Umbelliferae family or in some essential oils, such as oils of clove or marjoram. Human exposure to myristicin is low but widespread due to consumption of these spices and essential oils, added to food (e.g. cola drinks) or in traditional medicine. Occasionally high dose exposure occurs, leading to various clinical symptoms, however the molecular mechanisms underlying them are unknown. Our previous studies revealed that myristicin is not genotoxic and yet presented apoptotic activity. Therefore, in this work we assessed the apoptotic mechanisms induced by myristicin in human leukaemia cells. In order to gain further insight on the potential of myristicin to modulate gene expression we also analysed alterations in expression of 84 genes associated with the DNA damage response pathway. The results obtained show that myristicin can induce apoptosis as characterised by alterations in the mitochondrial membrane potential, cytochrome c release, caspase-3 activation, PARP-cleavage and DNA fragmentation. The gene expression profile revealed an overall down regulation of DNA damage response genes after exposure to myristicin, with significant under-expression of genes associated with nucleotide excision repair (ERCC1), double strand break repair (RAD50, RAD51) and DNA damage signalling (ATM) and stress response (GADD45A, GADD45G). On the whole, we demonstrate that myristicin can alter mitochondrial membrane function, induce apoptosis and modulate gene expression in human leukaemia K562 cells. This study provides further detail on the molecular mechanisms underlying the biological activity of myristicin.

  7. Quantitative multiplex quantum dot in-situ hybridisation based gene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia

    SciTech Connect

    Tholouli, Eleni; MacDermott, Sarah; Hoyland, Judith; Yin, John Liu; Byers, Richard

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Development of a quantitative high throughput in situ expression profiling method. Black-Right-Pointing-Pointer Application to a tissue microarray of 242 AML bone marrow samples. Black-Right-Pointing-Pointer Identification of HOXA4, HOXA9, Meis1 and DNMT3A as prognostic markers in AML. -- Abstract: Measurement and validation of microarray gene signatures in routine clinical samples is problematic and a rate limiting step in translational research. In order to facilitate measurement of microarray identified gene signatures in routine clinical tissue a novel method combining quantum dot based oligonucleotide in situ hybridisation (QD-ISH) and post-hybridisation spectral image analysis was used for multiplex in-situ transcript detection in archival bone marrow trephine samples from patients with acute myeloid leukaemia (AML). Tissue-microarrays were prepared into which white cell pellets were spiked as a standard. Tissue microarrays were made using routinely processed bone marrow trephines from 242 patients with AML. QD-ISH was performed for six candidate prognostic genes using triplex QD-ISH for DNMT1, DNMT3A, DNMT3B, and for HOXA4, HOXA9, Meis1. Scrambled oligonucleotides were used to correct for background staining followed by normalisation of expression against the expression values for the white cell pellet standard. Survival analysis demonstrated that low expression of HOXA4 was associated with poorer overall survival (p = 0.009), whilst high expression of HOXA9 (p < 0.0001), Meis1 (p = 0.005) and DNMT3A (p = 0.04) were associated with early treatment failure. These results demonstrate application of a standardised, quantitative multiplex QD-ISH method for identification of prognostic markers in formalin-fixed paraffin-embedded clinical samples, facilitating measurement of gene expression signatures in routine clinical samples.

  8. Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype.

    PubMed

    Fernandes, Mónica T; Ghezzo, Marinella N; Silveira, André B; Kalathur, Ravi K; Póvoa, Vanda; Ribeiro, Ana R; Brandalise, Sílvia R; Dejardin, Emmanuel; Alves, Nuno L; Ghysdael, Jacques; Barata, João T; Yunes, José Andres; dos Santos, Nuno R

    2015-12-01

    Lymphotoxin-mediated activation of the lymphotoxin-β receptor (LTβR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-α and LTβ (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTα1 β2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTβR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr(-/-) mice present markedly less leukaemic thymocytes than age-matched TEL-JAK2;Ltbr(+/+) mice and interference with LTβR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTβR signalling in thymic stromal cells, thus promoting leukaemogenesis.

  9. Minimal Residual Disease (MRD) Detection with Translocations and T-Cell Receptor and Immunoglobulin Gene Rearrangements in Adult Acute Lymphoblastic Leukaemia Patients: A Pilot Study.

    PubMed

    Sayitoğlu, Müge; Ar, M Cem; Hatırnaz, Özden; Öngören, Şeniz; Üre, Ümit; Başlar, Zafer; Sırma, Sema; Aydın, Yıldız; Özbek, Uğur; Ferhanoğlu, Burhan

    2008-09-05

    Monitoring minimal residual disease has become increasingly important in clinical practice of ALL management. Break-point fusion regions of leukaemia related chromosomal aberrations and rearranged immunoglobulin (Ig) and T cell-receptor (TCR) genes, which can be detected by polymerase chain reaction (PCR), are used as leukaemia specific markers in genetic studies of MRD. A total of 31 consecutive patients with newly diagnosed ALL were screened for eligibility criteria. Of those 26 were included in the study. One patient with partial response following induction therapy and four patients who were lost to follow-up after induction were excluded from the study; thus 21 patients were evaluated for MRD. Chromosomal aberrations were detected in 5 (24%) of the patients and were used for MRD monitoring. Three patients had t(9;22) translocation, the other 2 had t(4;11) and t(1;19). MRD-based risk stratification of the 16 patients analysed for Ig/TCR rearrangements revealed 3 low-risk, 11 intermediate-risk and 2 high-risk patients. MRD monitoring is progressively getting to be a more important predictive factor in adult ALL patients. As reported by others confirmed by our limited data there is a good correlation between MRD status and clinical outcome in patients receiving chemotherapy. The pilot-study presented here is the first that systematically and consecutively performs a molecular MRD monitoring of ALL patients in Turkey.

  10. Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3-13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: evidence for two new tumour-suppressor genes.

    PubMed Central

    Hatta, Y.; Takeuchi, S.; Yokota, J.; Koeffler, H. P.

    1997-01-01

    Identification of the key genetic alterations leading to ovarian cancer is in its infancy. Polymerase chain reaction (PCR)-based analysis of loss of heterozygosity (LOH) is a powerful method for detecting regions of altered tumour-suppressor genes. Focusing on chromosome 12, we examined 23 ovarian cancer samples for LOH using 31 highly polymorphic microsatellite markers and found the chromosomal localization of two putative tumour-suppressor genes. Two commonly deleted regions were 12p12.3-13.1 in 6/23 (26%) and 12q23-ter in 7/23 (30%) samples. LOH on chromosome 12 was more common in late-stage ovarian carcinomas. The region of LOH at 12p12.3-13.1 includes the genes that code for the ETS-family transcriptional factor, known as TEL, and the cyclin-dependent kinase inhibitor, known as p27Kip1. Mutational analysis of both TEL and p27Kip1 using single-strand conformation polymorphism (SSCP) showed no abnormalities, suggesting that the altered gene in this region is neither of these genes. Taken together, our data suggest that new tumour-suppressor genes in the region of chromosomes 12p12.3-13.1 and 12q23-ter may be involved in the development of ovarian cancer. Images Figure 1 Figure 2 Figure 4 PMID:9155043

  11. Adult Acute Leukaemia

    PubMed Central

    Atkinson, K.; Wells, D. G.; Clink, H. McD.; Kay, H. E. M.; Powles, R.; McElwain, T. J.

    1974-01-01

    Seventy-eight adult patients with acute leukaemia were classified cytologically into 3 categories: acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML) or acute undifferentiated leukaemia (AUL). The periodic acid-Schiff stain was of little value in differentiating the 3 groups. The treatment response in each group was different: 94% of patients with ALL (16/17) achieved complete remission with prednisone, vincristine and other drugs in standard use in childhood ALL; 59% of patients with AML (27/46) achieved complete remission with cytosine arabinoside and daunorubicin (22 patients), or 6-thioguanine and cyclophosphamide (2 patients), 6-thioguanine, cyclophosphamide and Adriamycin (1 patient), and cytosine and Adriamycin (1 patient); only 2 out of 14 patients (14%) with acute undifferentiated leukaemia achieved complete remission using cytosine and daunorubicin after an initial trial of prednisone and vincristine had failed. Prednisone and vincristine would seem to be of no value in acute undifferentiated leukaemia. It would seem also that no benefit is obtained by classifying all patients with acute leukaemia over 20 years of age as “adult acute leukaemia” and treating them with the same polypharmaceutical regimen. The problems posed by each disease are different and such a policy serves only to obscure them. ImagesFig. 1Fig. 2Fig. 3 PMID:4141625

  12. Chronic lymphocytic leukaemia

    PubMed Central

    Kipps, Thomas J.; Stevenson, Freda K.; Wu, Catherine J.; Croce, Carlo M.; Packham, Graham; Wierda, William G.; O’Brien, Susan; Gribben, John; Rai, Kanti

    2017-01-01

    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer. PMID:28102226

  13. OPLS-DA as a suitable method for selecting a set of gene transcripts discriminating RAS- and PTPN11-mutated cells in acute lymphoblastic leukaemia.

    PubMed

    Musumarra, Giuseppe; Condorelli, Daniele F; Fortuna, Cosimo G

    2011-01-01

    OPLS discriminant analysis (OPLS-DA) was successfully applied for the selection of a limited number of gene transcripts necessary to discriminate PTPN11 and RAS mutated cells in acute lymphoblastic leukaemia (ALL) patients. The original set of 273 variables with VIP (1) values higher than 2.0 in the OPLS-DA model could be further reduced to 200 by elimination of less informative variables in the PCA class models adopted for SIMCA classification. The above 200 transcripts not only achieve a satisfactory discrimination accuracy between PTPN11 and RAS mutated cells but also indicate clearly that wild type samples belong to none of the mutated class models. In this list it was possible to identify candidate genes that could be involved in the molecular mechanisms discriminating PTPN11 and RAS mutations in ALL. Among them CBFA2T2, a member of the "ETO" family, is known because of its homology and association with the product of RUNX1-CBFA2T1 gene fusion generated by t(8;21) translocation, one frequent cause of acute myeloid leukemia.

  14. The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity.

    PubMed

    Davis, Zadie; Forconi, Francesco; Parker, Anton; Gardiner, Anne; Thomas, Peter; Catovsky, Daniel; Rose-Zerilli, Matthew; Strefford, Jonathan C; Oscier, David

    2016-04-01

    IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia (CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment (TTFT) among Stage A patients and in overall survival (OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline.

  15. Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T-lineage tumours.

    PubMed

    Longville, Brooke A C; Anderson, Denise; Welch, Mathew D; Kees, Ursula R; Greene, Wayne K

    2015-01-01

    The class 1A aldehyde dehydrogenase (ALDH1A) subfamily of genes encode enzymes that function at the apex of the retinoic acid (RA) signalling pathway. We detected aberrant expression of ALDH1A genes, particularly ALDH1A2, in a majority (72%) of primary paediatric T cell acute lymphoblastic leukaemia (T-ALL) specimens. ALDH1A expression was almost exclusive to T-lineage, but not B-lineage, ALL. To determine whether ALDH1A expression may have relevance to T-ALL cell growth and survival, the effect of inhibiting ALDH1A function was measured on a panel of human ALL cell lines. This revealed that T-ALL proliferation had a higher sensitivity to modulation of ALDH1A activity and RA signalling as compared to ALL cell lines of B-lineage. Consistent with these findings, the genes most highly correlated with ALDH1A2 expression were involved in cell proliferation and apoptosis. Evidence that such genes may be targets of regulation via RA signalling initiated by ALDH1A activity was provided by the TNFRSF10B gene, encoding the apoptotic death receptor TNFRSF10B (also termed TRAIL-R2), which negatively correlated with ALDH1A2 and showed elevated transcription following treatment of T-ALL cell lines with the ALDH1A inhibitor citral (3,7-dimethyl-2,6-octadienal). These data indicate that ALDH1A expression is a common event in T-ALL and supports a role for these enzymes in the pathobiology of this disease.

  16. Molecular expression of l-asparaginase gene from Nocardiopsis alba NIOT-VKMA08 in Escherichia coli: A prospective recombinant enzyme for leukaemia chemotherapy.

    PubMed

    Meena, Balakrishnan; Anburajan, Lawrance; Vinithkumar, Nambali Valsalan; Shridhar, Divya; Raghavan, Rangamaran Vijaya; Dharani, Gopal; Kirubagaran, Ramalingam

    2016-09-30

    l-Asparaginase is an antineoplastic agent that selectively reduces the level of l-asparagine in blood and diminishes the proliferation of cancerous cells. Studies were carried out on the cloning and heterologous expression of l-asparaginase biosynthesis gene (ansA) from Nocardiopsis alba NIOT-VKMA08 to achieve the stable inducible system that overproduces the glutaminase-free recombinant l-asparaginase. Overexpression of recombinant l-asparaginase was achieved with an optimized final concentration of 1.5mM of isopropyl-β-d-thiogalactoside (IPTG) and the enzyme was expressed as a soluble protein. The recombinant enzyme was purified using nickel-nitrilotriacetic acid (Ni-NTA) chromatography and the purified enzyme disclosed an elevated level of asparaginase activity (158.1IU/mL). Optimum pH and temperature of the purified l-asparaginase for the hydrolysis of l-asparagine were 8.0 and 37°C and it was very specific for its natural substrate, l-asparagine. Detailed studies were carried out on the kinetics of enzyme reaction, catalytic activity, temperature and ionic strength and the thermostability of the l-asparaginase enzyme. The functional characterisation of the recombinant l-asparaginase was studied through Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), in silico sequence analysis and protein structural modelling. Glutaminase activity was not detected in the recombinant l-asparaginase, which could reduce the probable side effects during leukaemia therapy.

  17. Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia.

    PubMed

    Guo, Jianfeng; Cahill, Mary R; McKenna, Sharon L; O'Driscoll, Caitriona M

    2014-12-01

    Leukaemia is a bone marrow cancer occurring in acute and chronic subtypes. Acute leukaemia is a rapidly fatal cancer potentially causing death within a few weeks, if untreated. Leukaemia arises as a result of disruption to haematopoietic precursors, caused either by acquired gene fusions, gene mutations or inappropriate expression of the relevant oncogenes. Current treatment options have made significant progress, but the 5 year survival for acute leukaemia remains under 10% in elderly patients, and less than 50% for some types of acute leukaemia in younger adults. For chronic leukaemias longer survival is generally expected and for chronic myeloid leukaemia patients on tyrosine kinase inhibitors the median survival is not yet reached and is expected to exceed 10 years. Chemotherapy and haematopoietic stem cell transplantation (HSCT) for acute leukaemia provide the mainstay of therapy for patients under 65 and both carry significant morbidity and mortality. Alternative and superior therapeutic strategies for acute leukaemias are urgently required. Recent molecular-based knowledge of recurring chromosome rearrangements, in particular translocations and inversions, has resulted in significant advances in understanding the molecular pathogenesis of leukaemia. Identification of a number of unique fusion genes has facilitated the development of highly specific small interfering RNAs (siRNA). Although delivery of siRNA using multifunctional nanoparticles has been investigated to treat solid cancers, the application of this approach to blood cancers is at an early stage. This review describes current treatments for leukaemia and highlights the potential of leukaemic fusion genes as therapeutic targets for RNA interference (RNAi). In addition, the design of biomimetic nanoparticles which are capable of responding to the physiological environment of leukaemia and their potential to advance RNAi therapeutics to the clinic will be critically evaluated.

  18. Tel-Hashomer camptodactyly syndrome with hirsuitism in an Indian family.

    PubMed

    Patel, Zareen M; Adhia, Rashmi A

    2004-10-01

    Two new cases with the Tel-Hashomer camptodactyly syndrome have been ascertained in an Indian family. This report emphasizes the autosomal recessive nature of disease and documents an additional feature of hirsuitism not previously described. The gene for Tel-Hashomer camptodactyly syndrome is present in all populations around the world.

  19. TEL/ETV6 induces apoptosis in 32D cells through p53-dependent pathways

    SciTech Connect

    Yamagata, Tetsuya; Maki, Kazuhiro; Waga, Kazuo; Mitani, Kinuko . E-mail: kinukom-tky@umin.ac.jp

    2006-08-25

    TEL is an ETS family transcription factor that is critical for maintaining hematopoietic stem cells in adult bone marrow. To investigate the roles of TEL in myeloid proliferation and differentiation, we introduced TEL cDNA into mouse myeloid 32Dcl3 cells. Overexpression of TEL repressed interleukin-3-dependent proliferation through blocking cell cycle progression. Also, the presence of TEL triggered apoptosis through the mitochondrial intrinsic pathway on exposure to granulocyte colony-stimulating factor. We found an increase in p53 protein and its DNA binding in the TEL-overexpressing cells. Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma. Consistently, induction of apoptosis was delayed by pifithrin-{alpha} treatment and completely blocked by increased expression of Bcl-2 in the TEL-overexpressing cells. These data collectively suggest that TEL exerts a tumor suppressive function through augmenting the p53 pathway and facilitates normal development of myelopoiesis.

  20. Haematopoietic development and leukaemia in Down syndrome.

    PubMed

    Roberts, Irene; Izraeli, Shai

    2014-12-01

    Children with constitutional trisomy 21 (cT21, Down Syndrome, DS) are at a higher risk for both myeloid and B-lymphoid leukaemias. The myeloid leukaemias are often preceded by a transient neonatal pre-leukaemic syndrome, Transient Abnormal Myelopoiesis (TAM). TAM is caused by cooperation between cT21 and acquired somatic N-terminal truncating mutations in the key haematopoietic transcription factor GATA1. These mutations, which are not leukaemogenic in the absence of cT21, are found in almost one-third of neonates with DS. Analysis of primary human fetal liver haematopoietic cells and of human embryonic stem cells demonstrates that cT21 itself substantially alters human fetal haematopoietic development. Consequently, many haematopoietic developmental defects are observed in neonates with DS even in the absence of TAM. Although studies in mouse models have suggested a pathogenic role of deregulated expression of several chromosome 21-encoded genes, their role in human leukaemogenesis remains unclear. As cT21 exists in all embryonic cells, the molecular basis of cT21-associated leukaemias probably reflects a complex interaction between deregulated gene expression in haematopoietic cells and the fetal haematopoietic microenvironment in DS.

  1. TEL2 suppresses metastasis by down-regulating SERPINE1 in nasopharyngeal carcinoma.

    PubMed

    Sang, Yi; Chen, Ming-Yuan; Luo, Donghua; Zhang, Ru-Hua; Wang, Li; Li, Mei; Luo, Rongzhen; Qian, Chao-Nan; Shao, Jian-Yong; Zeng, Yi-Xin; Kang, Tiebang

    2015-10-06

    Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). However, the molecular mechanisms of NPC metastasis are poorly understood. Here, using our customized gene microarray containing all of the known human transcription factors and the current markers for epithelial-mesenchymal transition, we report that TEL2 was down-regulated in highly metastatic NPC cells and the metastatic tissues in lymph node. Mechanistically, TEL2 inhibits the cell migration and invasion in vitro and metastasis in vivo by directly suppressing the SERPINE1 promoter in NPC. Consistently, an inverse correlation was observed between the protein levels of TEL2 and SERPINE1 using clinical NPC samples. Collectively, we have provided the first evidence that TEL2 plays a key role in NPC metastasis by directly down-regulating SERPINE1, and that this novel axis of TEL2 / SERPINE1 may be valuable to develop new strategies for treating NPC patients with metastasis.

  2. Neurological complications of childhood leukaemia.

    PubMed Central

    Campbell, R H; Marshall, W C; Chessells, J M

    1977-01-01

    We have reviewed the neurological complications not directly attributable to leukaemic infiltration in a group of 438 children with leukaemia or lymphoma. 61 children had one or more complications due chiefly to bleeding, infection, or drug toxicity. Early death from intracranial haemorrhage occurred in 1% of children with lymphoblastic leukaemia and 7% of children with myeloblastic leukaemia. Measles and chicken pox were the most serious infective complications; one child remains severely retarded after presumed measles encephalitis, one child with chicken pox died, and a second remains disabled. 2 additional cases of measles encephalitis and one of progressive multifocal leucoencephalopathy are described. Drugs which caused neurotoxicity included vincristine, cytosine arabinoside, L-asparaginase, and phenothiazines, but most problems were caused by methotrexate. Methotrexate toxicity was more prevalent and more serious in children who had had previous central nervous system leukaemia. We conclude that viral infections and methotrexate pose the greatest neurological hazards to children with leukaemia. PMID:596922

  3. The yeast telomere length regulator TEL2 encodes a protein that binds to telomeric DNA.

    PubMed Central

    Kota, R S; Runge, K W

    1998-01-01

    TEL2 is required for telomere length regulation and viability in Saccharomyces cerevisiae. To investigate the mechanism by which Tel2p regulates telomere length, the majority (65%) of the TEL2 ORF was fused to the 3'-end of the gene for maltose binding protein, expressed in bacteria and the purified protein used in DNA binding studies. Rap1p, the major yeast telomere binding protein, recognizes a 13 bp duplex site 5'-GGTGTGTGGGTGT-3' in yeast telomeric DNA with high affinity. Gel shift experiments revealed that the MBP-Tel2p fusion binds the double-stranded yeast telomeric Rap1p site in a sequence-specific manner. Analysis of mutated sites showed that MBP-Tel2p could bind 5'-GTGTGTGG-3' within this 13 bp site. Methylation interference analysis revealed that Tel2p contacts the 5'-terminal guanine in the major groove. MBP-Tel2p did not bind duplex telomeric DNA repeats from vertebrates, Tetrahymena or Oxytricha. These results suggest that Tel2p is a DNA binding protein that recognizes yeast telomeric DNA. PMID:9490802

  4. Residential exposures to pesticides and childhood leukaemia

    PubMed Central

    Metayer, Catherine; Buffler, Patricia A.

    2008-01-01

    Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case–control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of ∼600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene–environment interaction studies. PMID:18940823

  5. Comparison of loop-mediated isothermal amplification (LAMP) and nested-PCR assay targeting the RE and B1 gene for detection of Toxoplasma gondii in blood samples of children with leukaemia.

    PubMed

    Fallahi, Shirzad; Seyyed Tabaei, Seyyed Javad; Pournia, Yadollah; Zebardast, Nozhat; Kazemi, Bahram

    2014-07-01

    Toxoplasmosis diagnosis constitutes an important measure for disease prevention and control. In this paper, a newly described DNA amplification technique, loop-mediated isothermal amplification (LAMP), and nested-PCR targeting the repeated element (RE) and B1 gene, were compared to each other for the detection of Toxoplasma gondii DNA in blood samples of children with leukaemia. One hundred ten blood samples from these patients were analyzed by LAMP and nested-PCR. Out of 50 seropositive samples (IgM+, IgG+), positive results were obtained with 92% and 86% on RE, B1-LAMP and 82% and 68% on RE, B1-nested PCR analyses, respectively. Of the 50 seronegative samples, three, two and one samples were detected positive by RE-LAMP, B1-LAMP and RE-nested PCR assays, respectively, while none were detected positive by B1-nested PCR. None of the 10 IgM-, IgG+ samples was detected positive after testing LAMP and nested-PCR assays in duplicate. This is the first report of a study in which the LAMP method was applied with high sensitivity and efficacy for the diagnosis of T. gonii in blood samples of children with leukaemia.

  6. Acute lymphoblastic leukaemia

    PubMed Central

    Inaba, Hiroto; Greaves, Mel; Mullighan, Charles G.

    2013-01-01

    Summary Acute lymphoblastic leukaemia (ALL) is seen in both children and adults, but its incidence peaks between ages 2 and 5 years. The causation of ALL is considered to be multi-factorial, including exogenous or endogenous exposures, genetic susceptibility, and chance. The survival rate of paediatric ALL has improved to approximately 90% in recent trials with risk stratification by biologic features of leukaemic cells and response to therapy, therapy modification based on patient pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. While most children can be cured, the prognosis of infants and adults with ALL remains poor. Recent genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic alterations and sequence mutations that contribute to leukaemogenesis, define new ALL subtypes, influence responsiveness to treatment, and may provide novel prognostic markers and therapeutic targets for personalized medicine. PMID:23523389

  7. First Spectroscopic Solutions of Two Southern Eclipsing Binaries: HO Tel and QY Tel

    NASA Astrophysics Data System (ADS)

    Sürgit, D.; Erdem, A.; Engelbrecht, C. A.; van Heerden, P.; Manick, R.

    2015-07-01

    We present preliminary results from the analysis of spectroscopic observations of two southern eclipsing binary stars, HO Tel and QY Tel. The grating spectra of these two systems were obtained at the Sutherland Station of the South African Astronomical Observatory in 2013. Radial velocities of the components were determined by the Fourier disentangling technique. Keplerian radial velocity models of HO Tel and QY Tel give their mass ratio as 0.921±0.005 and 1.089±0.007, respectively.

  8. Transcription control by the ENL YEATS domain in acute leukaemia.

    PubMed

    Erb, Michael A; Scott, Thomas G; Li, Bin E; Xie, Huafeng; Paulk, Joshiawa; Seo, Hyuk-Soo; Souza, Amanda; Roberts, Justin M; Dastjerdi, Shiva; Buckley, Dennis L; Sanjana, Neville E; Shalem, Ophir; Nabet, Behnam; Zeid, Rhamy; Offei-Addo, Nana K; Dhe-Paganon, Sirano; Zhang, Feng; Orkin, Stuart H; Winter, Georg E; Bradner, James E

    2017-03-09

    Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.

  9. Variable but consistent pattern of Meningioma 1 gene (MN1) expression in different genetic subsets of acute myelogenous leukaemia and its potential use as a marker for minimal residual disease detection

    PubMed Central

    Rosso, Valentina; Calabrese, Chiara; Signorino, Elisabetta; Bot-Sartor, Giada; Nicoli, Paolo; Gallo, Daniela; Bracco, Enrico; Morotti, Alessandro; Panuzzo, Cristina; Gottardi, Enrico; Cilloni, Daniela

    2016-01-01

    Meningioma 1 (MN1) gene overexpression has been reported in acute myeloid leukaemia (AML) patients and identified as a negative prognostic factor. In order to characterize patients presenting gene overexpression and to verify if MN1 transcript could be a useful marker for minimal residual disease detection, MN1 was quantified in 136 AML patients with different cytogenetic risk and in 50 normal controls. In 20 patients bearing a fusion gene transcript suitable for minimal residual disease quantitative assessment and in 8 patients with NPM1 mutation, we performed a simultaneous analysis of MN1 and the fusion-gene transcript or NPM1 mutation during follow-up. Sequential MN1 and WT1 analysis was also performed in 13 AML patients lacking other molecular markers. The data obtained show that normal cells consistently express low levels of MN1 transcript. In contrast, high levels of MN1 expression are present in 47% of patients with normal karyotype and in all cases with inv(16). MN1 levels during follow-up were found to follow the pattern of other molecular markers (fusion gene transcripts, NPM1 and WT1). Increased MN1 expression in the BM during follow up was always found to be predictive of an impending hematological relapse. PMID:27765915

  10. Acute leukaemia following renal transplantation.

    PubMed

    Subar, M; Gucalp, R; Benstein, J; Williams, G; Wiernik, P H

    1996-03-01

    Four renal transplant patients on immunosuppressive therapy who presented with acute myeloid leukaemia are described. In two cases, azathioprine may have played an important role as a cofactor in leukaemogenesis. In a third case, the alkylating agent cyclophosphamide may have contributed. All patients were treated for leukaemia with full doses of cytotoxic chemotherapy and, in each case, a functioning renal allograft was preserved throughout the treatment despite attenuation of immunosuppressive therapy. Three patients achieved complete remission. Of the three, one is surviving at 2 years and two expired during the pancytopenic phase of their treatment with no active leukaemia present, and with intact renal function. As increasing expertise in the field of organ transplantation allows patients to survive longer, such patients' exposure to immunosuppressive and potentially leukaemogenic drugs is prolonged. The risk of secondary neoplasia has been previously documented in this population. Two of the four cases reported here suffered from polycystic kidney disease as their underlying condition. While this report suggests that the leukaemias are related to renal transplantation, we cannot rule out an association with the underlying disease which led to the transplant. This report further suggests that the leukaemia that develops in such patients may respond to standard therapy, and that such treatment does not compromise the transplanted kidney.

  11. Subsequent leukaemia in autoimmune disease patients.

    PubMed

    Hemminki, Kari; Liu, Xiangdong; Försti, Asta; Ji, Jianguang; Sundquist, Jan; Sundquist, Kristina

    2013-06-01

    Previous studies have shown that patients diagnosed with some autoimmune (AI) diseases are at an increased risk of leukaemia but limited data are available on survival. We systematically analysed the risks (standardized incidence ratio, SIR) and survival (hazard ratio, HR) in nine types of leukaemia among 402 462 patients hospitalized for any of 33 AI diseases and compared to persons not hospitalized for AI diseases. Risk for all leukaemia was increased after 13 AI diseases and survival was decreased after six AI diseases. SIRs were increased after all AI diseases for seven types of leukaemia, including SIR 1·69 (95% confidence interval (CI): 1·29-2·19) for acute lymphoblastic leukaemia (ALL), 1·85 (95% CI: 1·65-2·07) for acute myeloid leukaemia, 1·68 (95% CI: 1·37-2·04) for chronic myeloid leukaemia, 2·20 (95% CI: 1·69-2·81) for 'other myeloid leukaemia', 2·45 (95% 1·99-2·98) for 'other and unspecified leukaemia', 1·81 (95% CI: 1·11-2·81) for monocytic leukaemia, and 1·36 (95% CI: 1·08-1·69) for myelofibrosis. The HRs were increased for four types of leukaemia, most for myelofibrosis (1·74, 95% CI: 1·33-2·29) and ALL (1·42, 95% CI: 1·03-1·95). Some AI diseases, including rheumatoid arthritis, were associated with increased SIRs and HRs in many types of leukaemia. The present data showed increases in risk and decreases in survival for many types of leukaemia after various AI diseases. Leukaemia is a rare complication in AI disease but findings about this comorbidity at the time of leukaemia diagnosis may help to optimize the treatment and improve survival.

  12. Acute Myeloid Leukaemia

    PubMed Central

    Villela, Luis; Bolaños-Meade, Javier

    2013-01-01

    The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30–40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients’ outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used ‘7+3’ regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients. PMID:21861539

  13. Eosinophilic leukaemia in a cat.

    PubMed

    Sharifi, Hassan; Nassiri, Seyed Mahdi; Esmaelli, Hossein; Khoshnegah, Javad

    2007-12-01

    A 14-year-old female domestic shorthair cat was presented to Tehran University Veterinary Teaching Hospital for a persistent fever, anorexia, intermittent vomiting, weight loss and weakness. The main clinical signs were pale mucous membranes, dehydration and splenomegaly. The complete blood count and serum biochemistry tests revealed non-regenerative anaemia, thrombocytopenia and increased alkaline phosphatase (ALP) activity. An enzyme-linked immunosorbent assay (ELISA) test for feline leukaemia virus was negative. Blood film and bone marrow examination revealed a large number of immature eosinophils with variable sizes and numbers of faintly azurophilic granules. Cytochemical staining of blood film demonstrated 70% positive cells for ALP activity. Four percent CD34 positive cells were detected by flow cytometry. As eosinophilic leukaemia is difficult to identify by light microscopy, well-defined diagnostic criteria and the use of flow cytometry and cytochemical staining can improve the ability to correctly diagnose this type of leukaemia in cats.

  14. Associations of novel genetic variations in the folate-related and ARID5B genes with the pharmacokinetics and toxicity of high-dose methotrexate in paediatric acute lymphoblastic leukaemia.

    PubMed

    Csordas, Katalin; Lautner-Csorba, Orsolya; Semsei, Agnes F; Harnos, Andrea; Hegyi, Marta; Erdelyi, Daniel J; Eipel, Oliver T; Szalai, Csaba; Kovacs, Gabor T

    2014-08-01

    High-dose methotrexate (HD-MTX) plays an important role in the consolidation therapy of acute lymphoblastic leukaemia (ALL) in many treatment regimens worldwide. However, there is a large interpatient variability in the pharmacokinetics and toxicity of the drug. We investigated the influence of single nucleotide polymorphisms (SNPs) in genes of the folate metabolic pathway, transporter molecules and transcription proteins on the pharmacokinetics and toxicity of MTX and 7-hydroxy-methotrexate (7-OH-MTX). 63 SNPs of 14 genes were genotyped and a total of 463 HD-MTX courses (administered according to the ALL-BFM 95 and ALL IC-BFM 2002 protocols) were analysed. Haematological, hepatic and renal toxicities, estimated by routine laboratory parameters were evaluated. Random forest and regression trees were used for variable selection and model building. Linear mixed models were established to prove the significance of the selected variables. SNPs (rs4948502, rs4948496, rs4948487) of the ARID5B gene were associated with the serum levels of MTX (P < 0·02), serum levels and area under the curve of 7-OH-MTX (P < 0·02) and with hypoproteinaemia (P = 0·004). SLCO1B1 rs4149056 also showed a significant association with serum MTX levels (P < 0·001). Our findings confirm the association of novel genetic variations in folate-related and ARID5B genes with the serum MTX levels and acute toxicity.

  15. RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.

    PubMed

    Estécio, Marcos R H; Maddipoti, Sirisha; Bueso-Ramos, Carlos; DiNardo, Courtney D; Yang, Hui; Wei, Yue; Kondo, Kimie; Fang, Zhihong; Stevenson, William; Chang, Kun-Sang; Pierce, Sherry A; Bohannan, Zachary; Borthakur, Gautam; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2015-05-01

    Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.

  16. High expression of connective tissue growth factor accelerates dissemination of leukaemia.

    PubMed

    Wells, J E; Howlett, M; Halse, H M; Heng, J; Ford, J; Cheung, L C; Samuels, A L; Crook, M; Charles, A K; Cole, C H; Kees, U R

    2016-09-01

    To improve treatment of acute lymphoblastic leukaemia (ALL), a better understanding of disease development is needed to tailor new therapies. Connective tissue growth factor (CTGF/CCN2) is highly expressed in leukaemia cells from the majority of paediatric patients with B-lineage ALL (pre-B ALL). CTGF is a matricellular protein and plays a role in aggressive cancers. Here we have genetically engineered leukaemia cells to modulate CTGF expression levels. Elevated CTGF levels accelerated disease dissemination and reduced survival in NOD/SCID mice. In vitro studies showed that CTGF protein induces stromal cell proliferation, promotes adhesion of leukaemia cells to stromal cells and leads to overexpression of genes associated with cell cycle and synthesis of extracellular matrix (ECM). Corresponding data from our leukaemia xenograft models demonstrated that CTGF leads to increased proliferation of non-leukaemia cells and deposition of ECM in the bone marrow. We document for the first time a functional role of CTGF in altering disease progression in a lymphoid malignancy. The findings provide support for targeting the bone marrow microenvironment in aggressive forms of leukaemia.

  17. Natural killer cell leukaemia.

    PubMed

    Gandhi, Jamish

    2009-01-01

    A 42-year-old white woman, who was a general practitioner referral to the medical team, presented with a 3-day history of left upper quadrant pain; an urgent private ultrasound scan had showed splenomegaly. She was initially admitted with sepsis without an obvious cause but with a differential diagnosis of a haematological malignancy. Her admission blood tests showed a mildly reduced white cell count and low platelets. Her symptoms progressed and she developed right upper quadrant pain. Her blood counts deteriorated showing a disseminated intravascular coagulation (DIC) picture and mildly deranged liver function tests. Blood films were non-diagnostic. A CT scan of the abdomen/pelvis showed splenomegaly and also hepatomegaly and ascites, not seen in her initial ultrasound scan. Multiple cultures of blood/urine/ascites and infective serology were unremarkable.She was transferred to a larger tertiary centre under the care of the surgeons with presumed abdominal sepsis and underwent an open laparotomy, which showed a big firm liver and spleen but no obvious cause for sepsis. The infectious disease team were unable to find a cause, and haematology became involved to investigate the possibility of a haematological malignancy. The patient underwent two bone marrow biopsies, a percutaneous liver biopsy and had flow cytometry of her ascitic fluid, which revealed the diagnosis of a natural killer cell leukaemia. After some slight improvement on steroids, the patient was given cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab (CHOP-R) chemotherapy. The patient had an initial response to chemotherapy, with reduction in ascitic volume and hepatosplenomegaly, and normalisation of her coagulation. This was accompanied by an overall improvement in her physical condition. She had a second cycle of CHOP-R, but unfortunately approximately 2 weeks after that, she deteriorated rapidly. She was too weak for salvage chemotherapy, so she was put on comfort care. She died

  18. Childhood leukemia genetic bottleneck phenomenon related to TEL-AML1: the postulation by a mathematical model.

    PubMed

    Ivanovski, Petar; Ivanovski, Ivan; Nikolić, Dimitrije; Jovanović, Ivana

    2012-03-01

    Childhood leukemia bottleneck phenomenon is the most mysterious corollary of the prenatal origin discovery of leukemogenic chromosome translocations. The bottleneck is evidence that leukemia initiation, by in utero acquired chromosome translocations that generate functional fusion genes, is far more common than the incidence rate of corresponding leukemia. For childhood TEL-AML1(+) acute lymphoblastic leukemia (ALL) this equates to approximately 100 times. Practically this means that among a hundred children born with TEL-AML1 fusion gene, only one child will later in its life develop ALL. The key data necessary for unraveling of this mystery were discovered in 2002. It was the level of TEL-AML1(+) cells’ frequency. The bottleneck is caused by the very low body TEL-AML1(+) cell count. Only one out of a thousand B cells carries TEL-AML1 fusion gene. TEL-AML1(+) body cell count is low because TEL-AML1 fusion is generated at cell level of 10(-3) to 10(-4) just during the late fetal lymphopoiesis i.e. after the 36th gestational week.

  19. Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children's Oncology Group.

    PubMed

    Slater, Megan E; Linabery, Amy M; Blair, Cindy K; Spector, Logan G; Heerema, Nyla A; Robison, Leslie L; Ross, Julie A

    2011-11-01

    Several case-control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children's Oncology Group case-control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements ('MLL+') [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case-control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible.

  20. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.

    PubMed

    Dawson, Mark A; Prinjha, Rab K; Dittmann, Antje; Giotopoulos, George; Bantscheff, Marcus; Chan, Wai-In; Robson, Samuel C; Chung, Chun-wa; Hopf, Carsten; Savitski, Mikhail M; Huthmacher, Carola; Gudgin, Emma; Lugo, Dave; Beinke, Soren; Chapman, Trevor D; Roberts, Emma J; Soden, Peter E; Auger, Kurt R; Mirguet, Olivier; Doehner, Konstanze; Delwel, Ruud; Burnett, Alan K; Jeffrey, Phillip; Drewes, Gerard; Lee, Kevin; Huntly, Brian J P; Kouzarides, Tony

    2011-10-02

    Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.

  1. Epigenetic dysregulation of leukaemic HOX code in MLL-rearranged leukaemia mouse model.

    PubMed

    Ng, Ray Kit; Kong, Cheuk Ting; So, Chi Chiu; Lui, Wing Chi; Chan, Yuen Fan; Leung, Ka Chun; So, Kam Chung; Tsang, Ho Man; Chan, Li Chong; Sham, Mai Har

    2014-01-01

    HOX genes are frequently dysregulated in human leukaemia with the gene rearrangement between mixed lineage leukaemia (MLL) and partner genes. The resultant MLL fusion proteins are known to mediate leukaemia through disruption of the normal epigenetic regulation at the target gene loci. To elucidate the pathogenic role of MLL fusion proteins in HOX dysregulation in leukaemia, we generated a novel haematopoietic lineage-specific Mll-Een knock-in mouse model using a Cre-mediated inversion strategy. The Mll(Een) (/+) invertor mice developed acute myeloid leukaemia, with organomegaly of the spleen, liver and mesenteric lymph nodes caused by infiltration of blast cells. Using Mll-Een-expressing leukaemic cell lines derived from bone marrow of Mll(Een) (/+) mutant mice, we showed that induction of Hox genes in leukaemic cells was associated with hypomethylated promoter regions and an aberrant active chromatin state at the Hox loci. Knock-down of Prmt1 was insufficient to reverse the active chromatin status and the hypomethylated Hox loci, suggesting that Prmt1-mediated histone arginine methylation was only partially involved in the maintenance of Hox expression in leukaemic cells. Furthermore, in vivo analysis of bone marrow cells of Mll(Een) (/+) mice revealed a Hox expression profile similar to that of wild-type haematopoietic stem cells. The leukaemic Hox profile was highly correlated with aberrant hypomethylation of Hox promoters in the mutant mice, which highlights the importance of DNA methylation in leukaemogenic mechanisms induced by MLL fusion proteins. Our results point to the involvement of dynamic epigenetic regulations in the maintenance of the stem cell-like HOX code that initiates leukaemic stem cells in MLL-rearranged leukaemia. This provides insights for the development of alternative strategies for leukaemia treatment.

  2. Congenital leukaemia after heavy abuse of permethrin during pregnancy.

    PubMed

    Borkhardt, A; Wilda, M; Fuchs, U; Gortner, L; Reiss, I

    2003-09-01

    A single case is described of congenital leukaemia with 11q23/MLL rearrangement in a preterm female newborn. Because of arachnophobia, the mother had heavily abused aerosolised permethrin, a widely used household insecticide. Permethrin is considered comparatively safe, but, in view of the mother's history, its potential to induce cleavage of the MLL gene in cell culture was tested. Incubation of the BV173 cell line with 50 micro M permethrin readily induced MLL cleavage.

  3. Detection of aberrant transcription of major histocompatibility complex class II antigen presentation genes in chronic lymphocytic leukaemia identifies HLA-DOA mRNA as a prognostic factor for survival.

    PubMed

    Souwer, Yuri; Chamuleau, Martine E D; van de Loosdrecht, Arjan A; Tolosa, Eva; Jorritsma, Tineke; Muris, Jettie J F; Dinnissen-van Poppel, Marion J; Snel, Sander N; van de Corput, Lisette; Ossenkoppele, Gert J; Meijer, Chris J L M; Neefjes, Jacques J; Marieke van Ham, S

    2009-05-01

    In human B cells, effective major histocompatibility complex (MHC) class II-antigen presentation depends not only on MHC class II, but also on the invariant chain (CD74 or Ii), HLA-DM (DM) and HLA-DO (DO), the chaperones regulating the antigen loading process of MHC class II molecules. We analysed immediate ex vivo expression of HLA-DR (DR), CD74, DM and DO in B cell chronic lymphocytic leukaemia (B-CLL). Real-time reverse transcription polymerase chain reaction demonstrated a highly significant upregulation of DRA, CD74, DMB, DOA and DOB mRNA in purified malignant cells compared to B cells from healthy donors. The increased mRNA levels were not translated into enhanced protein levels but could reflect aberrant transcriptional regulation. Indeed, upregulation of DRA, DMB, DOA and DOB mRNA correlated with enhanced expression of class II transactivator (CIITA). In-depth analysis of the various CIITA transcripts demonstrated a significant increased activity of the interferon-gamma-inducible promoter CIITA-PIV in B-CLL. Comparison of the aberrant mRNA levels with clinical outcome identified DOA mRNA as a prognostic indicator for survival. Multivariate analysis revealed that the prognostic value of DOA mRNA was independent of the mutational status of the IGHV genes. Thus, aberrant transcription of DOA forms a novel and additional prognostic indicator for survival in B-CLL.

  4. The function of the RNA-binding protein TEL1 in moss reveals ancient regulatory mechanisms of shoot development.

    PubMed

    Vivancos, Julien; Spinner, Lara; Mazubert, Christelle; Charlot, Florence; Paquet, Nicolas; Thareau, Vincent; Dron, Michel; Nogué, Fabien; Charon, Céline

    2012-03-01

    The shoot represents the basic body plan in land plants. It consists of a repeated structure composed of stems and leaves. Whereas vascular plants generate a shoot in their diploid phase, non-vascular plants such as mosses form a shoot (called the gametophore) in their haploid generation. The evolution of regulatory mechanisms or genetic networks used in the development of these two kinds of shoots is unclear. TERMINAL EAR1-like genes have been involved in diploid shoot development in vascular plants. Here, we show that disruption of PpTEL1 from the moss Physcomitrella patens, causes reduced protonema growth and gametophore initiation, as well as defects in gametophore development. Leafy shoots formed on ΔTEL1 mutants exhibit shorter stems with more leaves per shoot, suggesting an accelerated leaf initiation (shortened plastochron), a phenotype shared with the Poaceae vascular plants TE1 and PLA2/LHD2 mutants. Moreover, the positive correlation between plastochron length and leaf size observed in ΔTEL1 mutants suggests a conserved compensatory mechanism correlating leaf growth and leaf initiation rate that would minimize overall changes in plant biomass. The RNA-binding protein encoded by PpTEL1 contains two N-terminus RNA-recognition motifs, and a third C-terminus non-canonical RRM, specific to TEL proteins. Removal of the PpTEL1 C-terminus (including this third RRM) or only 16-18 amino acids within it seriously impairs PpTEL1 function, suggesting a critical role for this third RRM. These results show a conserved function of the RNA-binding PpTEL1 protein in the regulation of shoot development, from early ancestors to vascular plants, that depends on the third TEL-specific RRM.

  5. Investigation of human parvovirus B19 occurrence and genetic variability in different leukaemia entities.

    PubMed

    da Costa, A C; Bendit, I; de Oliveira, A C S; Kallas, E G; Sabino, E C; Sanabani, S S

    2013-01-01

    Human parvovirus B19V (B19V) has been associated with various haematological disorders, but data on its prevalence in leukaemia are scarce. In this cross-sectional study, we investigated patients in Sao Paulo, Brazil with leukaemia to determine the molecular frequency of B19 variants and characterize the viral genetic variability by partial and complete sequencing of the coding of non-structural protein 1 (NS1)/viral capsid proteins 1 and 2 (VP1/VP2). The presence of B19V infections was investigated by PCR amplification of the viral NS1 gene fragment and confirmed by sequencing analysis. The NS1/VP1/VP2 and partially larger gene fragments of the NS1-positive samples were determined by overlapping nested PCR and direct sequencing results. The B19V NS1 was detected in 40 (16%) of 249 bone marrow samples including 12/78 (15.4%) acute lymphoblastic leukaemia, 25/155 (16.1%) acute myeloid leukaemia and 3/16 (18.7%) chronic myeloid leukaemia samples. Of the 40 participants, 25 (62.5%) were infected with genotype 1a and 15 (37.5%) with genotype 3b. The phylogenetic analysis of other regions revealed that 12/40 (30%) of the patients with leukaemia were co-infected with genotypes 1a and 3b. In addition, a new B19V intergenotypic recombinant (1a/3b) and an NS1 non-recombinant genotype 1a were detected in one patient. Our findings demonstrated a relatively high prevalence of B19V monoinfections and dual infections and provide, for the first time, evidence of inter-genotypic recombination in adults with leukaemia that may contribute to the genetic diversity of B19V and may also be a source of new emerging viral strains with future implications for diagnosis, therapy and efficient vaccine development.

  6. Reanalysis Of The PZ Tel System: Arguments For The Reality Of PZ Tel B To Be PZ Tel b

    NASA Astrophysics Data System (ADS)

    Jenkins, James

    2011-09-01

    I will present some new analysis of the PZ Tel system, which has recently been shown to host a young companion with a mass of around 30 Jupiter-masses, along with a debris disk of around 0.3 Lunar-masses. We have reanalyzed the iron abundance of the host star using our new spectral synthesis method, and contrary to previous results, we find the star to be super metal-rich, with a metallicity ([Fe/H]) of 0.2 dex. We also find the age of the system from chromospheric activities and pre-main sequence evolutionary models to be around 25Myrs. I will show some comparisons between the companion's bulk properties, such as broadband colours, and some of the latest evolutionary models as a function of metallicity. Finally, I will use these results to show how the companion to PZ Tel could be the first directly imaged extreme-Jovian extrasolar planet and not a low-mass brown dwarf. I acknowledge funding by Fondecyt through grant 3110004 and partial support from Centro de Astrofisica FONDAP 15010003, the GEMINI-CONICYT FUND and from the Comite Mixto ESO-GOBIERNO DE CHILE.

  7. BET inhibitor resistance emerges from leukaemia stem cells.

    PubMed

    Fong, Chun Yew; Gilan, Omer; Lam, Enid Y N; Rubin, Alan F; Ftouni, Sarah; Tyler, Dean; Stanley, Kym; Sinha, Devbarna; Yeh, Paul; Morison, Jessica; Giotopoulos, George; Lugo, Dave; Jeffrey, Philip; Lee, Stanley Chun-Wei; Carpenter, Christopher; Gregory, Richard; Ramsay, Robert G; Lane, Steven W; Abdel-Wahab, Omar; Kouzarides, Tony; Johnstone, Ricky W; Dawson, Sarah-Jane; Huntly, Brian J P; Prinjha, Rab K; Papenfuss, Anthony T; Dawson, Mark A

    2015-09-24

    Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.

  8. Childhood leukaemia and nuclear power

    SciTech Connect

    Berry, R.J.; Wakeford, R. )

    1992-01-01

    There has been considerable scientific and media interest in the question of whether the risk of childhood leukemia is raised near nuclear facilities, and, if so, the reasons why. Serious consideration of this issue was initiated by a media report of an unusually large number of cases around the Sellafield installation in England, and reports of excess cases in the vicinity of other facilities in Britain have followed. Detailed radiological assessments have demonstrated that radioactive discharges are most unlikely to have been the cause of these reported excess cases, seemingly contradicting the epidemiological evidence. However, epidemiology is an observational (non-experimental) science, and the results of such studies must be interpreted with considerable care. The influence of prior knowledge of data upon the structure of a study has been a particular inferential problem. Furthermore, there are indications that non-radiological factors may be important in communities near nuclear facilities. Recently, a study has shown an association between childhood leukaemia cases near Sellafield and the recorded occupational radiation doses received by fathers before the conception of these children; but this novel finding has received little independent scientific support. At present, the British childhood leukaemia findings have not been replicated in studies based in other countries, and the reasons for the reported case excesses around British nuclear facilities remain unclear.

  9. Cultural psychiatry in Tel Aviv: how relevant!

    PubMed

    Rohlof, Hans; Ulman, Anne-Marie

    2013-01-01

    The First Mediterranean Conference on Cultural Psychiatry took place in Tel Aviv, Israel. This conference was a great success. With about 200 participants, mostly from Israel but with also 46 participants coming from 13 other countries: Mediterranean countries, Europe, North America and Australia. It contained three intensive days of plenary lectures and symposia, and a very impressive film, "Waltz with Bashir". The proceedings included 88 lectures, and there were 8 posters, which meant that nearly half of the attending persons were giving a lecture, as is always the case in real scientific conferences. Four parallel programs were running at the same time, which made it very difficult to choose which to attend. Inevitably, this report reflects only a part of the conference.

  10. Advances in understanding the leukaemia microenvironment.

    PubMed

    Tabe, Yoko; Konopleva, Marina

    2014-03-01

    Dynamic interactions between leukaemic cells and cells of the bone marrow are a feature of haematological malignancies. Two distinct microenvironmental niches in the bone marrow, the 'osteoblastic (endosteal)' and 'vascular' niches, provide a sanctuary for subpopulations of leukaemic cells to evade chemotherapy-induced death and allow acquisition of drug resistance. Key components of the bone marrow microenvironment as a home for normal haematopoietic stem cells and the leukaemia stem cell niches, and the molecular pathways critical for microenvironment/leukaemia interactions via cytokines, chemokines and adhesion molecules as well as hypoxic conditions, are described in this review. Finally, the genetic abnormalities of leukaemia-associated stroma are discussed. Further understanding of the contribution of the bone marrow niche to the process of leukaemogenesis may provide new targets that allow destruction of leukaemia stem cells without adversely affecting normal stem cell self-renewal.

  11. Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia.

    PubMed

    Sun, Xiaoshen; Hasanali, Zainul S; Chen, Allshine; Zhang, Dianzheng; Liu, Xin; Wang, Hong-Gang; Feith, David J; Loughran, Thomas P; Xu, Kailin

    2015-02-01

    Natural killer (NK) large granular lymphocyte (LGL) leukaemia features a clonal proliferation of CD3(-) NK cells that can be classified into either aggressive or chronic categories. The NKL cell line, derived from an aggressive Asian NK cell leukaemia, and patient samples from chronic NK-LGL leukaemia were used in our study to probe for synergistic efficacy of the epigenetic drugs vorinostat (SAHA) and cladribine in this disease. We demonstrate that histone deacetylases (HDACs) are over-expressed in both aggressive and chronic NK leukaemia. Administration of the HDAC inhibitor SAHA reduces class I and II HDAC expression and enhances histone acetylation in leukaemic NK cells. In vitro combination treatment with SAHA and cladribine dose-dependently exerts synergistic cytotoxic and apoptotic effects on leukaemic NK cells. Expression profiling of apoptotic regulatory genes suggests that both compounds led to caspase-dependent apoptosis through activation of intrinsic mitochondrial and extrinsic death receptor pathways. Collectively, these data show that combined epigenetic therapy, using HDAC and DNA methyltransferase inhibitors, may be a promising therapeutic approach for NK-LGL leukaemia.

  12. CREBBP knockdown enhances RAS/RAF/MEK/ERK signalling in Ras pathway mutated acute lymphoblastic leukaemia but does not modulate chemotherapeutic response.

    PubMed

    Dixon, Zach A; Nicholson, Lindsay; Zeppetzauer, Martin; Matheson, Elizabeth; Sinclair, Paul; Harrison, Christine J; Irving, Julie A E

    2016-12-15

    Relapsed acute lymphoblastic leukaemia is the most common cause of cancer related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are particularly frequent in relapsed childhood acute lymphoblastic leukaemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukaemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukaemia cell lines and various primagraft acute lymphoblastic leukaemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but had no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukaemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signalling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukaemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signalling in acute lymphoblastic leukaemia but do not alter response to MEK inhibitors.

  13. Dermatoglyphics in Children with Acute Leukaemia

    PubMed Central

    Purvis-Smith, S. G.; Menser, Margaret A.

    1973-01-01

    The dermatoglyphics of 135 children with acute leukaemia differed significantly from those of normal controls, and examination of 174 of the patients' first degree relatives indicated that familial factors were involved. The findings suggested that within the racial group studied dermatoglyphics may partly identify a population subgroup which is at increased risk of leukaemogenesis. While these observations may not have immediate clinical application, they are likely to contribute to a greater understanding of individuals who have increased constitutional susceptibility to leukaemia. PMID:4519014

  14. Mitotic crossover promotes leukemogenesis in children born with TEL-AML1 via the generation of loss of heterozygosity at 12p.

    PubMed

    Ivanovski, Ivan; Garavelli, Livia; Djurić, Olivera; Ćirović, Aleksandar; Škorić, Dejan; Ivanovski, Petar I

    2015-06-30

    TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia bottleneck phenomenon. In most cases of TEL-AML1+ leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene, i.e. loss of heterozygosity at 12p, occurs postnatally during the mitotic proliferation of TEL-AML1+ cell in the mitotic crossing over process. Mitotic crossing over is a very rare event with a frequency rate of 10-6 in a 10 kb region. The exploration and identification of the environmental exposure(s) that cause(s) proliferation of the TELAML1+ cell in which approximately 106 mitoses are generated to cause 12p loss of heterozygosity, i.e. TEL gene deletion, may contribute to the introduction of preventive measures for leukemia.

  15. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.

    PubMed

    Ley, Timothy J; Mardis, Elaine R; Ding, Li; Fulton, Bob; McLellan, Michael D; Chen, Ken; Dooling, David; Dunford-Shore, Brian H; McGrath, Sean; Hickenbotham, Matthew; Cook, Lisa; Abbott, Rachel; Larson, David E; Koboldt, Dan C; Pohl, Craig; Smith, Scott; Hawkins, Amy; Abbott, Scott; Locke, Devin; Hillier, Ladeana W; Miner, Tracie; Fulton, Lucinda; Magrini, Vincent; Wylie, Todd; Glasscock, Jarret; Conyers, Joshua; Sander, Nathan; Shi, Xiaoqi; Osborne, John R; Minx, Patrick; Gordon, David; Chinwalla, Asif; Zhao, Yu; Ries, Rhonda E; Payton, Jacqueline E; Westervelt, Peter; Tomasson, Michael H; Watson, Mark; Baty, Jack; Ivanovich, Jennifer; Heath, Sharon; Shannon, William D; Nagarajan, Rakesh; Walter, Matthew J; Link, Daniel C; Graubert, Timothy A; DiPersio, John F; Wilson, Richard K

    2008-11-06

    Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.

  16. Synergistic targeted therapy for acute promyelocytic leukaemia: a model of translational research in human cancer.

    PubMed

    Mi, J-Q; Chen, S-J; Zhou, G-B; Yan, X-J; Chen, Z

    2015-12-01

    Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. It has been found that all-trans-retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML-RARα fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia-initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of 'bench to bedside' and 'bedside to bench', which can serve as a valuable example for the diagnosis and treatment of other malignancies.

  17. Constitutively active ABL family kinases, TEL/ABL and TEL/ARG, harbor distinct leukemogenic activities in vivo.

    PubMed

    Yokota, A; Hirai, H; Shoji, T; Maekawa, T; Okuda, K

    2017-04-07

    ABL (ABL1) and ARG (ABL2) are highly homologous to each other in overall domain structure and amino acid sequence, with the exception of their C-termini. As with ABL, translocations that fuse ARG to ETV6/TEL have been identified in patients with leukemia. To assess the in vivo leukemogenic activity of constitutively active ABL and ARG, we generated a bone marrow (BM) transplantation model using the chimeric forms TEL/ABL and TEL/ARG, which have comparable kinase activities. TEL/ABL rapidly induced fatal myeloid leukemia in recipient mice, whereas recipients of TEL/ARG-transduced cells did not develop myeloid leukemia; instead, they succumbed to a long-latency infiltrative mastocytosis that could be adoptively transferred to secondary recipients. Swapping of the C-termini of ABL and ARG altered disease latency and phenotypes. In a detailed in vitro study, TEL/ARG strongly promoted mast cell differentiation in response to SCF or IL-3, whereas TEL/ABL preferentially induced myeloid differentiation of hematopoietic stem/progenitor cells. These results indicate that ABL and ARG kinase activate distinct differentiation pathways to induce specific diseases in vivo, i.e., myeloid leukemia and mastocytosis, respectively. Further elucidation of the differences in their properties should provide important insight into the pathogenic mechanisms of oncogenes of the ABL kinase family.Leukemia accepted article preview online, 07 April 2017. doi:10.1038/leu.2017.114.

  18. Design and kinetic analysis of hammerhead ribozyme and DNAzyme that specifically cleave TEL-AML1 chimeric mRNA

    SciTech Connect

    Choi, Woo-Hyung; Choi, Bo-Ra; Kim, Jae Hyun; Yeo, Woon-Seok; Oh, Sangtaek; Kim, Dong-Eun

    2008-09-12

    In order to develop the oligonucleotides to abolish an expression of TEL-AML1 chimeric RNA, which is a genetic aberration that causes the acute lymphoblastic leukemia (ALL), hammerhead ribozymes and deoxyoligoribozymes that can specifically cleave TEL-AML1 fusion RNA were designed. Constructs of the deoxyribozyme with an asymmetric substrate binding arm (Dz26) and the hammerhead ribozyme with a 4 nt-bulged substrate binding arm in the stem III (buRz28) were able to cleave TEL-AML1 chimeric RNA specifically at sites close to the junction in vitro, without cleaving the normal TEL and AML1 RNA. Single-turnover kinetic analysis under enzyme-excess condition revealed that the buRz28 is superior to the Dz26 in terms of substrate binding and RNA-cleavage. In conjunction with current progress in a gene-delivery technology, the designed oligonucleotides that specifically cleave the TEL-AML1 chimeric mRNA are hoped to be applicable for the treatment of ALL in vivo.

  19. Immunotherapy for Acute Myelogenous Leukaemia

    PubMed Central

    Powles, R. L.; Crowther, D.; Bateman, C. J. T.; Beard, M. E. J.; McElwain, T. J.; Russell, J.; Lister, T. A.; Whitehouse, J. M. A.; Wrigley, P. F. M.; Pike, M.; Alexander, P.; Fairley, G. Hamilton

    1973-01-01

    One hundred and seven untreated patients with acute myelogenous leukaemia (AML) were admitted to St Bartholomew's Hospital between 10 October 1970 and 31 January 1973. Before receiving drugs to induce remission they were allocated alternatively into 2 groups to decide their remission treatment—a group to receive chemotherapy alone and a group to receive the same chemotherapy with immunotherapy. The patients were then given induction chemotherapy and 45 of them attained complete remission. All patients in remission then received chemotherapy consisting of 5 days treatment every 28 days. Patients receiving immunotherapy were also given multiple weekly intradermal injections of irradiated stored AML cells and Glaxo B.C.G. using a Heaf gun. There were 19 patients in the group which received only chemotherapy during remission; 7 of these patients remain alive (median survival after attaining remission 303 days) and only 5 are still in their first remission (median remission length 188 days). Twenty-three patients were allocated to receive immunotherapy during remission in addition to chemotherapy and 16 remain alive (median 545 days) and 8 are in their first remission (median 312 days). The difference in survival of the two groups is significant with a P value of 0·003. PMID:4271320

  20. Acute monocytic leukaemia in a cat.

    PubMed

    Nagashima, N; Kano, R; Hirai, A; Yamazaki, J; Inoue, C; Hisasue, M; Moore, P F; Hasegawa, A

    2005-09-17

    A three-year-old cat with lymphadenopathy, non-regenerative anaemia and marked leucocytosis (171.3 x 10(9) white blood cells/l) was diagnosed with monocytic leukaemia and treated with a combination of anticancer drugs. A number of mature and immature monocyte-like cells were detected in the peripheral blood and bone marrow; they proved to be monocytic cells by cytochemical examination and an analysis of their cell surface phenotype, indicating that the cat suffered from acute myeloid leukaemia, subclassified as monocytic leukaemia (M5). Treatment with cytarabine, doxorubicin, vincristine and prednisolone greatly reduced the number of blast cells in the cat's peripheral blood and bone marrow. The cat was in partial remission for 67 days and survived for 95 days after it was first examined.

  1. Leukaemia mortality around French nuclear sites.

    PubMed Central

    Hattchouel, J. M.; Laplanche, A.; Hill, C.

    1995-01-01

    This study was designed to investigate leukaemia mortality in the population under the age of 25 residing around the 13 French nuclear sites operating in 1985. In four geographical zones defined according to the distance from the site, 503 exposed communes were identified and followed up between 1968 and 1989. A total of 4,132,000 person-years of observation were accumulated. The number of leukaemia deaths observed (69) did not differ from the expected number (86.15) estimated according to national mortality statistics. There was no difference in the risks of leukaemia mortality according to sex, age, type of installation and no trend with an increasing distance from installations. PMID:7880754

  2. Klinefelter syndrome and acute basophilic leukaemia--case report.

    PubMed

    Ljubić, Nives; Lang, Nada; Skelin, Ika Kardum; Lasan, Ruzica; Dominis, Mara; Perković, Leila; Zupanić-Krmek, Dubraka; Grgurević-Batinica, Anita

    2010-06-01

    Patients with 47, XXY karyotype (Klinefelter syndrome) appear to have increased risk of developing cancer, especially male breast cancer, germ cell tumours and non Hodgkin lymphomas, but rarely acute myeloid leukaemia. We report a patient with acute basophilic leukaemia with 47, XXY karyotype in both the tumour and constitutional cells. Acute basophilic leukaemia is very rare disease comprising less than 1% of all acute myeloid leukaemias. Morphological characteristic of leukaemic blast cells is moderately basophilic cytoplasm containing a variable number of coarse basophilic granules. The most characteristic cytochemical reaction is metachromatic positivity with toluidine blue. Blast are myeloperoxidase negative. Also leukemic blasts express myeloid and monocyte markers. There is no consistent chromosomal abnormality identified in this leukaemia. This is the first reported case of acute basophilic leukaemia in patient with Klinefelter syndrome. In this article the medical history of the patient is given and the possible connection between Klinefelter syndrome and acute myeloid leukaemia is discussed.

  3. Extended-Spectrum Beta-Lactamases among Enterobacter Isolates Obtained in Tel Aviv, Israel

    PubMed Central

    Schlesinger, Jacob; Navon-Venezia, Shiri; Chmelnitsky, Inna; Hammer-Münz, Orly; Leavitt, Azita; Gold, Howard S.; Schwaber, Mitchell J.; Carmeli, Yehuda

    2005-01-01

    The extended-spectrum beta-lactamase (ESBL)-producing phenotype is frequent among Enterobacter isolates at the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. We examined the clonal relatedness and characterized the ESBLs of a collection of these strains. Clonal relatedness was determined by pulsed-field gel electrophoresis. Isoelectric focusing (IEF) and transconjugation experiments were performed. ESBL gene families were screened by colony hybridization and PCR for blaTEM, blaSHV, blaCTX-M, blaIBC, blaPER, blaOXA, blaVEB, and blaSFO; and the PCR products were sequenced. The 17 Enterobacter isolates studied comprised 15 distinct genotypes. All isolates showed at least one IEF band (range, one to five bands) whose appearance was suppressed by addition of clavulanate; pIs ranged from 5.4 to ≥8.2. Colony hybridization identified at least one family of beta-lactamase genes in 11 isolates: 10 harbored blaTEM and 9 harbored blaSHV. PCR screening and sequence analysis of the PCR products for blaTEM, blaSHV, and blaCTX-M identified TEM-1 in 11 isolates, SHV-12 in 7 isolates, SHV-1 in 1 isolate, a CTX-M-2-like gene in 2 isolates, and CTX-M-26 in 1 isolate. In transconjugation experiments with four isolates harboring blaTEM-1 and blaSHV-12, both genes were simultaneously transferred to the recipient strain Escherichia coli HB101. Plasmid mapping, PCR, and Southern analysis with TEM- and SHV-specific probes demonstrated that a single transferred plasmid carried both the TEM-1 and the SHV-12 genes. The widespread presence of ESBLs among Enterobacter isolates in Tel Aviv is likely due not to clonal spread but, rather, to plasmid-mediated transfer, at times simultaneously, of genes encoding several types of enzymes. The dominant ESBL identified was SHV-12. PMID:15728917

  4. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study.

    PubMed Central

    Stiller, C. A.; Chessells, J. M.; Fitchett, M.

    1994-01-01

    There is a well-known raised risk of leukaemia in children with neurofibromatosis type 1 (NF-1). We carried out the first detailed population-based study of leukaemia and non-Hodgkin lymphoma (NHL) associated with NF-1 in order to estimate the risk and elucidate the relationship between these conditions. Over the 17 year study period there were five cases of chronic myelomonocytic leukaemia (CMML) in patients with NF-1 (relative risk 221; 95% CI 71-514), 12 cases of acute lymphoblastic leukaemia (ALL) (relative risk 5.4; 95% CI 2.8-9.4) and five cases of NHL (relative risk 10.0; 95% CI 3.3-23.4). Marrow cytogenetics could be reviewed for seven patients. Specific abnormalities found were monosomy 21 in a child with CMML and 7p+, 17p- in a child with ALL. No abnormalities were reported of 17q, which includes the NF1 gene. CMML occurred predominantly in boys, who also had a family history of NF-1. ALL and NHL were more often found in children with no previous family history. PMID:7947106

  5. FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia.

    PubMed

    Leung, A Y H; Man, C-H; Kwong, Y-L

    2013-02-01

    Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome.

  6. HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias

    PubMed Central

    Calero-Nieto, F J; Joshi, A; Bonadies, N; Kinston, S; Chan, W-I; Gudgin, E; Pridans, C; Landry, J-R; Kikuchi, J; Huntly, B J; Gottgens, B

    2013-01-01

    The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2. PMID:23708655

  7. Single Molecule Measurements of Protelomerase TelK-DNA Complexes

    NASA Astrophysics Data System (ADS)

    Landry, Markita; Khafizov, Rustem; Huang, Wai Mun; Chemla, Yann

    2008-10-01

    Protein-DNA interactions lie at the heart of many essential cellular processes such as replication, recombination, and repair. Recent advances in optical ``tweezers'' have made it possible to resolve motions on the scale of a single base pair of DNA, 3.4å. High-resolution optical traps have the potential to reveal these interactions at their fundamental length scales and should reveal how certain proteins bind to DNA or recognize target sequences. Telomerases are enzymes that have been actively studied in various organisms because of their fundamental involvement with both cancer and aging^1. Protelomerase TelK is an enzyme responsible for forming closed DNA hairpin ends in linear DNA. TelK is not an ATP dependant enzyme, which is surprising given the degree of DNA distortion accomplished by the enzyme, and the large energy barrier intrinsic in DNA hairpin formation. Therefore, our focus is on TelK mutants lacking their c-terminal domain, and TelK YF mutants lacking their tyrosine active site amino acid. Preliminary data have shown remarkable differences in protein binding and unbinding forces caused by the removal of a single oxygen atom from a 73 kDa protein. Further measurements using high-resolution optical tweezers should provide fundamental insights into the nature and importance of the electrostatic interactions between TelK and its DNA substrate. 1. Shay, J. et al. Rad. Res. 155, 188 (2001) [1] Huang, W. et al. Mol. Cell. 27, 901 (2007).

  8. Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study.

    PubMed

    Koehler, Philipp; Hamprecht, Axel; Bader, Oliver; Bekeredjian-Ding, Isabelle; Buchheidt, Dieter; Doelken, Gottfried; Elias, Johannes; Haase, Gerhard; Hahn-Ast, Corinna; Karthaus, Meinolf; Kekulé, Alexander; Keller, Peter; Kiehl, Michael; Krause, Stefan W; Krämer, Carolin; Neumann, Silke; Rohde, Holger; La Rosée, Paul; Ruhnke, Markus; Schafhausen, Philippe; Schalk, Enrico; Schulz, Katrin; Schwartz, Stefan; Silling, Gerda; Staib, Peter; Ullmann, Andrew; Vergoulidou, Maria; Weber, Thomas; Cornely, Oliver A; Vehreschild, Maria J G T

    2017-02-01

    Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently.

  9. Is Having Clonal Cytogenetic Abnormalities the Same as Having Leukaemia.

    PubMed

    Farina, Mirko; Rossi, Giuseppe; Bellotti, Daniella; Marchina, Eleonora; Gale, Robert Peter

    2016-01-01

    A finding of cytogenetic abnormalities, even when these are clonal and even when the abnormalities are typically associated with leukaemia, is not the same as a person having leukaemia. We describe a person who had acute myeloid leukaemia (AML) and achieved a complete haematological remission and who then had persistent and transient clonal cytogenetic abnormalities for 22 years but no recurrence of leukaemia. These data suggest that clones of myeloid cells with mutations and capable of expanding to levels detectable by routine cytogenetic analyses do not all eventuate in leukaemia, even after a prolonged observation interval. The possibility of incorrectly diagnosing a person as having leukaemia becomes even greater when employing more sensitive techniques to detect mutations such as by polymerase chain reaction and whole-exome or whole-genome sequencing. Caution is needed when interpreting clonal abnormalities in AML patients with normal blood and bone marrow parameters.

  10. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number.

    PubMed Central

    Parsons, D W; McAndrew, P E; Iannaccone, S T; Mendell, J R; Burghes, A H; Prior, T W

    1998-01-01

    The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in approximately 95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3' end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5' UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number. PMID:9837824

  11. SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance.

    PubMed

    Cruickshank, V Adam; Sroczynska, Patrycja; Sankar, Aditya; Miyagi, Satoru; Rundsten, Carsten Friis; Johansen, Jens Vilstrup; Helin, Kristian

    2015-01-01

    Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia. We observed the selective requirement for these proteins for leukaemic cell expansion and self-renewal in-vitro as well as in leukaemia. Gene expression profiling in human cells of each of these three factors suggests that they have overlapping functions in leukaemia. The gene expression changes induced by loss of the three proteins demonstrate that they are required for the expression of haematopoietic stem cell associated genes but in contrast to previous results obtained in mouse cells, the three proteins are not required for the expression of c-MYC regulated genes.

  12. Acute Myeloid Leukaemia of Donor Cell Origin Developing 17 Years after Allogenic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukaemia

    PubMed Central

    Jiménez, Pilar; Alvarez, J. Carlos; Garrido, Pilar; Lorente, J. Antonio; Palacios, Jorge; Ruiz-Cabello, Francisco

    2012-01-01

    Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID:23675279

  13. Feverfew: weeding out the root of leukaemia.

    PubMed

    Guzman, Monica L; Jordan, Craig T

    2005-09-01

    Malignant stem cells are central to the pathogenesis and perpetuation of acute myelogenous leukaemia (AML). Despite their crucial role, standard chemotherapy often does not target these critical cells and, thus, the 'root' of leukaemic disease is not eradicated. To derive better therapies, unique molecular features of malignant stem cells have been characterised for AML and evaluated with regard to ablation of disease. In the course of such studies, the compound parthenolide, which is derived from the medicinal plant feverfew, has recently been shown to preferentially induce AML stem cells to undergo apoptosis. Importantly, parthenolide had no discernable effect on normal blood cells. Thus, this naturally occurring agent may provide new avenues of investigation for the treatment of leukaemia. In this article, characteristics of parthenolide are reviewed.

  14. Prolonged remission maintenance in acute myeloid leukaemia.

    PubMed

    Spiers, A S; Goldman, J M; Catovsky, D; Costello, C; Galton, D A; Pitcher, C S

    1977-08-27

    Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia.

  15. Prolonged remission maintenance in acute myeloid leukaemia.

    PubMed Central

    Spiers, A S; Goldman, J M; Catovsky, D; Costello, C; Galton, D A; Pitcher, C S

    1977-01-01

    Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia. PMID:268229

  16. Teaching Gender in Israel: Experiences at the Tel Aviv University

    ERIC Educational Resources Information Center

    Fenster, Tovi

    2011-01-01

    This paper examines the ways in which neoliberal economic policies are affecting academic work in Israeli universities, prioritizing programs that can generate their own funding, External philanthropic support from North America has enabled creation of an interdisciplinary Women and Gender Studies Program at Tel Aviv University that draws…

  17. New TEL Environments for Vocational Education--Teacher's Instructional Perspective

    ERIC Educational Resources Information Center

    Hämäläinen, Raija; Cattaneo, Alberto

    2015-01-01

    Modern vocational education is increasingly taking place in new technology-enhanced learning (TEL) settings. On the one hand, vocational education can benefit from the opportunities of technological development. On the other hand, such technologies may create new challenges for teachers. Therefore, there is a particular need to pay more attention…

  18. Infection during remission induction in childhood leukaemia

    PubMed Central

    Chessells, Judith M; Leiper, Alison D

    1980-01-01

    We have analysed our experience in the management of suspected infection in a group of 221 children with acute leukaemia undergoing induction of first remission. Patients with suspected infection received early empirical antibiotic therapy with cephalothin and gentamicin pending results of bacteriological investigations. Infection occurred in 17% of children with acute lymphoblastic leukaemia (ALL) whose initial treatment comprised prednisolone and vincristine, and was serious in 6·5%. 27% of children with ALL treated with intensive induction had infections which were serious in 20%; the figures for children with acute myeloblastic leukaemia (AML) were 49% and 22% respectively. The organisms responsible for most infections were Pseudomonas aeruginosa and Staphylococcus aureus; the former being most often associated with bacteraemia. One child (0·5%) died from infection. We conclude that with the use of early empirical antibiotic therapy, and granulocytes when appropriate, infection is no longer a major cause of death during remission induction. No special precautions are necessary to prevent its acquisition in most cases of ALL. In patients receiving early intensive treatment, including those with AML, measures designed to prevent acquisition of infection may reduce morbidity and enable the use of more effective chemotherapy. PMID:6929664

  19. Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence.

    PubMed

    Bleckmann, Kirsten; Schrappe, Martin

    2016-03-01

    The presence of the BCR/ABL1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) is a rare finding and has been an adverse prognostic factor associated with a high risk of therapeutic failure. The current key components of treatment are intensive polychemotherapy and a BCR/ABL1 kinase domain inhibitor. This treatment approach has been applied in a few clinical trials by paediatric leukaemia study groups. Thus, this subtype of ALL serves as the first model system for truly targeted treatment. The role of haematopoietic stem cell transplantation (HSCT) is increasingly called into question, at least in a favourable, though not yet clearly defined, subset of patients. Currently, the choice of the most effective tyrosine kinase inhibitor is not yet settled, in particular, in view of potential reduction of overall treatment intensity.

  20. Antibody-based therapies in B-cell lineage acute lymphoblastic leukaemia.

    PubMed

    Le Jeune, Caroline; Thomas, Xavier

    2015-02-01

    Targeted therapies represent a major breakthrough in the treatment of adult acute lymphoblastic leukaemia (ALL). Because lymphoblastic leukaemia cells express a variety of specific antigens, those ones can serve as targets for monoclonal antibodies (MoAbs). Anti-CD20 (rituximab), anti-CD19 (blinatumomab, SAR3419), anti-CD22 (epratuzumab, inotuzumab ozogamicin) and anti-CD52 (alemtuzumab) have therefore been developed. Possible strategies even include recruitment of CD3 cytotoxic T cells (blinatumomab) or adoptive T-cell therapy by gene transfer of CD19-chimeric antigen receptors (CD19-CARs). Recent data show that antibody-based therapy is a highly promising treatment approach. However, optimal treatment approach still needs to be defined.

  1. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.

    PubMed

    Zhang, Jinghui; Ding, Li; Holmfeldt, Linda; Wu, Gang; Heatley, Sue L; Payne-Turner, Debbie; Easton, John; Chen, Xiang; Wang, Jianmin; Rusch, Michael; Lu, Charles; Chen, Shann-Ching; Wei, Lei; Collins-Underwood, J Racquel; Ma, Jing; Roberts, Kathryn G; Pounds, Stanley B; Ulyanov, Anatoly; Becksfort, Jared; Gupta, Pankaj; Huether, Robert; Kriwacki, Richard W; Parker, Matthew; McGoldrick, Daniel J; Zhao, David; Alford, Daniel; Espy, Stephen; Bobba, Kiran Chand; Song, Guangchun; Pei, Deqing; Cheng, Cheng; Roberts, Stefan; Barbato, Michael I; Campana, Dario; Coustan-Smith, Elaine; Shurtleff, Sheila A; Raimondi, Susana C; Kleppe, Maria; Cools, Jan; Shimano, Kristin A; Hermiston, Michelle L; Doulatov, Sergei; Eppert, Kolja; Laurenti, Elisa; Notta, Faiyaz; Dick, John E; Basso, Giuseppe; Hunger, Stephen P; Loh, Mignon L; Devidas, Meenakshi; Wood, Brent; Winter, Stuart; Dunsmore, Kimberley P; Fulton, Robert S; Fulton, Lucinda L; Hong, Xin; Harris, Christopher C; Dooling, David J; Ochoa, Kerri; Johnson, Kimberly J; Obenauer, John C; Evans, William E; Pui, Ching-Hon; Naeve, Clayton W; Ley, Timothy J; Mardis, Elaine R; Wilson, Richard K; Downing, James R; Mullighan, Charles G

    2012-01-11

    Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  2. Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia.

    PubMed

    Sutton, Rosemary; Shaw, Peter J; Venn, Nicola C; Law, Tamara; Dissanayake, Anuruddhika; Kilo, Tatjana; Haber, Michelle; Norris, Murray D; Fraser, Chris; Alvaro, Frank; Revesz, Tamas; Trahair, Toby N; Dalla-Pozza, Luciano; Marshall, Glenn M; O'Brien, Tracey A

    2015-02-01

    Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P < 0·0001) or post-HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B-other ALL had more relapses (CIR 50%, LFS 41%) than T-ALL and the main precursor-B subtypes including BCR-ABL1, KMT2A (MLL), ETV6-RUNX1 (TEL-AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy.

  3. Acute leukaemia following malignant ependymoma: a case report

    SciTech Connect

    Pai, M.R.; Advani, S.H.; Gopal, R.; Nair, C.N.; Saikia, T.; Kamat, D.M.

    1985-05-01

    Though an increasing number of chemotherapy- and radiotherapy-related leukaemias are being reported, acute promyelocytic leukaemia developing as a therapy-related second malignancy is still uncommon. Here the authors report a case of acute promyelocytic leukemia, microgranular variant, developing in a case of intracranial malignant ependymoma, 1.5 years following treatment with craniospinal radiotherapy.

  4. Secondary pure erythroid leukaemia in relapsed acute lymphoblastic leukaemia: lineage switch or chemotherapy effect?

    PubMed

    Gupta, Sanjeev Kumar; Kumar, Rajive; Chharchhodawala, Taher; Kumar, Lalit

    2014-05-19

    Pure erythroid leukaemia is a rare subtype of acute myeloid leukaemia (AML) and its occurrence at acute lymphoblastic leukaemia (ALL) relapse has not been reported earlier. A 39-year-old man received chemotherapy for Philadelphia-negative B cell ALL. Subsequently, he developed pure erythroid leukaemia with >80% immature erythroid precursors in bone marrow showing block positivity on periodic acid-Schiff stain, expressing CD71, CD34 but lacking CD235a. The interval between exposure to multidrug chemotherapy including cyclophosphamide and AML diagnosis was 2 years and 9 months. No cytogenetic abnormality was detected at the time of relapse. The patient died 2 weeks after starting AML chemotherapy. The relatively narrow time interval (usually 5-10 years) between chemotherapy and AML development and normal karyotype at relapse raises a possibility of lineage switch besides therapy-related AML as the likely pathogenesis. Further exploration of such cases may unravel the pathways responsible for lineage assignment in pluripotent stem cells.

  5. Generalized leukaemia cutis from a small cell variant of T-cell prolymphocytic leukaemia presenting with exfoliative dermatitis.

    PubMed

    Jeong, Ki-Heon; Lew, Bark-Lynn; Sim, Woo-Young

    2009-01-01

    T-cell prolymphocytic leukaemia (T-PLL) is a rare, aggressive neoplasm of mature T lymphocytes. The small cell variant occurs in approximately 20% of T-PLL patients. The skin findings of leukaemia consist of leukaemia-specific skin lesions, which are infiltrated by leukaemia cells, and non-specific lesions. The former type of lesion signifies leukaemia cutis. Leukaemia cutis presents clinically as tumours, nodules, or patches on the scalp, face and trunk. We report here an 82-year-old Korean male patient who presented with erythema, erosion, vesicles, and scales on his entire body with no clear underlying cause. He had been treated with oral retinoids, steroids, and phototherapy for the diagnoses of drug eruption, pityriasis rubra pilaris, and exfoliative dermatitis at other hospitals. We suspected a hidden malignancy and diagnosed small cell variant T-PLL through blood and bone marrow examination. A skin biopsy specimen showed dense infiltration of small lymphocytes in the dermis. Most of the atypical lymphocytes stained positively with CD markers such as CD2, CD3, CD4, CD5, CD7 and CD8, thereby confirming the presence of leukaemia cells. To our knowledge, this is the first case of generalized leukaemia cutis from small cell variant of T-PLL presenting with exfoliative dermatitis over the whole body.

  6. [History of the Hôtel-Dieu of Bourges].

    PubMed

    Albou, P

    1996-01-01

    Bourges hospital (Hôtel-Dieu de Bourges, 1527) is one of the last to be built in France modeled in the Beaune style (1443) with chapel and wards linked in one line. The former gothic part, built between 1510 and 1527, was later completed by two Renaissance doors (1511 and 1533) and by two classical style wings built after the 1628 plague. Following the Revolution, the gothic part was divided by a floor which somewhat alters the interior appearance of the whole construction. The closing of the general care unit in November 1994 (and transfer of the Bourges General Hospital to new premises) now renders feasible the restoration of the former hospital (Hôtel-Dieu) almost unknown until now, thereby giving it the place it might fully desserve in the architectural and tourist heritage of Bourges.

  7. Effects of Saccharomyces cerevisiae mec1, tel1, and mre11 mutations on spontaneous and methylmethane sulfonate-induced genome instability.

    PubMed

    Suetomi, Kazuhiro; Mochizuki, Mai; Suzuki, Shiori; Yamamoto, Hiroaki; Yamamoto, Kazuo

    2010-02-01

    In eukaryotes, together with the Mre11/Rad50/Xrs2 (or Nbs1) complex, a family of related protein kinases (the ATM family) is involved in checkpoint activation in response to DNA double-strand breaks. In Saccharomyces cerevisiae, two members of this family, MEC1 and TEL1, have functionally redundant roles in DNA damage repair. Strains with mutations in their mec1 as well as mre11 genes are very sensitive to DNA damaging agents, show defective induction of damage-induced cell-cycle checkpoints, and defective damage-induced homologous recombination. However, the fact that both the mec1Delta and mre11Delta strains exhibit the spontaneous hyper-recombination phenotype is paradoxical in light of the homologous recombination defects in these strains. In this study, we constructed yeast mec1, tel1, and mre11 null mutations and characterized their genome stability properties. Spontaneous and methylmethane sulfonate (MMS)-induced point mutations, base-substitutions, and frameshifts occurred to an almost equal extent in the wild-type, mec1Delta, tel1Delta, and mre11Delta strains. Thus, Mec1, Tel1, and Mre11 do not play roles in the point mutation response. We then found that the mec1Delta, mre11Delta, and mec1Delta tel1Delta strains demonstrated increased rates of spontaneous loss of heterozygosity (LOH), which includes crossover, gene conversion, and chromosome loss, compared with the wild-type strain. In the tel1Delta strain, the rate of spontaneous LOH was as low as that in the wild-type strain. Finally, no induction of LOH by MMS was observed in the mec1Delta, mre11Delta, or mec1Delta tel1Delta strain; however, it was detected in the wild-type and tel1Delta strains upon exposure to MMS. The elevated level of spontaneous LOH but not MMS-induced LOH in the mec1Delta, mre11Delta, and mec1Delta tel1Delta strains suggests the presence of high levels of spontaneous recombinogenic DNA damage, which differs from the damage induced by MMS treatment, in these strains.

  8. Structure of the intact ATM/Tel1 kinase

    NASA Astrophysics Data System (ADS)

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-05-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.

  9. Structure of the intact ATM/Tel1 kinase.

    PubMed

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-05-27

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.

  10. Structure of the intact ATM/Tel1 kinase

    PubMed Central

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-01-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents. PMID:27229179

  11. High expression of connective tissue growth factor in pre-B acute lymphoblastic leukaemia.

    PubMed

    Boag, Joanne M; Beesley, Alex H; Firth, Martin J; Freitas, Joseph R; Ford, Jette; Brigstock, David R; de Klerk, Nicholas H; Kees, Ursula R

    2007-09-01

    In recent years microarrays have been used extensively to characterize gene expression in acute lymphoblastic leukaemia (ALL). Few studies, however, have analysed normal haematopoietic cell populations to identify altered gene expression in ALL. We used oligonucleotide microarrays to compare the gene expression profile of paediatric precursor-B (pre-B) ALL specimens with two control cell populations, normal CD34(+) and CD19(+)IgM(-) cells, to focus on genes linked to leukemogenesis. A set of eight genes was identified with a ninefold higher average expression in ALL specimens compared with control cells. All of these genes were significantly deregulated in an independent cohort of 101 ALL specimens. One gene, connective tissue growth factor (CTGF, also known as CCN2), had exceptionally high expression, which was confirmed in three independent leukaemia studies. Further analysis of CTGF expression in ALL revealed exclusive expression in B-lineage, not T-lineage, ALL. Within B-lineage ALL approximately 75% of specimens were consistently positive for CTGF expression, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies using Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. These findings indicate that CTGF is secreted by pre-B ALL cells and may play a role in the pathophysiology of this disease.

  12. Intravenous immune globulin in chronic lymphocytic leukaemia.

    PubMed Central

    Gamm, H; Huber, C; Chapel, H; Lee, M; Ries, F; Dicato, M A

    1994-01-01

    The most common complication of chronic lymphocytic leukaemia (CLL) is infection, which occurs mainly in advanced stages of disease or in those patients with hypogammaglobulinaemia. Intravenous immune globulin (IVIG) has been shown to be a useful prophylactic therapy against infections in such patients. A randomized, double-blind study on 36 patients receiving either 500 mg/kg or 250 mg/kg IVIG every 4 weeks was undertaken to determine the dose regimen required. There was no significant difference in the two treatment groups and we found that CLL patients were equally protected with low-dose IVIG. PMID:8033428

  13. Childhood leukaemia, nuclear sites, and population mixing

    PubMed Central

    Kinlen, L

    2011-01-01

    The excess of childhood leukaemia (CL) in Seascale, near the Sellafield nuclear reprocessing site in rural NW England, suggested that an epidemic of an underlying infection, to which CL is a rare response, is promoted by marked population mixing (PM) in rural areas, in which the prevalence of susceptibles is higher than average. This hypothesis has been confirmed by 12 studies in non-radiation situations. Of the five established CL excesses near nuclear sites, four are associated with significant PM; in the fifth, the Krummel power station in Germany, the subject has not been thoroughly investigated. PMID:21063418

  14. Emerging technologies in paediatric leukaemia

    PubMed Central

    2015-01-01

    Genetic changes, in particular chromosomal aberrations, are a hallmark of acute lymphoblastic lymphoma (ALL) and accurate detection of them is important in ensuring assignment to the appropriate drug protocol. Our ability to detect these genetic changes has been somewhat limited in the past due to the necessity to analyse mitotically active cells by conventional G-banded metaphase analysis and by mutational analysis of individual genes. Advances in technology include high resolution, microarray-based techniques that permit examination of the whole genome. Here we will review the current available methodology and discuss how the technology is being integrated into the diagnostic setting. PMID:26835367

  15. Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling

    PubMed Central

    Valiuliene, Giedre; Stirblyte, Ieva; Cicenaite, Dovile; Kaupinis, Algirdas; Valius, Mindaugas; Navakauskiene, Ruta

    2015-01-01

    Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukaemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL, is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukaemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up-regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro-apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells. PMID:25864732

  16. Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling.

    PubMed

    Valiuliene, Giedre; Stirblyte, Ieva; Cicenaite, Dovile; Kaupinis, Algirdas; Valius, Mindaugas; Navakauskiene, Ruta

    2015-07-01

    Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukaemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL, is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukaemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up-regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro-apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells.

  17. Oligonucleotide therapeutics for human leukaemia.

    PubMed

    Gewirtz, A M

    1997-01-01

    The concept of antisense oligonucleotide 'therapeutics' has generated a great deal of controversy. Questions abound regarding the mechanism of action of these compounds, their reliability and their ultimate utility. These problems are compounded by the 'hype', which has attended their development, and the inability of workers in this area to meet the expectations raised by its most zealous proponents. Nevertheless, it is worth pointing out that there have been some notable gene disruption successes with this technique that have stood up to rigorous scrutiny. Our own work with c-myb as a target is perhaps a reasonable example. Though much remains to be accomplished before antisense drugs are commonly, and usefully, employed in the clinic, it is important to remember what motivates their development. Gene-targeted drugs have the promise of exquisite specificity and the potential to do much good with little toxicity. Accordingly, antisense oligonucleotides can serve as a paradigm of rational drug development. For all these reasons then, we believe that efforts should be increased to decipher the mechanism of action of antisense oligodeoxynucleotides, and to learn how they may be successfully employed in the clinic.

  18. Leukaemia in Nagasaki atomic bomb survivors from 1945 through 1959*

    PubMed Central

    Tomonaga, Masanobu

    1962-01-01

    This review of the Nagasaki leukaemia experience during a period of 14 years after the detonation of the atomic bomb, together with comparisons with data from Hiroshima and from other series of post-radiation leukaemia cases, again demonstrates beyond reasonable doubt the leukaemogenic effect on man of ionizing radiation. An increased risk of leukaemia following doses probably as low as 100 rads (air-entry dose) of whole-body radiation is demonstrated on the basis of the available estimates of atomic bomb radiation doses. At doses above this level the increase in leukaemia incidence may be linearly related to the radiation dose. The data are too limited to allow of an evaluation of the risk represented by doses at the lower levels of radiation; but it seems clear that, if a threshold dose for leukaemia induction exists, it is lower than the threshold dose for the clinical expression of acute radiation syndrome. The sex and age distribution of radiation-induced leukaemia and the types of leukaemia observed are also discussed. PMID:13921808

  19. Large geomagnetic field anomalies revealed in Bronze to Iron Age archeomagnetic data from Tel Megiddo and Tel Hazor, Israel

    NASA Astrophysics Data System (ADS)

    Shaar, Ron; Tauxe, Lisa; Ron, Hagai; Ebert, Yael; Zuckerman, Sharon; Finkelstein, Israel; Agnon, Amotz

    2016-05-01

    Geomagnetic field measurements from the past few centuries show heightened secular variation activity in the southern hemisphere associated with the south Atlantic anomaly (SAA). It is uncertain whether geomagnetic anomalies at a similar scale have existed in the past owing to limited coverage and uncertainties in the paleomagnetic database. Here we provide new evidence from archaeological sources in the Levant suggesting a large positive northern hemisphere anomaly, similar in magnitude to the SAA during the 9th-8th centuries BCE, called ;Levantine Iron Age anomaly;. We also report an additional geomagnetic spike in the 8th century. The new dataset comprises 73 high precision paleointensity estimates from ca. 3000 BCE to 732 BCE, and five directional measurements between the 14th and the 9th centuries BCE. Well-dated pottery and cooking ovens were collected from twenty archaeological strata in two large contemporaneous stratigraphical mounds (tells) in Israel: Tel Megiddo and Tel Hazor. The new data are combined with previously published data and interpreted automatically using the PmagPy Thellier GUI program. The Tel Megiddo and Tel Hazor data sets demonstrate excellent internal consistency and remarkable agreement with published data from Mesopotamia (Syria). The data illustrate the evolution of an extreme geomagnetic high that culminated in at least two spikes between the 11th and the 8th centuries BCE (Iron Age in the Levant). The paleomagnetic directional data of the 9th century BCE show positive inclination anomalies, and deviations of up to 22° from the averaged geocentric axial dipole (GAD) direction. From comparison of the Levantine archaeomagnetic data with IGRF model for 2015 we infer the ;Levantine Iron Age anomaly; between the 10th and the 8th centuries BCE is a local positive anomaly. The eastward extent of the anomaly is currently unknown.

  20. Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1.

    PubMed

    Mohibullah, Neeman; Keeney, Scott

    2017-02-01

    The Spo11-generated double-strand breaks (DSBs) that initiate meiotic recombination are dangerous lesions that can disrupt genome integrity, so meiotic cells regulate their number, timing, and distribution. Mechanisms of this regulation remain poorly understood. Here, we use Spo11-oligonucleotide complexes, a byproduct of DSB formation, to reveal aspects of the contribution of the Saccharomyces cerevisiae DNA damage-responsive kinase Tel1 (ortholog of mammalian ATM). A tel1Δ mutant has globally increased amounts of Spo11-oligonucleotide complexes and altered Spo11-oligonucleotide lengths, consistent with conserved roles for Tel1 in control of DSB number and processing. A kinase-dead tel1 mutation similarly increases Spo11-oligonucleotide levels but mutating known Tel1 phosphotargets on Hop1 and Rec114 does not, implicating Tel1 kinase activity and clarifying roles of Tel1 phosphorylation substrates. Deep sequencing of Spo11 oligonucleotides demonstrates that Tel1 shapes the genome-wide DSB landscape in unexpected ways. Early in meiosis, Tel1 absence causes widespread changes in DSB distributions across large chromosomal domains. Many of these changes are erased as meiosis proceeds, however, illustrating homeostatic behavior of DSB regulatory systems. We further find that effects of Tel1 are distinct but partially overlapping with previously described contributions of the recombination regulator Cst9 (also known as Zip3). Finally, we provide evidence indicating that Tel1-dependent DSB interference influences the population-average DSB landscape but also demonstrate that locally inhibitory effects of an artificial hotspot insertion can be both Tel1-independent and chromosomal context-dependent. Our findings delineate Tel1 roles in regulating number and location of DSBs and illuminate the complex interplay between Tel1 and other pathways for DSB control.

  1. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure.

    PubMed

    de Thé, Hugues; Chen, Zhu

    2010-11-01

    The fusion oncogene, promyelocytic leukaemia (PML)-retinoic acid receptor-α (RARA), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML-RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.

  2. A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein.

    PubMed Central

    Jousset, C; Carron, C; Boureux, A; Quang, C T; Oury, C; Dusanter-Fourt, I; Charon, M; Levin, J; Bernard, O; Ghysdael, J

    1997-01-01

    TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co-immunoprecipitation and GST chromatography analyses that TEL and TEL-derived fusion proteins form homotypic oligomers in vitro and in vivo. Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS-1, ETS-2, FLI-1, ERG-2 and GABP alpha in vertebrates and PNTP2, YAN and ELG in Drosophila. TEL-induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL-platelet derived growth factor receptor beta (PDGFR beta), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS-1, ERG-2 and GABP alpha show that oligomerization is a specific property of the TEL amino-terminal conserved domain. These results indicate that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators. PMID:9009269

  3. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    PubMed Central

    Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2012-01-01

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

  4. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M C; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M; Puente, Diana A; Freije, José M P; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C; de Sanjosé, Silvia; Piris, Miguel A; de Alava, Enrique; San Miguel, Jesús; Royo, Romina; Gelpí, Josep L; Torrents, David; Orozco, Modesto; Pisano, David G; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A; Futreal, P Andrew; Stratton, Michael R; Campbell, Peter J; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2011-06-05

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.

  5. Infiltration of central nervous system in adult acute myeloid leukaemia.

    PubMed Central

    Pippard, M J; Callender, S T; Sheldon, P W

    1979-01-01

    Out of 64 consecutive unselected patients with acute myeloid leukaemia studied during 1973-6, five developed clinical evidence of spread to the central nervous system (CNS). Neuroradiological examination showed cerebral deposits in three, in whom rapid symptomatic relief was obtained with radiotherapy. In two of these patients who developed solid intracranial deposits haematological remission could be reinduced or maintained; they were still alive 86 and 134 weeks later. When patients presented with spread to the CNS complicating generalised uncontrolled leukaemia they had short survivals. CNS infiltration may respond dramatically to appropriate treatment provided that it is not associated with generalised uncontrolled leukaemia, which has a poor prognosis. In view of this, routine "prophylaxis" of the CNS in adult acute myeloid leukaemia does not seem justified at present. Images FIG 1 FIG 2 FIG 3 PMID:283873

  6. Epidemiological evidence of childhood leukaemia around nuclear power plants.

    PubMed

    Janiak, Marek K

    2014-07-01

    A few reports of increased numbers of leukaemia cases (clusters) in children living in the vicinity of nuclear power plants (NPP) and other nuclear installations have triggered a heated debate over the possible causes of the disease. In this review the most important cases of childhood leukaemia clusters around NPPs are described and analyzed with special emphasis on the relationship between the environmental exposure to ionizing radiation and the risk of leukaemia. Since, as indicated, a lifetime residency in the proximity of an NPP does not pose any specific health risk to people and the emitted ionizing radiation is too small to cause cancer, a number of hypotheses have been proposed to explain the childhood leukaemia clusters. The most likely explanation for the clusters is 'population mixing', i.e., the influx of outside workers to rural regions where nuclear installations are being set up and where local people are not immune to pathogens brought along with the incomers.

  7. Serum & cerebrospinal fluid ferritin levels in children with acute leukaemia.

    PubMed

    Srinivasan, A; Rusia, U; Anand, N K; Sood, S K

    1989-06-01

    Serum and CSF ferritin were estimated in 35 consecutive patients of acute leukaemia at the time of admission and on induction of remission. Serum ferritin levels were significantly raised in 94 per cent patients of acute leukaemia. The mean (+/- SD) serum ferritin (314.36 +/- 158.4 micrograms/1) was significantly higher when compared with control values (P less than 0.001). Remission induction resulted in significant fall in serum ferritin values to a mean of 149 (+/- 98.7) micrograms/l (P less than 0.05). Serum ferritin is thus of value in assessing the state of remission and is a sensitive indicator of the leukaemic cell mass and the state of activity of the disease. CSF ferritin levels in acute leukaemia were comparable to normal control values. CSF ferritin did not reflect CNS involvement in acute leukaemia and therefore its value as a tumour marker of CNS infiltration is doubtful.

  8. [Biphenotypic acute leukaemia with Burkitt-like cytology].

    PubMed

    Coche, D; Bergues, B; Harrivel, V; Guillaume, N

    2009-01-01

    Biphenotypic acute leukaemia (BAL) represents about 5% of adult acute leukaemia. Based on a previously described scoring system, the European Group for Immunologic Classification of Leukaemia (EGIL) proposed a set of diagnostic criteria for BAL. This scoring system is based on the number and degree of the specificity of several markers for myeloid or T/B lymphoid blasts. Here, we report the case of a BAL with Burkitt-like cytology, corresponding to "the acute lymphoblastic leukaemia, Burkitt type" L3 for the FAB classification. By flow cytometry, the blasts showed a positivity for B lymphoid cytoplasmic (CD79a and mu) and membrane (CD19, CD22, CD24, IgM) markers AND a positivity for the myeloid (CD13, CD33, CD65, CD15) markers.

  9. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling.

    PubMed

    Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S; Costa, Magdaline; Farhang Ghahremani, Morvarid; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W; Janzen, Viktor; McCormack, Matthew P; Lock, Richard B; Curtis, David J; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P P; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J

    2015-01-07

    Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model.

  10. A solid state Marx generator for TEL2

    SciTech Connect

    Kamerdzhiev, V.; Pfeffer, H.; Saewert, G.; Shiltsev, V.; /Fermilab

    2007-06-01

    The solid-state Marx generator modulates the anode of the electron gun to produce the electron beam pulses in the second Tevatron Electron Lens (TEL2). It is capable of driving the 60 pF terminal with 600 ns pulses of up to 6 kV with a p.r.r. of 50 kHz. The rise and fall times are 150 ns. Stangenes Industries developed the unit and is working on a second version which will go to higher voltage and have the ability to vary its output in 396 ns intervals over a 5 {micro}s pulse.

  11. Leukaemia incidence in the Techa River Cohort: 1953–2007

    PubMed Central

    Krestinina, L Y; Davis, F G; Schonfeld, S; Preston, D L; Degteva, M; Epifanova, S; Akleyev, A V

    2013-01-01

    Background: Little is known about leukaemia risk following chronic radiation exposures at low dose rates. The Techa River Cohort of individuals residing in riverside villages between 1950 and 1961 when releases from the Mayak plutonium production complex contaminated the river allows quantification of leukaemia risks associated with chronic low-dose-rate internal and external exposures. Methods: Excess relative risk models described the dose–response relationship between radiation dose on the basis of updated dose estimates and the incidence of haematological malignancies ascertained between 1953 and 2007 among 28 223 cohort members, adjusted for attained age, sex, and other factors. Results: Almost half of the 72 leukaemia cases (excluding chronic lymphocytic leukaemia (CLL)) were estimated to be associated with radiation exposure. These data are consistent with a linear dose response with no evidence of modification. The excess relative risk estimate was 0.22 per 100 mGy. There was no evidence of significant dose effect for CLL or other haematopoietic malignancies. Conclusion: These analyses demonstrate that radiation exposures, similar to those received by populations exposed as a consequence of nuclear accidents, are associated with long-term dose-related increases in leukaemia risks. Using updated dose estimates, the leukaemia risk per unit dose is about half of that based on previous dosimetry. PMID:24129230

  12. Serum paraproteins in chronic lymphocytic leukaemia.

    PubMed Central

    Sinclair, D; Dagg, J H; Mowat, A M; Parrott, D M; Stott, D I

    1984-01-01

    The presence of paraproteins in the sera of 10 patients with chronic lymphocytic leukaemia (CLL) was investigated using immunoisoelectric focusing. Monoclonal immunoglobulins were found in nine of these 10 sera. Five sera contained a single monoclonal IgM paraprotein, one serum contained a single monoclonal IgG paraprotein, while three sera contained more than one monoclonal paraprotein--namely, IgM + IgD, IgM + IgG, and IgM + IgD + IgG. The results indicate that the malignant B cells of CLL may be at a later stage of differentiation than previously assumed and serum monoclonal immunoglobulin could be of value as a tumour marker. Images PMID:6707229

  13. Blastic leukaemias (AML): a biologist's view.

    PubMed

    Cáceres-Cortés, Julio Roberto

    2013-05-01

    Acute myeloblastic leukaemia is characterised by the extreme clonal proliferation of haematopoietic precursor cells with abnormal or arrested differentiation. Chemotherapy of acute leukaemia is channelled towards the reduction and eradication of leukaemic cells. However, relapse is generally assumed to occur in residual host cells, which are refractory to or elude therapy. The cancer stem cell hypothesis has gained considerable importance in recent years and could interpret this behaviour. This persuasive theory states that cells within a tumour are organised in a hierarchy similar to that of normal tissues and are maintained by a small subset of cells responsible for tumour dormancy. These cells, defined as 'tumour initiating cells' (TICs), possess several properties of normal tissue stem cells. Recently, the TICs associated with AML have been shown to comprise distinct, hierarchically arranged classes similar to those observed for haematopoietic stem cells. We know now that the growth and survival of blasts in AML are driven by the same growth factors that stimulate normal cells. Furthermore, direct evidence of the role of membrane stem cell factor and its receptor c-Kit in cell-cell interactions and cell survival in primary AML blasts have been provided, defining the importance of juxtacrine stimulation. Inhibition of c-Kit signalling induces combinations of cell death: autophagy (compensatory mechanism towards survival) and apoptosis. While recent work confirmed that c-Kit inhibitors reduce cancer cell proliferation, it also demonstrated that future inappropriate prescriptions could cause normal tissue deterioration. The purpose of this paper was to review some of the salient features of leukaemic blasts in support of the proposal that research into neoplasia be increased. Rather than presenting the details of various studies, I have attempted to indicate general areas in which work has been done or is in progress. It is hoped that this survey of the subject

  14. Treatment Options for High-Risk Chronic Lymphocytic Leukaemia

    PubMed Central

    Hewamana, Saman; Dearden, Claire

    2011-01-01

    Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western world. The natural history of CLL is extremely variable with a survival time from initial diagnosis that ranges from 2 to more than 20 years. Understanding the clinical diversity and allowing the subclassification of CLL into various prognostic groups not only assists in predicting future outcome for patients, but also helps to direct treatment decisions. Chlorambucil and fludarabine were the standard therapy for CLL for decades. Randomized studies have reported superior overall response and progression-free survival (PFS) for fludarabine compared with alkylator-based therapy and for the fludarabine-cyclophospamide (FC) combination over fludarabine alone. More recently the addition of rituximab to the FC regimen (R-FC) has shown significant improvement in overall response, PFS and overall survival compared with FC alone. However, there are patients for whom this regimen still provides less satisfactory results. Within the above studies CLL patients who have some of the poorer prognostic markers, such as unmutated IgVH genes and/or high beta-2 microglobulin (B2M), and those who fail to achieve a minimal residual disease (MRD) negative remission are likely to have a shorter PFS compared with those without these features. Various strategies have been explored to improve the outcome for such patients. These include the addition of agents to a frontline R-FC regimen, use of consolidation and consideration of maintenance. The only group that can be clearly identified pretreatment for whom conventional fludarabine-based therapies produce significantly inferior response rates, PFS and overall survival are the patients who harbour a genetic fault; deletion or mutation or a combination of deletion and mutation of tumour protein p53 (TP53). TP53 inactivation is a less common finding at first treatment but becomes much more common in fludarabine-refractory patients. Alemtuzumab and high

  15. The Effect and Mechanisms of Proliferative Inhibition of Crocin on Human Leukaemia Jurkat Cells

    PubMed Central

    Sun, Y; Wang, Z; Wang, L; Wang, L-Z; Zang, C; Sun, L-R

    2015-01-01

    ABSTRACT Targeted therapy is a potentially useful approach for the treatment of T-lineage acute lymphoblastic leukaemia. This study aimed to find a highly effective, low toxic anti-tumour drug and further investigate its mechanisms. Jurkat cells were used as the object and were stimulated by different concentrations of crocin. By cell count, growth curve, methyl thiazolyl tetrazolium (MTT) method for the detection of cell proliferation, annexin V/propidium iodide (PI) method for the apoptosis rates, and reverse transcription-polymerase chain reaction (RT-PCR) for Bcl-2 and Bax gene expression, the effect and mechanisms of proliferative inhibition of crocin on Jurkat cells were further explored. Crocin promoted Jurkat cell apoptosis and inhibited cell growth, in a dose-time-dependent manner. The mechanism might be related to the inhibition of Bcl-2 gene expression and the promotion of Bax gene expression. These results suggest that crocin can be used as a suitable clinical agent for the treatment of T-lineage acute lymphoblastic leukaemia. PMID:27398676

  16. Mortality from brain cancer and leukaemia among electrical workers.

    PubMed Central

    Loomis, D P; Savitz, D A

    1990-01-01

    The relation of brain cancer and mortality from leukaemia to electrical occupations was investigated in a case-control study based on all deaths in 1985 and 1986 in the 16 states in the United States that report occupational data from death certificates to the national vital statistics registry. The case series comprised all 2173 men who died of primary brain cancer (International Classification of Diseases-9 ((ICD-9) code 191) and all 3400 who died of leukaemia (ICD-9 codes 204-208). Each was matched with 10 controls who died of other causes in the same year. Men employed in any electrical occupation had age race adjusted odds ratios (ORs) of 1.4 (95% confidence interval (CI) 1.1-1.7) for brain cancer and 1.0 (95% CI 0.8-1.2) for leukaemia, compared with men in all other occupations. Brain cancer odds ratios were larger for electrical engineers and technicians (OR 2.7, 95% CI 2.1-3.4), telephone workers (OR 1.6, 95% CI 1.1-2.4), electric power workers (OR 1.7, 95% CI 1.1-2.7), and electrical workers in manufacturing industries (OR 2.1, 95% CI 1.3-3.4). There was some evidence of excess leukaemia among the same groups (ORs of 1.1-1.5) despite absence of an association for all electrical workers. The excess of deaths from brain cancer was concentrated among men aged 65 or older, whereas leukaemia was associated with electrical work only among younger decedents and those with acute lymphocytic leukaemia. These results from a large and geographically diverse population corroborate reports of increased mortality from brain cancer among electrical workers, but gives only limited support to suggestions of excess deaths from leukaemia. PMID:2207035

  17. Leukaemia of natural killer cell large granular lymphocyte type with HLA-DR-CD16-CD56bright+ phenotype.

    PubMed Central

    Prieto, J; Ríos, E; Parrado, A; Martín, A; de Blas, J M; Rodríguez, J M

    1996-01-01

    The case is reported of a 45 year old woman with the rare leukaemia of natural killer cell large granular lymphocyte (NK/ LGL) type. Cytometric analysis of leukaemic blasts showed that they were positive for CD2, CD38, and CD56 antigens but negative for a series of antigens including CD3, CD7, CD16, and HLA-DR. Rearrangements of the beta T cell receptor, and heavy and kappa immunoglobulin genes were not detected and neither were chromosomal abnormalities. Leukaemic blasts developed NK cytotoxicity. The patient failed to respond to aggressive chemotherapy and died three months after diagnosis. The lack of expression of HLA-DR is an extraordinary characteristic of this case, as all cases of acute NK cell leukaemias described to date expressed HLA-DR. The immunophenotype observed in the NK cell leukaemic blasts may represent the counterpart of a hypothetical normal cell precursor in an early stage of ontogenic NK cell development. PMID:9038741

  18. Critical Perspectives on TEL: Art and Design Education, Theory, Communities and Space

    ERIC Educational Resources Information Center

    Sclater, Madeleine; Lally, Vic

    2016-01-01

    This paper explores three themes, emerging from the Inter-Life project, an Art and Design education and social skills project set in a virtual world. We argue that they connect with the concerns raised by critical Technology-Enhanced Learning (TEL) researchers at the Alpine Rendezvous workshop entitled "TEL: the Crisis and the Response."…

  19. Framework of Quality Assurance of TEL Integration into an Educational Organization

    ERIC Educational Resources Information Center

    Volungeviciene, Airina; Tereseviciene, Margarita; Tait, Alan

    2014-01-01

    This research paper addresses the issues of integration of technology enhanced learning (TEL) into an educational organization. Good practice experience cannot be directly transferred to new organisations due to different contextual conditions. The TEL integration depends significantly upon a very rapid development of services and information…

  20. Occupational exposure to solvents and hairy cell leukaemia

    PubMed Central

    Clavel, J.; Mandereau, L.; Conso, F.; Limasset, J. C.; Pourmir, I.; Flandrin, G.; Hemon, D.

    1998-01-01

    OBJECTIVES: The role of occupational exposures in hairy cell leukaemia was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to solvents other than benzene in hairy cell leukaemia. METHODS: The study included 226 male cases and 425 matched controls, exposure to solvents was evaluated by expert case by case review of the detailed data on occupational exposures generated by specific interviews. Also, exposure to solvents was evaluated with an independently constructed job exposure matrix (JEM). RESULTS: No association was found between hairy cell leukaemia and previous employment in a job exposed to solvents (odds ratio (OR) 0.9 95% confidence interval (95% CI) 0.6 to 1.3). ORs for the main occupational tasks exposed to solvents were around 1 and did not increase with the frequency or the duration of the tasks. No specific type of paint or glue was found to be significantly associated with hairy cell leukaemia. No association was found with exposure to solvents, taken as a whole, with either expert assessments or the JEM. No association was found with aromatic, chlorinated, or oxygenated subgroups of solvents. The ORs did not increase with the average intensity of exposure assessed by the experts, with the frequency of use, or with the duration of exposure. Finally, no association was found with non-occupational exposure to solvents. CONCLUSIONS: The study did not show any association between exposure to solvents and hairy cell leukaemia.   PMID:9536165

  1. Mechanisms of the insecticidal action of TEL (Talisia esculenta lectin) against Callosobruchus maculatus (Coleoptera: Bruchidae).

    PubMed

    Macedo, Maria Lígia Rodrigues; de Castro, Márcia Mota; Freire, Maria das Graças Machado

    2004-06-01

    Plant lectins have insecticidal activity that is probably mediated through their ability to bind carbohydrates. To examine the influence of sugars on the insecticidal activity of a lectin from Talisia esculenta seeds (TEL), the lectin was mixed with mannose, glucose, or mannose plus glucose. Mannose abolished the insecticidal activity. Affinity chromatography showed that TEL bound to midgut proteins of the insect Callosobruchus maculatus. Immunoblotting showed that TEL recognized some proteins, probably glycoproteins, present in the midgut membrane of this insect. The principal proteases responsible for digestive proteolysis in fourth instar larvae of C. maculatus were purified by chromatography on activated thiol-Sepharose. These purified proteases were unable to digest TEL after a 15-h incubation. These results suggest that the insecticidal activity of TEL involves a specific carbohydrate-lectin interaction with glycoconjugates on the surface of digestive tract epithelial cells, as well as binding to assimilatory glycoproteins present in midgut extracts and resistance to enzymatic digestion by cysteine proteinases.

  2. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

    PubMed Central

    Gu, Zhaohui; Churchman, Michelle; Roberts, Kathryn; Li, Yongjin; Liu, Yu; Harvey, Richard C.; McCastlain, Kelly; Reshmi, Shalini C.; Payne-Turner, Debbie; Iacobucci, Ilaria; Shao, Ying; Chen, I-Ming; Valentine, Marcus; Pei, Deqing; Mungall, Karen L.; Mungall, Andrew J.; Ma, Yussanne; Moore, Richard; Marra, Marco; Stonerock, Eileen; Gastier-Foster, Julie M.; Devidas, Meenakshi; Dai, Yunfeng; Wood, Brent; Borowitz, Michael; Larsen, Eric E.; Maloney, Kelly; Mattano Jr, Leonard A.; Angiolillo, Anne; Salzer, Wanda L.; Burke, Michael J.; Gianni, Francesca; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Moorman, Anthony V.; Patel, Bella; Fielding, Adele K.; Rowe, Jacob M.; Luger, Selina M.; Bhatia, Ravi; Aldoss, Ibrahim; Forman, Stephen J.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Marcucci, Guido; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Steven; Kantarjian, Hagop M.; Konopleva, Marina; Paietta, Elisabeth; Willman, Cheryl L.; L. Loh, Mignon; P. Hunger, Stephen; Mullighan, Charles G.

    2016-01-01

    Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered. PMID:27824051

  3. Treatment of adult acute lymphoblastic leukaemia.

    PubMed

    Jacobs, P; Wood, L; Novitzky, N

    1990-01-01

    Eighty-five consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 24 years (range 10-69 years), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, Adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate and monthly intrathecal therapy, with drug intensification comprising either vincristine, Adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was obtained in 59 patients (69%) and only the French-American-British (FAB) L1 morphology was a significant predictive factor (P = 0.048). Twenty-three patients failed to achieve CR and of these 12 had primary drug resistance. Median follow-up is currently 260 weeks, median predicted survival of all patients is 58 weeks and for those who achieved CR it is 104 weeks. Median duration of CR is 70 weeks. Of the prognostic factors for survival, only FAB L1 subtype was significant. Bone marrow relapses occurred in 29 patients, and of these 9 (31%) achieved CR. There has been CNS relapse in two patients and both have died. Eleven patients continue in CR off therapy, with a median of 152 weeks. This regimen is effective, with acceptable toxicity, and a number of patients are potentially cured. The incidence of resistant and relapsing disease is an argument for further intensifying both induction and postinduction therapy.

  4. Management of Adult Acute Myelogenous Leukaemia

    PubMed Central

    Crowther, D.; Powles, R. L.; Bateman, C. J. T.; Beard, M. E. J.; Gauci, C. L.; Wrigley, P. F. M.; Malpas, J. S.; Fairley, G. Hamilton; Scott, Ronald Bodley

    1973-01-01

    Consecutive adult patients admitted to St. Bartholomew's Hospital with acute myelogenous leukaemia have been treated with a remission induction drug schedule consisting of daunorubicin and cytosine arabinoside. Intermittent five-day courses were used in 72 patients, and a complete remission was obtained in 39 patients (54%). An alternative drug schedule in 22 patients resulted in fewer remissions but this may have been due to age differences in the two groups. Age and initial platelet count were found to be important factors in determining the success of remission induction therapy; the older patients and those with low platelet counts responded less well. A series of 23 patients who achieved remissions was divided into two groups; one received intermittent combination chemotherapy as the only form of maintenance, and the other was given weekly immunotherapy in addition to the chemotherapy. The immunotherapy consisted of irradiated allogeneic leukaemic cells and B.C.G. Eight of the 10 patients on chemotherapy alone have already relapsed compared with five out of 13 patients in the immunotherapy group. It is hoped that these promising initial results with this form of maintenance will be confirmed as more patients enter the maintenance trials. PMID:4513355

  5. Structural studies on leukaemia inhibitory factor

    SciTech Connect

    Norton, R.S.; Maurer, T.; Smith, D.K.; Nicola, N.A.

    1994-12-01

    Leukaemia Inhibitory Factor (LIF) is a pleiotropic cytokine that acts on a wide range of target cells, including mega-karyocytes, osteoblasts, hepatocytes, adipocytes, neurons, embryonic stem cells, and primordial germ cells. Many of its activities are shared with other cytokines, particularly interleukin-6, oncostatin-M, ciliary neurotrophic factor, and granulocyte colony-stimulating factor (G-CSF). Although secreted in vivo as a glycoprotein, nonglycosylated recombinant protein expressed in E. coli is fully active and has been used in our nuclear magnetic resonance (NMR) studies of the three-dimensional structure and structure-function relationships of LIF. With 180 amino acids and a molecular mass of about 20 kDa, OF is too large for direct structure determination by two-dimensional and three-dimensional {sup 1}HNMR. It is necessary to label the protein with the stable isotopes {sup 15}N and {sup 13}C and employ heteronuclear three-dimensional NMR in order to resolve and interpret the spectral information required for three-dimensional structure determination. This work has been undertaken with both human LIF and a mouse-human chimaera that binds to the human LIF receptor with the same affinity as the human protein and yet expresses in E. coli at much higher levels. Sequence-specific resonance assignments and secondary structure elements for these proteins will be presented and progress towards determination of their three-dimensional structures described.

  6. Leukaemia and Sellafield: is there a heritable link?

    PubMed Central

    Tawn, E J

    1995-01-01

    The demonstration of a statistical association between paternal preconceptional irradiation and childhood leukaemia appeared to provide a satisfactory explanation for the excess of cases in the village of Seascale, close to the Sellafield nuclear installation, and became the basis of two legal claims for compensation. In the ensuing scientific debate the biological plausibility of a causal interpretation of this association focused on the heritability of leukaemia and a comparison of the genetic risks implied by this finding with current information on the induction of genetic damage by irradiation. After a wide ranging review of the mechanistic issues it is concluded that there is no genetic basis for a causal relationship and this, together with recent appraisals of epidemiological studies, suggests that the association between childhood leukaemia and paternal preconceptional irradiation exposure is most likely to be a chance finding. PMID:7643351

  7. Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways.

    PubMed

    Sanchez, Y; Desany, B A; Jones, W J; Liu, Q; Wang, B; Elledge, S J

    1996-01-19

    Mutants of the Saccharomyces cerevisiae ataxia telangiectasia mutated (ATM) homolog MEC1/SAD3/ESR1 were identified that could live only if the RAD53/SAD1 checkpoint kinase was overproduced. MEC1 and a structurally related gene, TEL1, have overlapping functions in response to DNA damage and replication blocks that in mutants can be provided by overproduction of RAD53. Both MEC1 and TEL1 were found to control phosphorylation of Rad53p in response to DNA damage. These results indicate that RAD53 is a signal transducer in the DNA damage and replication checkpoint pathways and functions downstream of two members of the ATM lipid kinase family. Because several members of this pathway are conserved among eukaryotes, it is likely that a RAD53-related kinase will function downstream of the human ATM gene product and play an important role in the mammalian response to DNA damage.

  8. Measurable residual disease testing in acute myeloid leukaemia.

    PubMed

    Hourigan, C S; Gale, R P; Gormley, N J; Ossenkoppele, G J; Walter, R B

    2017-04-07

    There is considerable interest in developing techniques to detect and/or quantify remaining leukaemia cells termed measurable or, less precisely, minimal residual disease (MRD) in persons with acute myeloid leukaemia (AML) in complete remission defined by cytomorphological criteria. An important reason for AML MRD testing is the possibility of estimating the likelihood (and timing) of leukaemia relapse. A perfect MRD-test would precisely quantify leukaemia cells biologically able and likely to cause leukaemia relapse within a defined interval. AML is genetically diverse and there is currently no uniform approach to detecting such cells. Several technologies focused on immune phenotype or cytogenetic and/or molecular abnormalities have been developed, each with advantages and disadvantages. Many studies report a positive MRD-test at diverse time points during AML therapy identifies persons with a higher risk of leukaemia relapse compared with those with a negative MRD-test even after adjusting for other prognostic and predictive variables. No MRD-test in AML has perfect sensitivity and specificity for relapse prediction at the cohort- or subject-levels and there are substantial rates of false-positive and -negative tests. Despite these limitations, correlations between MRD-test results and relapse risk have generated interest in MRD-test result directed therapy interventions. However, convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRD-test is lacking and needs testing in randomized trials. Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting. Such data are needed to determine whether results of MRD-testing can be used as a surrogate endpoint in AML therapy trials. This could make drug-testing more efficient and accelerate regulatory approvals. Although MRD-testing in AML has advanced substantially, much remains to be done

  9. Can anthocyanins improve maintenance therapy of Ph(+) acute lymphoblastic leukaemia?

    PubMed

    Köchling, Joachim; Schmidt, Manuel; Rott, Yvonne; Sagner, Michael; Ungefroren, Hendrik; Wittig, Burghard; Henze, Günter

    2013-04-01

    Chemotherapy and tyrosine kinase inhibitors provide high remission rates. However, prognosis of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph(+) ALL) still remains poor. Because most adults eventually relapse without allogeneic stem cell transplantation, which is not available for all patients, novel strategies are required for relapse prevention. As the integrity of the immune system is essential for the control of remaining leukaemia cells, we compared the efficacy of anthocyanins, imatinib and a DNA-based vaccine as non-immunosuppressant components with 6-mercaptopurine (6-MP) to control minimal residual disease in vitro and in vivo using different leukaemia cell lines and syngeneic mice. Proliferation of Ph(+) ALL was significantly better inhibited by anthocyanin-rich berry extract or imatinib compared with 6-MP. Although anthocyanins induced apoptosis in some leukaemia cell lines, the level of caspase-3, caspase-8 and caspase-9 was significantly lower compared with imatinib and 6-MP. When used as single components, anthocyanins and imatinib mesylate failed to eradicate pre-existing Ph(+) ALL in syngeneic mice, while 6-MP led to 10% and DNA vaccination to 56% survival. Intriguingly, only the combination of DNA vaccination with berry extract but not with the isolated anthocyanin, cyanidin-3-rutinoside or imatinib further increased leukaemia-free and overall survival, and 90% of lethally challenged mice survived. We suggest that induction and enhancement of a leukaemia-specific immunity by DNA vaccination and anthocyanin-rich berry extract can also decrease the relapse rate in patients with Ph(+) ALL. Furthermore, this approach may serve as strategy for maintenance therapy of other malignancies.

  10. Chronic lymphocytic leukaemia: case control epidemiological study in Yorkshire.

    PubMed Central

    Cartwright, R. A.; Bernard, S. M.; Bird, C. C.; Darwin, C. M.; O'Brien, C.; Richards, I. D.; Roberts, B.; McKinney, P. A.

    1987-01-01

    This is the second report of a large case control study of lymphoma/leukaemia occurring in Yorkshire during 1979-84, and deals with chronic lymphocytic leukaemia presenting either in its haematological (CLL) or more solid lymphomatous (malignant lymphoma-lymphocytic or MLL) forms. In all, 330 cases and 561 controls were interviewed. The results support the concept that CLL/MLL is a condition of multiple aetiologies with evidence for genetic predisposition through an excess of family cases, immune perturbation demonstrated by excessive previous skin diseases and phenylbutazone use, and viral involvement shown by links with infectious diseases and multiple sclerosis. PMID:3304389

  11. Chronic lymphocytic leukaemia: case control epidemiological study in Yorkshire.

    PubMed

    Cartwright, R A; Bernard, S M; Bird, C C; Darwin, C M; O'Brien, C; Richards, I D; Roberts, B; McKinney, P A

    1987-07-01

    This is the second report of a large case control study of lymphoma/leukaemia occurring in Yorkshire during 1979-84, and deals with chronic lymphocytic leukaemia presenting either in its haematological (CLL) or more solid lymphomatous (malignant lymphoma-lymphocytic or MLL) forms. In all, 330 cases and 561 controls were interviewed. The results support the concept that CLL/MLL is a condition of multiple aetiologies with evidence for genetic predisposition through an excess of family cases, immune perturbation demonstrated by excessive previous skin diseases and phenylbutazone use, and viral involvement shown by links with infectious diseases and multiple sclerosis.

  12. Influence of radiation quality on mouse chromosome 2 deletions in radiation-induced acute myeloid leukaemia.

    PubMed

    Brown, Natalie; Finnon, Rosemary; Manning, Grainne; Bouffler, Simon; Badie, Christophe

    2015-11-01

    Leukaemia is the prevailing neoplastic disorder of the hematopoietic system. Epidemiological analyses of the survivors of the Japanese atomic bombings show that exposure to ionising radiation (IR) can cause leukaemia. Although a clear association between radiation exposure and leukaemia development is acknowledged, the underlying mechanisms remain incompletely understood. A hemizygous deletion on mouse chromosome 2 (del2) is a common feature in several mouse strains susceptible to radiation-induced acute myeloid leukaemia (rAML). The deletion is an early event detectable 24h after exposure in bone marrow cells. Ultimately, 15-25% of exposed animals develop AML with 80-90% of cases carrying del2. Molecular mapping of leukaemic cell genomes identified a minimal deleted region (MDR) on chromosome 2 (chr2) in which a tumour suppressor gene, Sfpi1 is located, encoding the transcription factor PU.1, essential in haematopoiesis. The remaining copy of Sfpi1 has a point mutation in the coding sequence for the DNA-binding domain of the protein in 70% of rAML, which alters a single CpG sequence in the codon for arginine residue R235. In order to identify chr2 deletions and Sfpi.1/PU.1 loss, we performed array comparative genomic hybridization (aCGH) on a unique panel of 79rAMLs. Using a custom made CGH array specifically designed for mouse chr2, we analysed at unprecedentedly high resolution (1.4M array- 148bp resolution) the size of the MDR in low LET and high-LET induced rAMLs (32 X-ray- and 47 neutron-induced). Sequencing of Sfpi1/PU.1DNA binding domain identified the presence of R235 point mutations, showing no influence of radiation quality on R235 type or frequency. We identified for the first time rAML cases with complex del2 in a subset of neutron-induced AMLs. This study allowed us to re-define the MDR to a much smaller 5.5Mb region (still including Sfpi1/PU.1), identical regardless of radiation quality.

  13. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

    PubMed Central

    Kocak, Hande; Ballew, Bari J.; Bisht, Kamlesh; Eggebeen, Rebecca; Hicks, Belynda D.; Suman, Shalabh; O’Neil, Adri; Giri, Neelam; Maillard, Ivan; Alter, Blanche P.; Keegan, Catherine E.; Nandakumar, Jayakrishnan

    2014-01-01

    Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC. PMID:25233904

  14. Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes

    SciTech Connect

    Takai, Hiroyuki; Xie, Yihu; de Lange, Titia; Pavletich, Nikola P.

    2010-09-20

    We reported previously that the stability of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs) depends on their interaction with Tel2, the ortholog of yeast Tel2 and Caenorhabditis elegans Clk-2. Here we provide evidence that Tel2 acts with Hsp90 in the maturation of PIKK complexes. Quantitative immunoblotting showed that the abundance of Tel2 is low compared with the PIKKs, and Tel2 preferentially bound newly synthesized ATM, ATR, mTOR, and DNA-PKcs. Tel2 complexes contained, in addition to Tti1-Tti2, the Hsp90 chaperone, and inhibition of Hsp90 interfered with the interaction of Tel2 with the PIKKs. Analysis of in vivo labeled nascent protein complexes showed that Tel2 and Hsp90 mediate the formation of the mTOR TORC1 and TORC2 complexes and the association of ATR with ATRIP. The structure of yeast Tel2, reported here, shows that Tel2 consists of HEAT-like helical repeats that assemble into two separate {alpha}-solenoids. Through mutagenesis, we identify a surface patch of conserved residues involved in binding to the Tti1-Tti2 complex in vitro. In vivo, mutation of this conserved patch affects cell growth, levels of PIKKs, and ATM/ATR-mediated checkpoint signaling, highlighting the importance of Tti1-Tti2 binding to the function of Tel2. Taken together, our data suggest that the Tel2-Tti1-Tti2 complex is a PIKK-specific cochaperone for Hsp90.

  15. Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.

    PubMed

    Trentin, Luca; Bresolin, Silvia; Giarin, Emanuela; Bardini, Michela; Serafin, Valentina; Accordi, Benedetta; Fais, Franco; Tenca, Claudya; De Lorenzo, Paola; Valsecchi, Maria Grazia; Cazzaniga, Giovanni; Kronnie, Geertruy Te; Basso, Giuseppe

    2016-10-04

    To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations.

  16. Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation

    PubMed Central

    Bacher, Jeffery W.

    2013-01-01

    Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML. PMID:22987027

  17. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

    PubMed Central

    Irvine, David A.; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L.; Moka, Hothri A.; Ho, Yinwei; Nixon, Colin; Manley, Paul W.; Wheadon, Helen; Goodlad, John R.; Holyoake, Tessa L.; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  18. Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis

    PubMed Central

    Trentin, Luca; Bresolin, Silvia; Giarin, Emanuela; Bardini, Michela; Serafin, Valentina; Accordi, Benedetta; Fais, Franco; Tenca, Claudya; De Lorenzo, Paola; Valsecchi, Maria Grazia; Cazzaniga, Giovanni; Kronnie, Geertruy te; Basso, Giuseppe

    2016-01-01

    To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations. PMID:27698462

  19. Treatment of acute lymphoblastic leukaemia (ALL).

    PubMed

    Jacobs, P; Wood, L

    1992-08-01

    Forty-six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi-squared = 3.91: p < 0.05). Eight of the 10 non-responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow-up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French-American-British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease-free at 65+ months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.

  20. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation

    PubMed Central

    Hartmann, Luise; Dutta, Sayantanee; Opatz, Sabrina; Vosberg, Sebastian; Reiter, Katrin; Leubolt, Georg; Metzeler, Klaus H.; Herold, Tobias; Bamopoulos, Stefanos A.; Bräundl, Kathrin; Zellmeier, Evelyn; Ksienzyk, Bianka; Konstandin, Nikola P.; Schneider, Stephanie; Hopfner, Karl-Peter; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Middeke, Jan Moritz; Stölzel, Friedrich; Thiede, Christian; Wolf, Stephan; Bohlander, Stefan K.; Preiss, Caroline; Chen-Wichmann, Linping; Wichmann, Christian; Sauerland, Maria Cristina; Büchner, Thomas; Berdel, Wolfgang E.; Wörmann, Bernhard J.; Braess, Jan; Hiddemann, Wolfgang; Spiekermann, Karsten; Greif, Philipp A.

    2016-01-01

    The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion. PMID:27252013

  1. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.

    PubMed

    Ma, Xiaotu; Edmonson, Michael; Yergeau, Donald; Muzny, Donna M; Hampton, Oliver A; Rusch, Michael; Song, Guangchun; Easton, John; Harvey, Richard C; Wheeler, David A; Ma, Jing; Doddapaneni, HarshaVardhan; Vadodaria, Bhavin; Wu, Gang; Nagahawatte, Panduka; Carroll, William L; Chen, I-Ming; Gastier-Foster, Julie M; Relling, Mary V; Smith, Malcolm A; Devidas, Meenakshi; Guidry Auvil, Jaime M; Downing, James R; Loh, Mignon L; Willman, Cheryl L; Gerhard, Daniela S; Mullighan, Charles G; Hunger, Stephen P; Zhang, Jinghui

    2015-03-19

    There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

  2. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia

    PubMed Central

    Ma, Xiaotu; Edmonson, Michael; Yergeau, Donald; Muzny, Donna M.; Hampton, Oliver A.; Rusch, Michael; Song, Guangchun; Easton, John; Harvey, Richard C.; Wheeler, David A.; Ma, Jing; Doddapaneni, HarshaVardhan; Vadodaria, Bhavin; Wu, Gang; Nagahawatte, Panduka; Carroll, William L.; Chen, I-Ming; Gastier-Foster, Julie M.; Relling, Mary V.; Smith, Malcolm A.; Devidas, Meenakshi; Auvil, Jaime M. Guidry; Downing, James R.; Loh, Mignon L.; Willman, Cheryl L.; Gerhard, Daniela S.; Mullighan, Charles G.; Hunger, Stephen P.; Zhang, Jinghui

    2015-01-01

    There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse. PMID:25790293

  3. Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia.

    PubMed

    Dandekar, Smita; Romanos-Sirakis, Eleny; Pais, Faye; Bhatla, Teena; Jones, Courtney; Bourgeois, Wallace; Hunger, Stephen P; Raetz, Elizabeth A; Hermiston, Michelle L; Dasgupta, Ramanuj; Morrison, Debra J; Carroll, William L

    2014-10-01

    While childhood acute lymphoblastic leukaemia (ALL) is now highly curable, the dismal prognosis for children who relapse warrants novel therapeutic approaches. Previously, using an integrated genomic analysis of matched diagnosis-relapse paired samples, we identified overactivation of the Wnt pathway as a possible mechanism of recurrence. To validate these findings and document whether Wnt inhibition may sensitize cells to chemotherapy, we analysed the expression of activated β-catenin (and its downstream target BIRC5) using multiparameter phosphoflow cytometry and tested the efficacy of a recently developed Wnt inhibitor, iCRT14, in ALL cell lines and patient samples. We observed increased activation of β-catenin at relapse in 6/10 patients. Furthermore, treatment of leukaemic cell lines with iCRT14 led to significant downregulation of Wnt target genes and combination with traditional chemotherapeutic drugs resulted in a synergistic decrease in viability as well as a significant increase in apoptotic cell death. Finally, pre-treatment of purified blasts from patients with relapsed leukaemia with the Wnt inhibitor followed by exposure to prednisolone, restored chemosensitivity in these cells. Our results demonstrate that overactivation of the Wnt pathway may contribute to chemoresistance in relapsed childhood ALL and that Wnt-inhibition may be a promising therapeutic approach.

  4. Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

    PubMed

    Kajtár, Béla; Rajnics, Péter; Egyed, Miklós; Alizadeh, Hussain

    2015-01-01

    The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature.

  5. Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells

    PubMed Central

    George, Joshy; Uyar, Asli; Young, Kira; Kuffler, Lauren; Waldron-Francis, Kaiden; Marquez, Eladio; Ucar, Duygu; Trowbridge, Jennifer J.

    2016-01-01

    The precise identity of a tumour's cell of origin can influence disease prognosis and outcome. Methods to reliably define tumour cell of origin from primary, bulk tumour cell samples has been a challenge. Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstrate that transforming haematopoietic stem cells (HSCs) and multipotent progenitors results in more aggressive AML than transforming committed progenitor cells. Transcriptome profiling reveals a gene expression signature broadly distinguishing stem cell-derived versus progenitor cell-derived AML, including genes involved in immune escape, extravasation and small GTPase signal transduction. However, whole-genome profiling of open chromatin reveals precise and robust biomarkers reflecting each cell of origin tested, from bulk AML tumour cell sampling. We find that bulk AML tumour cells exhibit distinct open chromatin loci that reflect the transformed cell of origin and suggest that open chromatin patterns may be leveraged as prognostic signatures in human AML. PMID:27397025

  6. ATF7IP as a novel PDGFRB fusion partner in acute lymphoblastic leukaemia in children.

    PubMed

    Kobayashi, Kenichiro; Mitsui, Kazumasa; Ichikawa, Hitoshi; Nakabayashi, Kazuhiko; Matsuoka, Masaki; Kojima, Yasuko; Takahashi, Hiroyuki; Iijima, Kazutoshi; Ootsubo, Kaori; Oboki, Keisuke; Okita, Hajime; Yasuda, Kazuki; Sakamoto, Hiromi; Hata, Kenichiro; Yoshida, Teruhiko; Matsumoto, Kenji; Kiyokawa, Nobutaka; Ohara, Akira

    2014-06-01

    We identified ATF7IP as a novel PDGFRB fusion partner in B-progenitor acute lymphoblastic leukaemia (B-ALL) and showed that B-ALL with ATF7IP/PDGFRB translocation is included within the genomic lesions of a Philadelphia chromosome (Ph)-like ALL subgroup. Comprehensive analyses of previous repositories of gene expression data sets disclosed that B-ALL cases with high PDGFRB expression level in the context of the Ph-like ALL gene are likely to have a PDGFRB translocation. Thus, it is possible that measurement of the PDGFRB expression level can be utilized as a screening test for the detection of the cryptic PDGFRB translocation, especially within the Ph-like ALL subgroup.

  7. Oxidative stress responses and NRF2 in human leukaemia.

    PubMed

    Abdul-Aziz, Amina; MacEwan, David J; Bowles, Kristian M; Rushworth, Stuart A

    2015-01-01

    Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival.

  8. Chronic recurrent multifocal osteomyelitis after acute lymphoblastic leukaemia.

    PubMed

    Abril, J C; Castillo, F; Loewinsonh, A F; Rivas, C; Bernacer, M

    1994-04-01

    We describe an 8 year old girl who developed chronic recurrent multifocal osteomyelitis (CRMO) in the ilium and clavicle. Treatment for an acute lymphoblastic leukaemia had been finished two months before. After antibiotic therapy, the clinical symptoms improved and no fresh lesions appeared. The aetiology of CRMO is unknown, but we feel that infection may precipitate an immunological reaction.

  9. Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood.

    PubMed Central

    Nysom, K.; Holm, K.; Olsen, J. H.; Hertz, H.; Hesse, B.

    1998-01-01

    The aim of this study was to examine pulmonary function after acute lymphoblastic leukaemia in childhood and identify risk factors for reduced pulmonary function. We studied a population-based cohort of 94 survivors of acute lymphoblastic leukaemia in childhood who were in first remission after treatment without spinal irradiation or bone marrow transplantation. Pulmonary function test results were compared with reference values for our laboratory, based on 348 healthy subjects who had never smoked from a local population study. A median of 8 years after cessation of therapy (range 1-18 years) the participants had a slight, subclinical, restrictive ventilatory insufficiency and reduced transfer factor and transfer coefficient. The changes in lung function were related to younger age at treatment and to more dose-intensive treatment protocols that specified more use of cranial irradiation and higher cumulative doses of anthracyclines, cytosine arabinoside and intravenous cyclophosphamide than previous protocols. We conclude that, 8 years after treatment without bone marrow transplantation or spinal irradiation, survivors of childhood acute lymphoblastic leukaemia in first remission were without pulmonary symptoms but had signs of slight restrictive pulmonary disease including reduced transfer factor. The increased dose intensity of many recent protocols for childhood acute lymphoblastic leukaemia may lead to increased late pulmonary toxicity. PMID:9662245

  10. Expression of low molecular weight proteins in patients with leukaemia.

    PubMed

    Sheikh, N; Abid, R; Qureshi, A W; Basheer, T

    2012-06-01

    The current study is conducted to observe the differences in the level of low molecular weight proteins in the sera of patients with leukaemia in comparison to healthy subjects (control group). The sera of patients with leukaemia showed 15 peaks in the densitometric curve in comparison to the seven peaks of the controls. The peaks in the experimental samples that coincide with those in the control were of 134.14, 113.15, 76.06, 63.25, 48.07, 22.85 and 16.47 kDa molecular weights, respectively. Most of the new peaks appeared between the proteins of molecular weight 36-29 kDa in the experimental groups. Mean density of the 134.14 kDa protein band showed an increase in the protein in experimental groups I and II only whereas 113.15 and 22.85 kDa protein were increased in all experimental groups of patients with leukaemia. The expression of 76.06 and 63.25 kDa protein fraction was downregulated in the patients with leukaemia. A decline in the level of the protein of 48.07 kDa was observed in patients with leukaemia except in group I. Unlike the other protein fractions, the level of the protein of 16.47 kDa was significantly (p < 0.05) increased with a maximum density in group II. Intergroup experimental) comparison revealed an increasing pattern of 95.44 and 89.21 kDa with maximum level in group III sera. However the protein fractions of 38.07 and 34.94 kDa varied in the serum with maximum density in Group IV Protein fractions of 32.92 and 31.24 kDa were expressed in all age groups of patients with leukaemia with a maximum density in group III whereas the percentage densities of 14.42 and 13.56 kDa protein were quite different. This preliminary study will provide a basis to study the role of different proteins in patients with leukaemia.

  11. Time Trends and Geographical Distribution of Childhood Leukaemia in Basrah, Iraq, from 2004 to 2009

    PubMed Central

    Alrudainy, Laith A; Hassan, Jenan G; Salih, Hussam M; Abbas, Mohammed K; Majeed, Athar AS

    2011-01-01

    Objectives: This study aimed to assess the incidence and trend of childhood leukaemia in Basrah. Methods: This was a hospital-based cancer registry study carried out at the Pediatric Oncology Ward, Maternity & Children’s Hospital and other institutes in Basrah, Iraq. All children with leukaemia, aged 0 to 14 years diagnosed and registered in Basrah from January 2004 to December 2009 were included in the study. Their records were retrieved and studied. The pattern of childhood leukaemia by year of diagnosis, age at diagnosis, morphological subtypes, and geographical distribution was analysed. Rates of childhood leukaemia over time were calculated for six years using standard linear regression. Results: The total number of cases of childhood leukaemia was 181. The number of cases ranged from 21 in year 1, to 31 in the final year reaching a peak of 39 in 2006. Leukaemia rates did not change over the study period (test for trend was not significant, P = 0.81). The trend line shows a shift towards younger children (less than 5 years). The commonest types of leukaemia were acute lymphoblastic leukaemia (ALL), then acute myeloid leukaemia (AML) and finally chronic myeloid leukaemia (CML). Conclusion: Annual rates of childhood leukaemia in Basrah were similar to those in other countries with a trend towards younger children. This raises the question about the effect of environmental catastrophes in the alteration of some specific rates of childhood leukaemia, rather than the overall incidence rate. There is a need for further epidemiological studies to understand the aetiology of childhood leukaemia in Basrah. PMID:21969893

  12. Managing pregnancy in chronic myeloid leukaemia.

    PubMed

    Palani, Renuka; Milojkovic, Dragana; Apperley, Jane F

    2015-04-01

    Over the past decade, we have witnessed significant advances in knowledge of the biology and treatment of chronic myeloid leukaemia (CML). The development of molecular-targeted therapy with tyrosine kinase inhibitors (TKIs) has fundamentally changed the outcome of this disease. Treatment with TKIs is now the standard of care in patients with CML and has dramatically improved long-term survival in the majority of patients. Patients who achieve major molecular response (MMR) after 2 years of treatment with imatinib have survival rates comparable to those of the general population. The success of TKIs has led to durable molecular response and possibility of normal life expectancies, such that it is now timely to address quality of life aspects such as fertility, pregnancy and family planning. Pregnancy in CML presents specific management and therapeutic challenges for the patient and the physician. Despite the recent treatment advances, we still have limited data on the safety of TKIs in pregnancy and its effect on fertility. However, there is a cause for concern and heightened awareness following the occurrence of a constellation of rare congenital malformations and spontaneous abortions in association with imatinib therapy. When a patient becomes pregnant whilst receiving TKI therapy, the difficulty lies in balancing the risk to the foetus of continuing therapy versus the risk to the patient of treatment interruption and potentially losing optimal disease response. All couples should be counselled on the risks associated with pregnancy whilst receiving TKI therapy. This is an essential aspect in patient care and frequently not emphasized enough by physicians. At the time of diagnosis, fertility preservation should be discussed with both male and female patients of childbearing potential. They should be made aware of fertility options which are available such as semen cryopreservation, ovarian or oocyte retrieval and storage and embryo cryopreservation in view of the

  13. Whole genome sequence of Oscheius sp. TEL-2014 entomopathogenic nematodes isolated from South Africa

    PubMed Central

    Lephoto, Tiisetso E.; Mpangase, Phelelani T.; Aron, Shaun; Gray, Vincent M.

    2016-01-01

    We present the annotation of the draft genome sequence of Oscheius sp. TEL-2014 (Genbank accession number KM492926). This entomopathogenic nematode was isolated from grassland in Suikerbosrand Nature Reserve near Johannesburg in South Africa. Oscheius sp. Strain TEL has a genome size of 110,599,558 bp and a GC content of 42.24%. The genome sequence can be accessed at DDBJ/EMBL/GenBank under the accession number LNBV00000000. PMID:27054091

  14. New advances in leukaemia immunotherapy by the use of Chimeric Artificial Antigen Receptors (CARs): state of the art and perspectives for the near future.

    PubMed

    Biagi, Ettore; Marin, Virna; Attianese, Greta Maria Paola Giordano; Pizzitola, Irene; Tettamanti, Sarah; Cribioli, Elisabetta; Biondi, Andrea

    2011-09-22

    Leukaemia immunotherapy represents a fascinating and promising field of translational research, particularly as an integrative approach of bone marrow transplantation. Adoptive immunotherapy by the use of donor-derived expanded leukaemia-specific T cells has showed some kind of clinical response, but the major advance is nowadays represented by gene manipulation of donor immune cells, so that they acquire strict specificity towards the tumour target and potent lytic activity, followed by significant proliferation, increased survival and possibly anti-tumour memory state. This is achieved by gene insertion of Chimeric T-cell Antigen Receptors (CARs), which are artificial molecules containing antibody-derived fragments (to bind the specific target), joined with potent signalling T-Cell Receptor (TCR)-derived domains that activate the manipulated cells. This review will discuss the main application of this approach particularly focusing on the paediatric setting, raising advantages and disadvantages and discussing relevant perspectives of use in the nearest future.

  15. Childhood leukaemia incidence below the age of 5 years near French nuclear power plants.

    PubMed

    Laurier, D; Hémon, D; Clavel, J

    2008-09-01

    A recent study indicated an excess risk of leukaemia among children under the age of 5 years living in the vicinity of nuclear power plants in Germany. We present results relating to the incidence of childhood leukaemia in the vicinity of nuclear power plants in France for the same age range. These results do not indicate an excess risk of leukaemia in young children living near French nuclear power plants.

  16. Incidence of leukaemia and brain tumours in some "electrical occupations".

    PubMed Central

    Törnqvist, S; Knave, B; Ahlbom, A; Persson, T

    1991-01-01

    A 19 year follow up study was conducted to explore the association between occupations expected to be exposed to electromagnetic fields and the occurrence of leukaemia and brain tumours. Incidence of cancer between 1961-79 was calculated and the standardised morbidity ratio (SMR) with a 95% confidence interval (95% CI) was related to that of all Swedish working men. For all the selected "electrical occupations" the SMRs for total leukaemia and brain tumours were near unity. Increased risks were noted for all leukaemia among electrical/electronic engineers and technicians, (SMR 1.3; 95% CI 1.0-1.7) as well as in the sub-groups of telegraph/telephone (2.1; 1.1-3.6) and machine (2.6; 1.0-5.8) industries. Risk for chronic lymphoid leukaemia was increased in the same occupational category (1.7; 1.1-2.5) and in the sub-group of machine industry (4.8; 1.0-14.0), as well as for all linesmen (2.0; 1.0-3.5) and power linesmen (2.8; 1.1-5.7). Risk for acute myeloid leukaemia was increased among all miners (2.2; 1.0-4.1) and miners working in iron/ore mines (5.7; 2.1-12.4). Increased risk for all brain tumours (2.9; 1.2-5.9) and glioblastomas (3.4; 1.1-8.0) appeared among assemblers and repairmen in radio and TV industry. Raised risk for all brain tumours was seen for all welders (1.3; 1.0-1.7) and welders in iron/steel works (3.2; 1.0-7.4) and risk for glioblastomas was also increased for all welders (1.5; 1.1-2.1). No major changes in relative risk estimates were noted after the exclusion of persons who were over 65 at the time of diagnosis. Although a homogeneous pattern of increased risks of leukaemia or brain tumour was not noted, the hypothesis that magnetic fields might play a part in the origin of cancer cannot be rejected. PMID:1911402

  17. Friend leukaemia insertion (Fli)-1 is a prediction marker candidate for radiotherapy resistant oral squamous cell carcinoma.

    PubMed

    Shintani, S; Hamakawa, H; Nakashiro, K; Shirota, T; Hatori, M; Tanaka, M; Kuroshita, Y; Kurokawa, Y

    2010-11-01

    Radiotherapy is commonly used to treat oral squamous cell carcinoma (OSCC), but its therapeutic effects are unpredictable. To determine which genes correlate with radiation resistance in oral cancer, the authors evaluated radiation sensitivity using a standard colony formation assay with a gene microarray system for seven OSCC cell lines. They found significant associations between dozens of gene-expression levels and radiation resistance of OSCC cell lines. Following analysis of the different radiosensitive cancer cell lines, the friend leukaemia insertion (Fli)-1 gene was selected as a prediction marker gene for OSCC radiotherapy resistance. Fli-1 expression was associated with radiation resistance in OSCC patients. These data help to predict the effects radiation therapy has on OSCC, in turn contributing to the development of alternative radiation therapies.

  18. Recognition of intermolecular G-quadruplexes by full length nucleophosmin. Effect of a leukaemia-associated mutation.

    PubMed

    Bañuelos, Sonia; Lectez, Benoît; Taneva, Stefka G; Ormaza, Georgina; Alonso-Mariño, Marián; Calle, Xabier; Urbaneja, María A

    2013-07-11

    Nucleophosmin (NPM) is a nucleolar protein involved in ribosome biogenesis. NPM1 gene is frequently mutated in acute myeloid leukaemia (AML), correlating with aberrant cytoplasmic localization of the protein. NPM attachment to the nucleolus in physiological conditions probably depends on binding to nucleic acids, and this recognition could be altered in AML. NPM associates to guanine-rich DNA sequences, able to fold as "G-quadruplexes". We have analyzed the interaction of pentameric, full length NPM with G-rich oligonucleotides, finding that the protein binds preferentially high-order G-quadruplexes. AML-associated mutation significantly hampers DNA binding, pointing to a possible mechanism contributing to pathological mislocalization of NPM.

  19. Adenovirus protein IX sequesters host-cell promyelocytic leukaemia protein and contributes to efficient viral proliferation.

    PubMed

    Rosa-Calatrava, Manuel; Puvion-Dutilleul, Francine; Lutz, Pierre; Dreyer, Dominique; de Thé, Hugues; Chatton, Bruno; Kedinger, Claude

    2003-10-01

    The product of adenovirus type 5 (Ad5) gene IX, protein IX (pIX), is a multifunctional protein that stabilizes the viral capsid and has transcriptional activity. We show that pIX also contributes to the Ad5-induced reorganization of the host-cell nuclear ultrastructure: pIX induces the formation of specific and dynamic nuclear inclusions, and the host promyelocytic leukaemia (PML) protein, which is the main structural organizer of PML bodies, is stably relocated and confined within the pIX-induced inclusions late in infection. Our results suggest that Ad5 has evolved a unique strategy that leads to the sustained neutralization of PML bodies throughout infection, thereby ensuring optimal viral proliferation.

  20. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    PubMed Central

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E.; Cowley, Mark J.; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R.; Alexandrov, Ludmil B.; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  1. Adenovirus protein IX sequesters host-cell promyelocytic leukaemia protein and contributes to efficient viral proliferation

    PubMed Central

    Rosa-Calatrava, Manuel; Puvion-Dutilleul, Francine; Lutz, Pierre; Dreyer, Dominique; De Thé, Hugues; Chatton, Bruno; Kedinger, Claude

    2003-01-01

    The product of adenovirus type 5 (Ad5) gene IX, protein IX (pIX), is a multifunctional protein that stabilizes the viral capsid and has transcriptional activity. We show that pIX also contributes to the Ad5-induced reorganization of the host-cell nuclear ultrastructure: pIX induces the formation of specific and dynamic nuclear inclusions, and the host promyelocytic leukaemia (PML) protein, which is the main structural organizer of PML bodies, is stably relocated and confined within the pIX-induced inclusions late in infection. Our results suggest that Ad5 has evolved a unique strategy that leads to the sustained neutralization of PML bodies throughout infection, thereby ensuring optimal viral proliferation. PMID:14528266

  2. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    SciTech Connect

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stephane; Quesnel, Bruno; Commes, Therese; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stephanie; Gayevskiy, Velimir; Dinger, Marcel E.; Cowley, Mark J.; Selimoglu-Buet, Dorothee; Meyer, Vincent; Artiguenave, Francois; Deleuze, Jean -Francois; Preudhomme, Claude; Stratton, Michael R.; Alexandrov, Ludmil B.; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-02-24

    The cytidine analogues azacytidine and 5-aza-2’-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14 ± 5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Lastly, our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.

  3. Identification of novel molecular prognostic markers for paediatric T-cell acute lymphoblastic leukaemia.

    PubMed

    Gottardo, Nicholas G; Hoffmann, Katrin; Beesley, Alex H; Freitas, Joseph R; Firth, Martin J; Perera, Kanchana U; de Klerk, Nicolas H; Baker, David L; Kees, Ursula R

    2007-05-01

    In the last four decades the survival of patients with newly diagnosed childhood T-cell acute lymphoblastic leukaemia (T-ALL) has improved dramatically. In sharp contrast, relapsed T-ALL continues to confer a dismal prognosis. We sought to determine if gene expression profiling could uncover a signature of outcome for children with T-ALL. Using 12 patient specimens obtained before therapy started, we examined the gene expression profile by oligonucleotide microarrays. We identified three genes, CFLAR, NOTCH2 and BTG3, whose expression at the time of diagnosis accurately distinguished the patients according to disease outcome. These genes are involved in the regulation of apoptosis and cellular proliferation. The prognostic value of the three predictive genes was assessed in an independent cohort of 25 paediatric T-ALL patients using quantitative real-time reverse transcription polymerase chain reaction. Patients assigned to the adverse outcome group had a significantly higher cumulative incidence of relapse compared with patients assigned to the favourable outcome group (46% vs. 8%, P = 0.029). Five-year overall survival was also significantly worse in the patients assigned to the adverse outcome group (P = 0.0039). The independent influence of the 3-gene predictor was confirmed by multivariate analysis. Our study provides proof of principle that genome-wide expression profiling can detect novel molecular prognostic markers in paediatric T-ALL.

  4. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.

    PubMed

    Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R; Herrmann, Harald; Sison, Edward A; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J; Johns, Christopher; Chicas, Agustin; Mulloy, James C; Kogan, Scott C; Brown, Patrick; Valent, Peter; Bradner, James E; Lowe, Scott W; Vakoc, Christopher R

    2011-08-03

    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.

  5. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

    PubMed Central

    Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

    2012-01-01

    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID:21814200

  6. How animal models of leukaemias have already benefited patients.

    PubMed

    Ablain, Julien; Nasr, Rihab; Zhu, Jun; Bazarbachi, Ali; Lallemand-Breittenbach, Valérie; de Thé, Hugues

    2013-04-01

    The relative genetic simplicity of leukaemias, the development of which likely relies on a limited number of initiating events has made them ideal for disease modelling, particularly in the mouse. Animal models provide incomparable insights into the mechanisms of leukaemia development and allow exploration of the molecular pillars of disease maintenance, an aspect often biased in cell lines or ex vivo systems. Several of these models, which faithfully recapitulate the characteristics of the human disease, have been used for pre-clinical purposes and have been instrumental in predicting therapy response in patients. We plea for a wider use of genetically defined animal models in the design of clinical trials, with a particular focus on reassessment of existing cancer or non-cancer drugs, alone or in combination.

  7. Late marrow recurrences in childhood acute lymphoblastic leukaemia.

    PubMed Central

    Chessells, J M; Breatnach, F

    1981-01-01

    Thirty children with acute lymphoblastic leukemia had a recurrence in the bone marrow after treatment was stopped electively. A second haematological remission was achieved in 27 (90%), and the median duration of remission was shortest (six months) in those relapsing within six months of stopping treatment. Four of six children relapsing over one year after stopping treatment remained in second haematological remission. Leukaemic infiltration of the central nervous system developed in four patients remaining in marrow remission. It is concluded that conventional chemotherapy is unlikely to be effective in children with acute lymphoblastic leukaemia who relapse soon after stopping treatment, that "reprophylaxis" of the central nervous system probably with long-term intrathecal chemotherapy is essential, and that some patients relapsing after prolonged unmaintained remission may achieve long-term leukaemia-free survival. PMID:6791733

  8. Cerebellar mass as a location of acute lymphoblastic leukaemia.

    PubMed

    Desideri, Ilaria; Canovetti, Silvia; Pesaresi, Ilaria; Caniglia, Michele; Ciancia, Eugenio; Bartolozzi, Carlo; Puglioli, Michele; Cosottini, Mirco

    2014-09-01

    A 22-year-old man with acute lymphoblastic leukaemia was referred to our observation for headache, cervical pain and sopor. A computed tomography study revealed triventricular obstructive hydrocephalus due to a left cerebellar hyperdense mass impinging on the fourth ventricle. A magnetic resonance study demonstrated an area of hyperintensity on T2-weighted images, hypointensity on T1, restricted diffusivity and contrast enhancement involving the left hemispherical cerebellar cortex and the vermis and causing cerebellar herniation. After surgical excision of the lesion, histological examination revealed an infiltrate of lymphoblastic leukaemia with B cells. Leukaemic intracranial masses are rare. Our report describes a case presenting a cerebellar mass of leukaemic tissue characterized by high cellularity and low apparent diffusion coefficient value comparable to acute ischaemia. Therefore leukaemic intracranial mass has to be considered in the differential diagnosis of cerebellar masses.

  9. Immunological studies in a case of T-cell leukaemia

    PubMed Central

    Stathopoulos, G.; Papamichail, M.; Sheldon, P.; Catovsky, D.; Davies, A. J. S.; Holborow, E. J.; Wiltshaw, Eve

    1974-01-01

    The blood lymphocytes from a case of prolymphocytic leukaemia were subjected to a battery of different tests in order to establish as certainly as possible their T or B cell type of origin. The results of the tests for surface markers indicated the T-cell origin of the leukaemic cells in this patient, and this provided a good opportunity to determine the participation of T cells in the various tests proposed for measuring human lymphocyte function. Images PMID:4613733

  10. Leukaemia clusters in childhood: geographical analysis in Britain.

    PubMed Central

    Knox, E G

    1994-01-01

    STUDY OBJECTIVE--To validate previously demonstrated spatial clustering of childhood leukaemias by showing relative proximities of selected map features to cluster locations, compared with control locations. If clusters are real, then they are likely to be close to a determining hazard. DESIGN--Cluster postcode loci and partially matched control postcodes were compared in terms of distances to railways, main roads, churches, surface water, woodland areas, and railside industrial installations. Further supporting comparisons between non-clustered cases and random postcode controls with those map features representable as single grid points were made. SETTING--England, Wales, and Scotland 1966-83. SUBJECTS--Grid referenced registrations of 9406 childhood leukaemias and non-Hodgkin's lymphomas, including 264 pairs (or more) separated by < 150 m, and grid references of random postcodes in equal numbers. MAIN RESULTS--The 264 clusters showed relative proximities (or the inverse) to several map features, of which the most powerful was an association with railways. The non-railway associations seemed to be statistically indirect. Some railside industrial installations, identified from a railway atlas, also showed relative proximities to leukaemia clusters, as well as to non-clustered cases, but did not "explain" the railway effect. These installations, with seemingly independent geographical associations, included oil refineries, petrochemical plants, oil storage and oil distribution depots, power stations, and steelworks. CONCLUSIONS--The previously shown childhood leukaemia clusters are confirmed to be non-random through their systematic associations with certain map features when compared with the control locations. The common patterns of close association of clustered and non-clustered cases imply a common aetiological component arising from a common environmental hazard--namely the use of fossil fuels, especially petroleum. PMID:7964336

  11. Cerebrospinal fluid involvement in acute promyelocytic leukaemia at presentation

    PubMed Central

    Mishra, Jyoti; Gupta, Mayank

    2015-01-01

    In acute promyelocytic leukaemia (APL), extramedullary disease (EMD) is rare but can occur in those who relapse following therapy. Although the most common site of EMD in APL is central nervous system (CNS) and skin, CNS involvement in recently diagnosed patients with APL is very rare and rarely described. We report cerebrospinal fluid involvement in a case of APL, on day 3 of induction therapy. PMID:25754165

  12. Radiation measurement platform for balloon flights based on the TriTel silicon detector telescope

    NASA Astrophysics Data System (ADS)

    Zabori, Balazs; Hirn, Attila; Pazmandi, Tamas; Apathy, Istvan; Szanto, Peter; Deme, Sandor

    Several measurements have been performed on the cosmic radiation field from the surface of the Earth up to the maximum altitudes of research airplanes. However the cosmic radiation field is not well known between 15 km and 30 km. Our experiment idea based on to study the radiation environment in the stratosphere. The main technical goals of our experiment were to test at first time the TriTel 3D silicon detector telescope system for future ISS missons and to develop a balloon technology platform for advanced cosmic radiation and dosimetric measurements. The main scientific goals were to give an assessment of the cosmic radiation field at the altitude of the BEXUS balloons, to use the TriTel system to determine dosimetric and radiation quantities during the ballon flight and to intercompare the TriTel and Pille results to provide a correction factor definition method for the Pille ISS measurements. To fulfil the scientific and technological objectives several different dosimeter systems were included in the experiment: an advanced version of the TriTel silicon detector telescope, Geiger-Müller counters, Pille passive thermoluminescent dosimeters and Solid State Nuclear Track Detectors. The experiment was built by students from Hungarian universities and flew on board the BEXUS stratospheric balloon in Northern Sweden (from ESRANGE Space Center). The float altitude was approximately 28.6 km and the total flight time was about 4 hours. The active instruments measured in real time and the ground team received the collected data continuously during the mission. The main technical goals were received since the operation of the TriTel experienced no failures and the experiment worked as it expected. This paper presents the scientific goals and results. From the TriTel measurements the deposited energy spectra, the Linear Energy Transfer spectra, the average quality factor of the cosmic radiation as well as the absorbed dose and the dose equivalent were determined for the

  13. Inotuzumab ozogamicin in the management of acute lymphoblastic leukaemia.

    PubMed

    Morley, N J; Marks, D I

    2016-01-01

    Whilst most adult patients with acute lymphoblastic leukaemia will go into remission with standard induction chemotherapy, many will relapse. Response rates to standard salvage chemotherapy regimens are low and the outlook on relapse is very poor and associated with significant morbidity and mortality hence the need for newer targeted approaches. Inotuzumab ozogamicin (previously known as CMC-544) is an antibody-drug conjugate and consists of a monoclonal anti-CD22 antibody bound to calicheamicin. The target, CD22, is widely expressed on acute lymphoblastic leukaemia cells making it a potential therapeutic target. The calicheamicin is delivered intracellularly and causes leukaemia cell apoptosis. Overall response rates of 57% were observed in a Phase II study and the final results of a Phase III randomised controlled trial comparing this drug to the investigator choice 'standard of care' chemotherapy are eagerly awaited. Whilst initial results are promising, there have been concerns regarding liver toxicity and the incidence of veno-occlusive disease of the liver especially in patients who have previously received or go on to allogeneic stem cell transplant.

  14. Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia.

    PubMed

    Oram, S H; Thoms, J; Sive, J I; Calero-Nieto, F J; Kinston, S J; Schütte, J; Knezevic, K; Lock, R B; Pimanda, J E; Göttgens, B

    2013-06-01

    LMO1 is a transcriptional regulator and a T-acute lymphoblastic leukaemia (T-ALL) oncogene. Although first identified in association with a chromosomal translocation in T-ALL, the ectopic expression of LMO1 occurs far more frequently in the absence of any known mutation involving its locus. Given that LMO1 is barely expressed in any haematopoietic lineage, and activation of transcriptional drivers in leukaemic cells is not well described, we investigated the regulation of this gene in normal haematopoietic and leukaemic cells. We show that LMO1 has two promoters that drive reporter gene expression in transgenic mice to neural tissues known to express endogenous LMO1. The LMO1 promoters display bivalent histone marks in multiple blood lineages including T-cells, and a 3' flanking region at LMO1 +57 contains a transcriptional enhancer that is active in developing blood cells in transgenic mouse embryos. The LMO1 promoters become activated in T-ALL together with the 3' enhancer, which is bound in primary T-ALL cells by SCL/TAL1 and GATA3. Taken together, our results show that LMO1 is poised for expression in normal progenitors, where activation of SCL/TAL1 together with a breakdown of epigenetic repression of LMO1 regulatory elements induces ectopic LMO1 expression that contributes to the development and maintenance of T-ALL.

  15. [The arrival of the "grand pox" at the hôtel-Dieu de Lyon].

    PubMed

    Chevallier, Jacques

    2008-01-01

    Founded in 542, the Hospital hôtel-Dieu in Lyons is considered as the oldest French Hospital. At the beginning it was a place to receive and assist the poor and pilgrims and in the middle of the XVth century it received infectious patients during some epidemic periods. As King Charles VIII came back from Naples his troops suffering from syphilis arrived in Lyons in October 1495 and were treated in the Hospital hôtel-Dieu so that it became the first French Hospital to treat syphilitic patients. On the 7th of July 1496, a request of the "Consulat" gave the first information mentioned about syphilitic soldiers in Lyons and the well-known French physician Symphorien Champier was the first to publish about syphilis. For three centuries the Hospital hôtel-Dieu tried to move away syphilitic patients and it succeeded in 1802 as the Hospital L'Antiquaille was built.

  16. Translocation (9;17) a novel translocation in acute myeloid leukaemia.

    PubMed

    Brown, S A; Czepulkowski, B; Ireland, R

    1996-01-01

    We report a case of AML, acute myeloid leukaemia, with a novel translocation involving the short arms of chromosomes 9 and 17. The acute myeloid leukaemia was morphologically classified as FAB subtype M2. A prolonged remission was induced with chemotherapy, followed by a relapse which was associated with the finding of the same translocation.

  17. Acute promyelocytic leukaemia with a PML-RARA insertional translocation and a chromosome 21 abnormality in XYY syndrome: case report.

    PubMed

    He, Yi; Li, Xudong; Wang, Dongning; Zhang, Erhong; Hu, Yuan; Wang, Wenwen; Huang, Renwei; Xiao, Ruozhi

    2014-12-01

    The concomitant presence of the XYY syndrome with haematological malignancies is rare. This report presents a case of acute promyelocytic leukaemia (APL) with the promyelocytic leukaemia-retinoic acid receptor alpha (PML-RARA) gene insertional translocation and a chromosome 21 abnormality in a 29-year-old XYY male patient. Karyotype analysis revealed an abnormal karyotype of 47,XYY [14]/46,XYY,-21[16]. Fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analysis showed the existence of a PML-RARA fusion gene. The patient was treated by all-trans retinoic acid (ATRA) and chemotherapy. Laboratory results revealed that the coagulopathy improved and the patient achieved complete remission, based on bone-marrow morphology. The patient then received sequential monthly therapy using arsenic trioxide, followed by ATRA, followed by chemotherapy; he has survived disease-free for 36 months. Our findings suggest that the additional chromosomal abnormalities involving the sex chromosomes and chromosome 21 did not affect the prognosis of APL, and that the sequential treatment strategy had a good clinical effect without being associated with severe side-effects.

  18. Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B-cell acute lymphoblastic leukaemia.

    PubMed

    Randhawa, Shubhchintan; Cho, Byung S; Ghosh, Dipanjan; Sivina, Mariela; Koehrer, Stefan; Müschen, Markus; Peled, Amnon; Davis, Richard E; Konopleva, Marina; Burger, Jan A

    2016-08-01

    B cell acute lymphoblastic leukaemia (B-ALL) cells express high levels of CXCR4 chemokine receptors for homing and retention within the marrow microenvironment. Bone marrow stromal cells (BMSC) secrete CXCL12, the ligand for CXCR4, and protect B-ALL cells from cytotoxic drugs. Therefore, the therapeutic use of CXCR4 antagonists has been proposed to disrupt cross talk between B-ALL cells and the protective stroma. Because CXCR4 antagonists can have activating agonistic function, we compared the genetic and pharmacological deletion of CXCR4 in B-ALL cells, using CRISPR-Cas9 gene editing and CXCR4 antagonists that are in clinical use (plerixafor, BKT140). Both genetic and pharmacological CXCR4 inhibition significantly reduced B-ALL cell migration to CXCL12 gradients and beneath BMSC, and restored drug sensitivity to dexamethasone, vincristine and cyclophosphamide. NOD/SCID/IL-2rγnull mice injected with CXCR4 gene-deleted B-ALL cells had significant delay in disease progression and superior survival when compared to control mice injected with CXCR4 wild-type B-ALL cells. These findings indicate that anti-leukaemia activity of CXCR4 antagonists is primarily due to CXCR4 inhibition, rather than agonistic activity, and corroborate that CXCR4 is an important target to overcome stroma-mediated drug resistance in B-ALL.

  19. The potential of clofarabine in MLL-rearranged infant acute lymphoblastic leukaemia.

    PubMed

    Stumpel, Dominique J P M; Schneider, Pauline; Pieters, Rob; Stam, Ronald W

    2015-09-01

    MLL-rearranged acute lymphoblastic leukaemia (ALL) in infants is the most difficult-to-treat type of childhood ALL, displaying a chemotherapy-resistant phenotype, and unique histone modifications, gene expression signatures and DNA methylation patterns. MLL-rearranged infant ALL responds remarkably well to nucleoside analogue drugs in vitro, such as cytarabine and cladribine, and to the demethylating agents decitabine and zebularine as measured by cytotoxicity assays. These observations led to the inclusion of cytarabine into the treatment regimens currently used for infants with ALL. However, survival chances for infants with MLL-rearranged ALL do still not exceed 30-40%. Here we explored the in vitro potential of the novel nucleoside analogue clofarabine for MLL-rearranged infant ALL. Therefore we used both cell line models as well as primary patient cells. Compared with other nucleoside analogues, clofarabine effectively targeted primary MLL-rearranged infant ALL cells at the lowest concentrations, with median LC50 values of ∼25 nM. Interestingly, clofarabine displayed synergistic cytotoxic effects in combination with cytarabine. Furthermore, at concentrations of 5-10nM clofarabine induced demethylation of the promoter region of the tumour suppressor gene FHIT (Fragile Histidine Triad), a gene typically hypermethylated in MLL-rearranged ALL. Demethylation of the FHIT promoter region was accompanied by subtle re-expression of this gene both at the mRNA and protein level. We conclude that clofarabine is an interesting candidate for further studies in MLL-rearranged ALL in infants.

  20. Congenital Acute Myeloid Leukaemia with Pseudo-Chediak-Higashi Like Granules: A Case Report

    PubMed Central

    Barman, Sandip; Sharma, Pooja; Sikka, Meera

    2016-01-01

    Congenital leukaemia is a very rare entity comprising 0.8% of all childhood leukaemias. Pseudo-Chediak-Higashi Anomaly (PCHA) in acute leukaemia is a rarely described entity. However, co-existence of congenital myeloid leukaemia with PCHA is a very rare entity and to the best of our knowledge has not been described in literature till date. A full term new-born presented on the 27th day of life with severe gastroenteritis. Complete blood counts and peripheral smear examination revealed leucocytosis with presence of 76% blast cells. Approximately 15% of these blast cells showed presence of pseudo-Chediak-Higashi like granules. The diagnosis of acute myeloid leukaemia was confirmed by flow cytometry. The case report is presented due to its rarity and to highlight the differential diagnosis and clinical implications of this entity. PMID:28050385

  1. Granulocytic sarcoma in a patient with chronic myeloid leukaemia in complete haematological, cytogenetic and molecular remission

    PubMed Central

    Kittai, Adam; Yu, Eun-Mi; Tabbara, Imad

    2014-01-01

    Granulocytic sarcoma, also known as myeloid sarcoma, is an extramedullary tumour composed of immature myeloid cells. Granulocytic sarcoma is typically found in patients with acute myeloid leukaemia, accelerated phase or blast crisis of chronic myeloid leukaemia, myelodysplastic syndrome, or as an isolated event without bone marrow involvement. We present a case of granulocytic sarcoma in a patient with chronic myeloid leukaemia in the setting of complete haematological, molecular and cytogenetic remission. Our patient was first treated with imatinib for chronic-phase chronic myeloid leukaemia. After maintaining remission for 42 months, he developed a granulocytic sarcoma in his spine. In this case report, we describe our case, along with the three other cases reported in the literature. In addition to being a rare diagnosis, this case demonstrates the importance of being vigilant in diagnosing the cause of back pain and atypical symptoms in patients with a history of leukaemia. PMID:25538217

  2. Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

    PubMed Central

    Hawkins, M. M.; Wilson, L. M.; Stovall, M. A.; Marsden, H. B.; Potok, M. H.; Kingston, J. E.; Chessells, J. M.

    1992-01-01

    OBJECTIVE--To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN--Cohort study and a case-control study. SETTING--Britain and population based National Register of Childhood Tumours. SUBJECTS--Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES--Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS--Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS--Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer. PMID:1581717

  3. Hsp90 picks PIKKs via R2TP and Tel2.

    PubMed

    Vaughan, Cara K

    2014-06-10

    Phosphatidylinositol-3 kinase-like kinases (PIKKs) are dependent on Hsp90 for their activation via the R2TP complex and Tel2. In this issue of Structure, Pal and colleagues present the molecular mechanism by which PIKKs are recruited to Hsp90.

  4. Diffusion of Web Supported Instruction in Higher Education--The Case of Tel-Aviv University

    ERIC Educational Resources Information Center

    Soffer, Tal; Nachmias, Rafi; Ram, Judith

    2010-01-01

    This paper describes a study that focused on long-term web-supported learning diffusion among lecturers at Tel Aviv University (TAU), from an organizational point of view. The theoretical models we used to examine this process are Rogers' model for "Diffusion of Innovation" (1995) and Bass's "Diffusion Model" (1969). The study…

  5. [History of the renovation of the hôtel-Dieu of Bourges].

    PubMed

    Gitton, Philippe

    2006-01-01

    From the 16th to the 20th century "hôtel-Dieu" was the main hospital in the Berry capital. In the 30's the mayor decided to renovate the building but in 1994 the construction of a new hospital--"Centre Hospitalier Jacques-Coeur"--freed the ancient building which became a historical centre for culture et tourism in the region.

  6. First photometric study of two southern eclipsing binaries IS Tel and DW Aps

    NASA Astrophysics Data System (ADS)

    Özer, S.; Sürgit, D.; Erdem, A.; Öztürk, O.

    2017-02-01

    The paper presents the first photometric analysis of two southern eclipsing binary stars, IS Tel and DW Aps. Their V light curves from the All Sky Automated Survey were modelled by using Wilson-Devinney method. The final models give these two Algol-like binary stars as having detached configurations. Absolute parameters of the components of the systems were also estimated.

  7. Absolute parameters of eclipsing binaries in Southern Hemisphere sky - II: QY Tel

    NASA Astrophysics Data System (ADS)

    Erdem, A.; Sürgit, D.; Engelbrecht, C. A.; van Heerden, H. P.; Manick, R.

    2016-11-01

    This paper presents the first analysis of spectroscopic and photometric observations of the neglected southern eclipsing binary star, QY Tel. Spectroscopic observations were carried out at the South African Astronomical Observatory in 2013. New radial velocity curves from this study and V light curves from the All Sky Automated Survey were solved simultaneously using modern light and radial velocity curve synthesis methods. The final model describes QY Tel as a detached binary star where both component stars fill at least half of their Roche limiting lobes. The masses and radii were found to be 1.32 (± 0.06) M⊙, 1.74 (± 0.15) R⊙ and 1.44 (± 0.09) M⊙, 2.70 (± 0.16) R⊙ for the primary and secondary components of the system, respectively. The distance to QY Tel was calculated as 365 (± 40) pc, taking into account interstellar extinction. The evolution case of QY Tel is also examined. Both components of the system are evolved main-sequence stars with an age of approximately 3.2 Gy, when compared to Geneva theoretical evolution models.

  8. CBFβ is critical for AML1-ETO and TEL-AML1 activity

    PubMed Central

    Roudaia, Liya; Cheney, Matthew D.; Manuylova, Ekaterina; Chen, Wei; Morrow, Michelle; Park, Sangho; Lee, Chung-Tsai; Kaur, Prabhjot; Williams, Owen

    2009-01-01

    AML1-ETO and TEL-AML1 are chimeric proteins resulting from the t(8;21)(q22;q22) in acute myeloid leukemia, and the t(12;21)(p13;q22) in pre-B-cell leukemia, respectively. The Runt domain of AML1 in both proteins mediates DNA binding and heterodimerization with the core binding factor β (CBFβ) subunit. To determine whether CBFβ is required for AML1-ETO and TEL-AML1 activity, we introduced amino acid substitutions into the Runt domain that disrupt heterodimerization with CBFβ but not DNA binding. We show that CBFβ contributes to AML1-ETO's inhibition of granulocyte differentiation, is essential for its ability to enhance the clonogenic potential of primary mouse bone marrow cells, and is indispensable for its cooperativity with the activated receptor tyrosine kinase TEL-PDGFβR in generating acute myeloid leukemia in mice. Similarly, CBFβ is essential for TEL-AML1's ability to promote self-renewal of B cell precursors in vitro. These studies validate the Runt domain/CBFβ interaction as a therapeutic target in core binding factor leukemias. PMID:19179469

  9. Renata Adler Memorial Research Center for Child Welfare and Protection, Tel-Aviv University

    ERIC Educational Resources Information Center

    Ronen, Tammie

    2011-01-01

    The Renata Adler Memorial Research Center for Child Welfare and Protection operates within the Bob Shapell School of Social Work at Tel-Aviv University in Israel. The main aims of this research center are to facilitate study and knowledge about the welfare of children experiencing abuse or neglect or children at risk and to link such knowledge to…

  10. A Delphi Study on Technology Enhanced Learning (TEL) Applied on Computer Science (CS) Skills

    ERIC Educational Resources Information Center

    Porta, Marcela; Mas-Machuca, Marta; Martinez-Costa, Carme; Maillet, Katherine

    2012-01-01

    Technology Enhanced Learning (TEL) is a new pedagogical domain aiming to study the usage of information and communication technologies to support teaching and learning. The following study investigated how this domain is used to increase technical skills in Computer Science (CS). A Delphi method was applied, using three-rounds of online survey…

  11. Prognosis of acute lymphoblastic leukaemia in Ibadan, Nigeria.

    PubMed

    Okpala, I E; Olatunji, P O; Okunade, M A; Ogunsanwo, B A; Jeje, O M; Shokunbi, W A; Essien, E M

    1990-12-01

    Patients with acute lymphoblastic leukaemia (ALL) seen in University College Hospital, Ibadan, Nigeria, still have low rates of complete remission and relatively short survival. Yet the overall prognosis was expected to have improved because the proportions of adults, males and people of low socio-economic class among the patients have decreased steadily over the past three decades. Possible causes of the persistent poor performance were sought for in 30 new ALL patients seen in the hospital over a period of 2 years and 9 months. Unfavourable prognostic factors, lack of standard cytotoxic drugs, inadequate supportive care and absence of modern facilities for therapy combined to make their disease outcome worse than expected.

  12. The Effects of Herbs and Fruits on Leukaemia

    PubMed Central

    Saedi, Tayebeh Azam; Md Noor, Sabariah; Ismail, Patimah; Othman, Fauziah

    2014-01-01

    In developing countries, herbal therapy is the first and basis form of treatment for most types of diseases. About 75–80% of the world's population prefers herbal therapy as a major treatment due to its better adequacy and satisfactoriness, which enhance human body's symmetry with minimal side effects. Fruits and plants have been presented from the past as promising tools in becoming a natural anticancer agents. Many of these plant extracts are currently used in cancer therapy and prevention. This review paper will particularly explore and emphasize on herbs and fruits used in the treatment of the leukaemia. PMID:25250054

  13. Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia.

    PubMed

    Edlin, R; Connock, M; Tubeuf, S; Round, J; Fry-Smith, A; Hyde, C; Greenheld, W

    2010-05-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of azacitidine (aza) compared with conventional care regimes (CCR) for higher risk patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML), based on the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The patient outcomes governing relative effectiveness and cost-effectiveness were defined as overall survival, time to progression (TTP) to AML, adverse events and health-related quality of life (HRQoL). The clinical evidence was derived from an open-label randomised controlled trial referred to as study AZA-001. It compared aza with CCR in 358 patients with higher risk MDS, CMML and AML 20-30% blasts. The outcomes reported in AZA-001 included overall survival, TTP to AML and adverse events. No HRQoL results were reported; however, outcomes likely to impact on HRQoL were provided. The results showed that: the median overall survival was 24.5 months on aza, compared with 15.0 months in the CCR group (p = 0.0001); the response rates were low (complete remission 17% aza versus 8% CCR); the median time to transformation to AML was greater in the aza group (17.8 versus 11.5 months; p < 0.0001); and of patients who were red blood cell (RBC) transfusion-dependent at baseline, 45% of those on aza became RBC transfusion-independent during the treatment period, compared with 11.8% in the CCR group (p < 0.0001). The ERG reran the submission's search strategies after some modifications incorporating minor improvements. The ERG analysed the submitted economic model (model 1) and identified a number of inconsistencies and errors within the model. The manufacturer submitted a revised model for analysis by the ERG. Using the issues identified in the earlier analysis, the ERG conducted

  14. Quantitative relationship between functionally active telomerase and major telomerase components (hTERT and hTR) in acute leukaemia cells.

    PubMed

    Ohyashiki, J H; Hisatomi, H; Nagao, K; Honda, S; Takaku, T; Zhang, Y; Sashida, G; Ohyashiki, K

    2005-05-23

    Functionally active telomerase is affected at various steps including transcriptional and post-transcriptional levels of major telomerase components (hTR and human telomerase reverse transcriptase (hTERT)). We therefore developed a rapid and sensitive method to quantify hTERT and its splicing variants as well as the hTR by a Taqman real-time reverse transcriptase-polymerase chain reaction to determine whether their altered expression may contribute to telomere attrition in vivo or not. Fresh leukaemia cells obtained from 38 consecutive patients were used in this study. The enzymatic level of telomerase activity measured by TRAP assay was generally associated with the copy numbers of full-length hTERT+alpha+beta mRNA (P=0.0024), but did not correlate with hTR expression (P=0.6753). In spite of high copy numbers of full-length hTERT mRNA, telomerase activity was low in some cases correlating with low copy numbers of hTR, raising the possibility that alteration of the hTR : hTERT ratio may affect functionally active telomerase activity in vivo. The spliced nonactive hTERT mRNA tends to be lower in patients with high telomerase activity, suggesting that this epiphenomenon may play some role in telomerase regulation. An understanding of the complexities of telomerase gene regulation in biologically heterogeneous leukaemia cells may offer new therapeutic approaches to the treatment of acute leukaemia.

  15. RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures

    PubMed Central

    2014-01-01

    Background Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL). Methods Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique. Results Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed. Conclusions Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T). PMID:24571676

  16. Traffic-related air pollution and risk for leukaemia of an adult population.

    PubMed

    Raaschou-Nielsen, Ole; Ketzel, Matthias; Harbo Poulsen, Aslak; Sørensen, Mette

    2016-03-01

    Air pollution causes lung cancer, but associations with other cancers have not been established. We investigated whether long-term exposure to traffic-related air pollution is associated with the risk of the general population for leukaemia. We identified 1,967 people in whom leukaemia was diagnosed in 1992-2010 from a nation-wide cancer registry and selected 3,381 control people at random, matched on sex and year of birth, from the entire Danish population. Residential addresses since 1971 were traced in a population registry, and outdoor concentrations of NOx and NO2 , as indicators of traffic-related air pollution, were calculated at each address in a dispersion model. We used conditional logistic regression to estimate the risk for leukaemia after adjustment for income, educational level, cohabitation status and co-morbidity. In linear analyses, we found odds ratios for acute myeloid leukaemia of 1.20 (95% confidence interval: 1.04-1.38) per 20 µg/m(3) increase in NOx and 1.31 (1.02-1.68) per 10 µg/m(3) increase in NO2 , calculated as time-weighted average exposure at all addresses since 1971. We found no association with chronic myeloid or lymphocytic leukaemia. This study indicates an association between long-term exposure to traffic-related air pollution and acute myeloid leukaemia in the general population, but not for other subtypes of leukaemia.

  17. Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations.

    PubMed

    Rehe, Klaus; Wilson, Kerrie; Bomken, Simon; Williamson, Daniel; Irving, Julie; den Boer, Monique L; Stanulla, Martin; Schrappe, Martin; Hall, Andrew G; Heidenreich, Olaf; Vormoor, Josef

    2013-01-01

    Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-'high-risk' sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34(high) and CD34(low) blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.

  18. Occupational exposure to electromagnetic fields and acute leukaemia: analysis of a case-control study

    PubMed Central

    Willett, E; McKinney, P; Fear, N; Cartwright, R; Roman, E

    2003-01-01

    Aims: To investigate whether the risk of acute leukaemia among adults is associated with occupational exposure to electromagnetic fields. Methods: Probable occupational exposure to electromagnetic fields at higher than typical residential levels was investigated among 764 patients diagnosed with acute leukaemia during 1991–96 and 1510 sex and age matched controls. A job exposure matrix was applied to the self reported employment histories to determine whether or not a subject was exposed to electromagnetic fields. Risks were assessed using conditional logistic regression for a matched analysis. Results: Study subjects considered probably ever exposed to electromagnetic fields at work were not at increased risk of acute leukaemia compared to those considered never exposed. Generally, no associations were observed on stratification by sex, leukaemia subtype, number of years since exposure stopped, or occupation; there was no evidence of a dose-response effect using increasing number of years exposed. However, relative to women considered never exposed, a significant excess of acute lymphoblastic leukaemia was observed among women probably exposed to electromagnetic fields at work that remained increased irrespective of time prior to diagnosis or job ever held. Conclusion: This large population based case-control study found little evidence to support an association between occupational exposure to electromagnetic fields and acute leukaemia. While an excess of acute lymphoblastic leukaemia among women was observed, it is unlikely that occupational exposure to electromagnetic fields was responsible, given that increased risks remained during periods when exposure above background levels was improbable. PMID:12883018

  19. Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR.

    PubMed

    Kerst, Gunter; Kreyenberg, Hermann; Roth, Carmen; Well, Catrin; Dietz, Klaus; Coustan-Smith, Elaine; Campana, Dario; Koscielniak, Ewa; Niemeyer, Charlotte; Schlegel, Paul G; Müller, Ingo; Niethammer, Dietrich; Bader, Peter

    2005-03-01

    Minimal (i.e. submicroscopic) residual disease (MRD) predicts outcome in childhood acute lymphoblastic leukaemia (ALL). To be used clinically, MRD assays must be reliable and accurate. Two well-established techniques, flow cytometry (FC) and polymerase chain reaction (PCR), can detect leukaemic cells with a sensitivity of 0.01% (10(-4)). We analysed diagnostic samples of 45 ALL-patients (37 B-lineage ALL, eight T-lineage ALL) by four-colour FC and real-time PCR. Leukaemia-associated immunophenotypes, at a sensitivity of MRD detection by FC at the 0.01% level, were identified in 41 cases (91%); antigen-receptor gene rearrangements suitable for MRD detection with a sensitivity of 0.01% or better by PCR were identified in 38 cases (84%). The combined use of FC and PCR allowed MRD monitoring in all 45 patients. In 105 follow-up samples, MRD estimates by both methods were highly concordant, with a deviation factor of <5 by Bland-Altman analysis. Importantly, the concordance between FC and PCR was also observed in regenerating bone marrow samples containing high proportions of CD19(+) cells, and in samples studied 24 h after collection. We conclude that both MRD assays yield generally concordant results. Their combined use should enable MRD monitoring in virtually all patients and prevent false-negative results due to clonal evolution or phenotypic shifts.

  20. Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia.

    PubMed

    Dail, Monique; Wong, Jason; Lawrence, Jessica; O'Connor, Daniel; Nakitandwe, Joy; Chen, Shann-Ching; Xu, Jin; Lee, Leslie B; Akagi, Keiko; Li, Qing; Aster, Jon C; Pear, Warren S; Downing, James R; Sampath, Deepak; Shannon, Kevin

    2014-09-25

    Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to γ-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.

  1. Current standard treatment of adult acute promyelocytic leukaemia.

    PubMed

    Lo-Coco, Francesco; Cicconi, Laura; Breccia, Massimo

    2016-03-01

    The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease.

  2. Tobacco and the risk of acute leukaemia in adults

    PubMed Central

    Kane, E V; Roman, E; Cartwright, R; Parker, J; Morgan, G

    1999-01-01

    Self-reported smoking histories were collected during face-to-face interviews with 807 patients with acute leukaemia and 1593 age- and sex-matched controls. Individuals who had smoked regularly at some time during their lives were more likely to develop acute leukaemia than those who had never smoked (odds ratio (OR) = 1.2, 95% confidence interval (CI) 1.0–1.4). The association was strongest for current smokers, defined here as smoking 2 years before diagnosis (OR = 1.4, 95% CI 1.1–1.7). With respect to the numbers of years smoked, risk estimates were raised in all groups except those who had smoked for fewer than 10 years. Similarly, the odds ratio decreased as the number of years ‘stopped smoking’ increased, falling to one amongst those who had given up smoking for more than 10 years. No significant linear trends were found, however, with either the numbers of years smoked or the numbers of years stopped smoking, and no significant differences were found between AML and ALL. © 1999 Cancer Research Campaign PMID:10584886

  3. The versatility of haematopoietic stem cells: implications for leukaemia.

    PubMed

    Brown, Geoffrey; Hughes, Philip J; Michell, Robert H; Ceredig, Rhodri

    2010-08-01

    To understand the origins, and disease progression, of leukaemia we first need a clear idea of how the progeny of haematopoietic stem/precursor cells normally choose their fates. For about 30 years, 'classical' models of blood cell development have envisaged a branching tree with two trunks representing the two major families of cells: myeloid/erythroid and lymphoid. Recent debate about this apparent dichotomy has given rise to new models of haematopoiesis and new ways of viewing stem-cell behaviour. These suggest that stem and progenitor cells are more versatile than was first appreciated, so there can be multiple routes to one type of end cell. An important aspect of this versatility during haematopoiesis is that progenitor cells retain an unexpected portfolio of clandestine lineage potentials even when they seem to have progressed quite far along a particular developmental pathway. Here we examine this decision-making process and ask whether, developmentally, leukaemia stem cells are equally or less versatile than their normal counterparts.

  4. Oral mucositis in children suffering from acute lymphoblastic leukaemia

    PubMed Central

    2012-01-01

    Aim of the study Oral mucositis is the most commonly reported side effect observed in neoplastic patients treated with chemotherapy and radiotherapy of the head and neck region as well as in patients who have received a haematopoietic stem cell transplant. The aim of the study was to assess the oral mucosa status in children with acute lymphoblastic leukaemia (ALL) during antineoplastic therapy. Material and methods The clinical examination included 78 children aged 2-18 with ALL. The clinical examination was conducted using the dental preset tray. The condition of the oral mucosa was determined using the WHO scale for oral mucositis. Results In the first period of antineoplastic therapy the pathological lesions of the oral mucosa of the mucositis type were observed among the examined patients. The lesions had various levels of intensity. Pain was found to be the primary symptom of oral mucositis. In this study the following were observed: local erythema of the oral mucosa in 35%, white pseudomembranous lesions in 18%, erosions in 40% and oral ulcerative lesions in 4% of patients who underwent the antineoplastic therapy. Oral mucositis was observed in 3.17% of children after 6 months of chemotherapy. Conclusion Local treatment of oral mucositis with polyantibiotic-antifungal mixture, supporting antifungal systemic treatment, and improving the overall peripheral blood conditions in children suffering from acute lymphoblastic leukaemia improve the condition of the oral mucosa. PMID:23788849

  5. Visual acuity loss and OCT changes as initial signs of leukaemia

    PubMed Central

    Ortiz, Jose M; Ruiz-Moreno, Jose M; Pozo-Martos, Paola; Montero, Javier A

    2010-01-01

    AIM To report two cases where decreased visual acuity was the first symptom of leukaemia and optical coherence tomography (OCT) allowed identification and localization of the retinal lesions. METHODS Retrospective, interventional, case reports. RESULTS One case of lymphoblastic acute leukaemia and chronic lymphoid leukaemia were diagnosed following decreased visual acuity. OCT showed macular serous detachment in the first case. The second case presented hypo fluorescent retinal infiltrates which appeared as hyper reflective lesions by OCT. Retinal changes disappeared and visual acuity was recovered following complete remission of the neoplasm. CONCLUSION OCT is a valuable, non invasive diagnostic tool permitting detection, localization and follow-up of ocular dissemination of neoplasms. PMID:22553573

  6. Impact of NOD2 polymorphisms on infectious complications following chemotherapy in patients with acute myeloid leukaemia.

    PubMed

    Yomade, Olaposi; Spies-Weisshart, Bärbel; Glaser, Anita; Schnetzke, Ulf; Hochhaus, Andreas; Scholl, Sebastian

    2013-08-01

    We sought to investigate the relationship between polymorphisms of the NOD2 gene and infectious complications following intensive induction chemotherapy in patients with acute myeloid leukaemia (AML). We hypothesised that single nucleotide polymorphisms (SNPs) of the NOD2 gene are associated with a higher rate of infections during the phase of severe neutropenia. In 131 AML patients receiving induction therapy, the presence of the three most frequent polymorphisms of NOD2 (Arg702Trp, Gly908Arg, Leu1007fsinsC) was analysed. SNP analyses by means of genomic PCR incorporating fluorescence-labelled probes with characteristic melting curves were performed using the LightCycler platform. Our data suggest a significantly lower probability of mucositis or enteritis in AML patients lacking any of the three evaluated NOD2 polymorphisms. Furthermore, bloodstream cultures of AML patients carrying either a missense or a frameshift mutation of NOD2 were significantly more frequently tested positive concerning Streptococcus spp. In contrast, the presence of NOD2 polymorphisms had no impact on such important infectious complications as systemic inflammatory response syndrome or sepsis, the rate of central venous catheter infections or the incidence of pneumonia including fungal infections. Our data represent one of the first reports investigating the impact of polymorphisms of the innate immune system on infectious complications in patients with neutropenia following chemotherapy. A correlation between NOD2 polymorphisms and infectious events in AML patients is demonstrated.

  7. Mitochondrial cytochrome c oxidase subunit II variations predict adverse prognosis in cytogenetically normal acute myeloid leukaemia.

    PubMed

    Silkjaer, Trine; Nyvold, Charlotte Guldborg; Juhl-Christensen, Caroline; Hokland, Peter; Nørgaard, Jan Maxwell

    2013-10-01

    Alterations in the two catalytic genes cytochrome c oxidase subunits I and II (COI and COII) have recently been suggested to have an adverse impact on prognosis in patients with acute myeloid leukaemia (AML). In order to explore this in further detail, we sequenced these two mitochondrial genes in diagnostic bone marrow or blood samples in 235 patients with AML. In 37 (16%) patients, a non-synonymous variation in either COI or COII could be demonstrated. No patients harboured both COI and COII non-synonymous variations. Twenty-four (10%) patients had non-synonymous variations in COI, whereas 13 (6%) patients had non-synonymous variations in COII. The COI and COII are essential subunits of cytochrome c oxidase that is the terminal enzyme in the oxidative phosphorylation complexes. In terms of disease course, we observed that in patients with a normal cytogenetic analysis at disease presentation (CN-AML) treated with curative intent, the presence of a non-synonymous variation in the COII was an adverse prognostic marker for both overall survival and disease-free survival (DFS) in both univariate (DFS; hazard ratio (HR) 4.4, P = 0.006) and multivariate analyses (DFS; HR 7.2, P = 0.001). This is the first demonstration of a mitochondrial aberration playing an adverse prognostic role in adult AML, and we argue that its role as a potentially novel adverse prognostic marker in the subset of CN-AML should be explored further.

  8. Microsatellite instability in patients with chronic B-cell lymphocytic leukaemia

    PubMed Central

    Niv, E; Bomstein, Y; Yuklea, M; Lishner, M

    2005-01-01

    The purpose of our study was to evaluate the microsatellite instability (MSI) at selected loci with known involvement in the oncogenesis of chronic B-cell lymphocytic leukaemia (B-CLL). DNA from B cells (tumour cells) and from T cells (normal controls) of 27 samples of 26 patients with previously untreated B-CLL was extracted. Microsatellite instability in six microsatellite markers was tested using GeneScan Analysis Software. The rate of replication errors positive phenotype (RER+) was determined (MSI in more than 30% of examined loci). RER+ was found in four out of 27 paients (14.8%). A larger proportion of patients with stage C B-CLL exhibited RER+ than those with stage A or B (P<0.05). A higher prevalence of RER+ was demonstrated in a subgroup of patients with additional malignancies (three out of eight patients) in comparison with patients with B-CLL alone (1/19) (P=0.031). In conclusion, our study demonstrated that MSI might have a more prominent role in pathogenesis of B-CLL than reported todate. This may result from a selection of microsatellite markers adjacent to chromosomal loci, which are involved in B-cell malignancies, and using GeneScan Analysis Software, which is most modern and precise method of microsatellite analysis. PMID:15812543

  9. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia

    PubMed Central

    Parker, H; Rose-Zerilli, M J J; Larrayoz, M; Clifford, R; Edelmann, J; Blakemore, S; Gibson, J; Wang, J; Ljungström, V; Wojdacz, T K; Chaplin, T; Roghanian, A; Davis, Z; Parker, A; Tausch, E; Ntoufa, S; Ramos, S; Robbe, P; Alsolami, R; Steele, A J; Packham, G; Rodríguez-Vicente, A E; Brown, L; McNicholl, F; Forconi, F; Pettitt, A; Hillmen, P; Dyer, M; Cragg, M S; Chelala, C; Oakes, C C; Rosenquist, R; Stamatopoulos, K; Stilgenbauer, S; Knight, S; Schuh, A; Oscier, D G; Strefford, J C

    2016-01-01

    Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease. PMID:27282254

  10. Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model.

    PubMed

    Fischer, Meike; Schwieger, Maike; Horn, Stefan; Niebuhr, Birte; Ford, Anthony; Roscher, Susanne; Bergholz, Ulla; Greaves, Mel; Löhler, Jürgen; Stocking, Carol

    2005-11-17

    The t(12;21) translocation, generating the TEL/AML1 fusion protein, is the most common genetic lesion in childhood cancer. Using a bone marrow transplantation model, we demonstrate that TEL/AML1 expression impinges on normal hematopoietic differentiation, leading to the in vivo accumulation and persistence of an early progenitor compartment with a Sca1(+)/Kit(hi)/CD11b(+) phenotype and an increased self-renewal capacity, as documented by replating assays in vitro. Differentiation of these cells is not blocked, but the frequency of mature blood cells arising from TEL/AML1-transduced progenitors is low. Impaired differentiation is prominently observed in the pro-B-cell compartment, resulting in an proportional increase in early progenitors in vivo, consistent with the t(12;21) ALL phenotype. Despite the accumulation of both multipotent and B-cell progenitors in vivo, no leukemia induction was observed during an observation period of over 1 year. These results are consistent with findings in twins with concordant ALL, showing that TEL/AML1 generates a preleukemic clone in utero that persists for several years in a clinically covert fashion. Furthermore, our studies showed that the pointed domain of TEL/AML1, which recruits transcriptional repressors and directs oligomerization with either TEL/AML1 or wild-type TEL, was essential for the observed differentiation impairment and could not be replaced with another oligomerization domain.

  11. Photoperiod influences growth and mll (mixed-lineage leukaemia) expression in Atlantic cod.

    PubMed

    Nagasawa, Kazue; Giannetto, Alessia; Fernandes, Jorge M O

    2012-01-01

    Photoperiod is associated to phenotypic plasticity of somatic growth in several teleost species. However, the molecular mechanisms underlying this phenomenon are currently unknown but it is likely that epigenetic regulation by methyltransferases is involved. The MLL (mixed-lineage leukaemia) family comprises histone methyltransferases that play a critical role in regulating gene expression during early development in mammals. So far, these genes have received scant attention in teleost fish. In the present study, the mean weight of Atlantic cod juveniles reared under continuous illumination was found to be 13% greater than those kept under natural photoperiod conditions for 120 days. We newly determined cDNA sequences of five mll (mll1, mll2, mll3a, mll4b and mll5) and two setd1 (setd1a and setd1ba) paralogues from Atlantic cod. Phylogenetic analysis revealed that the cod genes clustered within the appropriate mll clade and comparative mapping of mll paralogues showed that these genes lie within a region of conserved synteny among teleosts. All mll and setd1 genes were highly expressed in gonads and fast muscle of adult cod, albeit at different levels, and they were differentially regulated with photoperiod in muscle of juvenile fish. Following only one day of exposure to constant light, mll1, mll4b and setd1a were up to 57% lower in these fish compared to the natural photoperiod group. In addition, mRNA expression of myogenic regulatory factors (myog and myf-5) and pax7 in fast muscle was also affected by different photoperiod conditions. Notably, myog was significantly elevated in the continuous illumination group throughout the time course of the experiment. The absence of a day/night cycle is associated with a generalised decrease in mll expression concomitant with an increase in myog transcript levels in fast muscle of Atlantic cod, which may be involved in the observed epigenetic regulation of growth by photoperiod in this species.

  12. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.

    PubMed

    Li, Yilong; Schwab, Claire; Ryan, Sarra L; Papaemmanuil, Elli; Robinson, Hazel M; Jacobs, Patricia; Moorman, Anthony V; Dyer, Sara; Borrow, Julian; Griffiths, Mike; Heerema, Nyla A; Carroll, Andrew J; Talley, Polly; Bown, Nick; Telford, Nick; Ross, Fiona M; Gaunt, Lorraine; McNally, Richard J Q; Young, Bryan D; Sinclair, Paul; Rand, Vikki; Teixeira, Manuel R; Joseph, Olivia; Robinson, Ben; Maddison, Mark; Dastugue, Nicole; Vandenberghe, Peter; Haferlach, Claudia; Stephens, Philip J; Cheng, Jiqiu; Van Loo, Peter; Stratton, Michael R; Campbell, Peter J; Harrison, Christine J

    2014-04-03

    Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

  13. Childhood leukaemia and lymphoma: African experience supports a role for environmental factors in leukaemogenesis.

    PubMed

    Williams, Christopher Ko; Foroni, Letizia; Luzzatto, Lucio; Saliu, Idris; Levine, Arthur; Greaves, Mel F

    2014-01-01

    Major differences exist in the nature of leukaemia and lymphoma in low-income African children compared to those in the high-income countries. These include the absence of the peak incidence of acute lymphoblastic leukaemia (ALL) in under-five-year olds that characterizes the disease in high-income countries. Conversely, chloroma association with acute myelogenous leukaemia (CA-AML/AMML) and Burkitt's lymphoma (BL) are rare in the high-income countries. This report describes clinical and laboratory as well as epidemiological features of childhood leukaemia and lymphoma reported betwen 1982 and 1984 in the city of Ibadan, Nigeria. The observed pattern of distribution of childhood haematological malignancies in the city is more consistent with the observations of Ludwik Gross's experiments on environmental influences, such as malnutrition and infections, animal leukaemogenesis, and mirroring the consequences of the primordial pressures that have shaped human genetics and pathophysiology.

  14. Childhood leukaemia and lymphoma: African experience supports a role for environmental factors in leukaemogenesis

    PubMed Central

    Williams, Christopher KO; Foroni, Letizia; Luzzatto, Lucio; Saliu, Idris; Levine, Arthur; Greaves, Mel F

    2014-01-01

    Major differences exist in the nature of leukaemia and lymphoma in low-income African children compared to those in the high-income countries. These include the absence of the peak incidence of acute lymphoblastic leukaemia (ALL) in under-five-year olds that characterizes the disease in high-income countries. Conversely, chloroma association with acute myelogenous leukaemia (CA-AML/AMML) and Burkitt’s lymphoma (BL) are rare in the high-income countries. This report describes clinical and laboratory as well as epidemiological features of childhood leukaemia and lymphoma reported betwen 1982 and 1984 in the city of Ibadan, Nigeria. The observed pattern of distribution of childhood haematological malignancies in the city is more consistent with the observations of Ludwik Gross’s experiments on environmental influences, such as malnutrition and infections, animal leukaemogenesis, and mirroring the consequences of the primordial pressures that have shaped human genetics and pathophysiology. PMID:25435906

  15. Oral complications and dental care in children with acute lymphoblastic leukaemia.

    PubMed

    Valéra, Marie-Cécile; Noirrit-Esclassan, Emmanuelle; Pasquet, Marléne; Vaysse, Fréderic

    2015-08-01

    Acute leukaemia is the most common type of childhood cancer, the acute lymphoblastic type accounting for the majority of cases. Children affected by leukaemia receive various forms of treatments including chemotherapeutic agents and stem cell transplants. Leukaemia and its treatment can directly or indirectly affect oral health and further dental treatments. The oral complications include mucositis, opportunistic infections, gingival inflammation and bleeding, xerostomia and carious lesions. An additional consideration in children is the impact of the treatments on the developing dentition and on orofacial growth. The aim of this review is to describe the oral complications in children with acute lymphoblastic leukaemia and the methods of prevention and management before, during and after the cancer treatment.

  16. Birth weight in offspring and leukaemia risk in parents--a nation-wide register-based cohort study from Denmark.

    PubMed

    Marklund, Maria; Rostgaard, Klaus; Hjalgrim, Lisa; Schmiegelow, Kjeld; Hjalgrim, Henrik

    2013-02-01

    Spurred by previous observations we assessed the relationship between offspring birth weight and parental leukaemia risk in a register-based investigation including 2.4 million parents of 2 million Danish children. Regardless of analytical approach, offspring birth weight was not associated with parental risk of leukaemia overall or of leukaemia subtypes except for a twofold increased acute lymphatic leukaemia risk in fathers of high birth weight offspring and an increasing paternal risk of chronic myeloid leukaemia with increasing offspring birth weight. These may both be chance findings. Our investigation indicates that offspring birth weight is not strongly associated with parental leukaemia risk.

  17. Survey of Oral Health Awareness in Neuchâtel 9th Graders.

    PubMed

    Neuhaus, Klaus W; Müller, Magali E; Lussi, Adrian

    The oral health habits of pupils had not yet been analyzed for the canton of Neuchâtel. A questionnaire was provided to 9th grade high school pupils (final year) of the three schools located in the Neuchâtel area to asses both oral health knowledge and habits in this connection. The average age was 15.5±0.8 years, and 78.1% of the questionnaires were returned. The prophylaxis program was conducted for a total of 4.5 h during pupils’ entire time at school. The results showed that both knowledge and oral health habits could be improved. As a positive outcome, 99% of the pupils brush their teeth before going to bed. Comparisons with similar 10-year-old studies from other cantons (Bern, Vaud) showed major differences in knowledge, for example on the importance of fluoridation. Only 54% of the pupils in Neuchâtel knew that fluoride offers some protection against caries, in spite of the fact that 89% thought that brushing with fluoridated toothpaste protects against caries. Most of the pupils used a fluoridated toothpaste. Furthermore, we found that self-reported sugar consumption was correlated with caries experience, but brushing frequency was not. We recommend introducing a review course for pupils in their last school year, in order to practice interdental cleaning, redefine appropriate, tooth-friendly snacks, and emphasize the importance of regular dental check-ups.

  18. Nuclear power plants and childhood leukaemia: lessons from the past and future directions.

    PubMed

    Kuehni, C; Spycher, B D

    2014-01-01

    In the 1980s, leukaemia clusters were discovered around nuclear fuel reprocessing plants in Sellafield and Dounreay in the United Kingdom. This raised public concern about the risk of childhood leukaemia near nuclear power plants (NPPs). Since then, the topic has been well-studied, but methodological limitations make results difficult to interpret. Our review aims to: (1.) summarise current evidence on the relationship between NPPs and risk of childhood leukaemia, with a focus on the Swiss CANUPIS (Childhood cancer and nuclear power plants in Switzerland) study; (2.) discuss the limitations of previous research; and (3.) suggest directions for future research. There are various reasons that previous studies produced inconclusive results. These include: inadequate study designs and limited statistical power due to the low prevalence of exposure (living near a NPP) and outcome (leukaemia); lack of accurate exposure estimates; limited knowledge of the aetiology of childhood leukaemia, particularly of vulnerable time windows and latent periods; use of residential location at time of diagnosis only and lack of data on address histories; and inability to adjust for potential confounders. We conclude that risk of childhood leukaemia around NPPs should continue to be monitored and that study designs should be improved and standardised. Data should be pooled internationally to increase the statistical power. More research needs to be done on other putative risk factors for childhood cancer such as low-dose ionizing radiation, exposure to certain chemicals and exposure to infections. Studies should be designed to allow examining multiple exposures.

  19. Emerging therapies for patients with advanced chronic lymphocytic leukaemia.

    PubMed

    Delgado, Julio; Briones, Javier; Sierra, Jorge

    2009-09-01

    Chronic lymphocytic leukaemia is a common lymphoid malignancy with a variable clinical course. While some patients never require treatment or can be managed effectively with palliative chemotherapy, others experience early disease progression and death. The development of new prognostic markers has helped in the identification of patients with high risk disease, even among those diagnosed at early stage. Recent prospective trials have established chemo-immunotherapy combinations as the new standard of care for CLL patients requiring therapy. Unfortunately, patients whose tumour cells have certain genomic aberrations, such as a chromosome 17 deletion, have a disease that is frequently refractory to conventional therapy and should have their treatment tailored accordingly. Younger patients with high risk disease should be referred for allogeneic haematopoietic cell transplantation if they have an appropriate donor. For the remaining high risk patients, a number of new compounds are emerging, which could lead to further improvement in their outcome.

  20. Selecting initial treatment of acute myeloid leukaemia in older adults.

    PubMed

    Podoltsev, Nikolai A; Stahl, Maximilian; Zeidan, Amer M; Gore, Steven D

    2016-10-08

    More than half of the patients with acute myeloid leukaemia (AML) are older than 60years. The treatment outcomes in this group remain poor with a median overall survival of <1year. Selecting initial treatment for these patients involves an assessment of 'fitness' for induction chemotherapy. This is done based on patient and disease-related characteristics which help to estimate treatment-related mortality and chance of complete remission with induction chemotherapy. If the risk of treatment-related mortality is high and/or the likelihood of a patient achieving a complete remission is low, lower-intensity treatment (low-dose cytarabine, decitabine and azacitidine) should be discussed. As outcomes in both groups of patients remain poor, enrolment into clinical trials of novel agents with varying mechanisms of action should be considered for all older adults with AML. Novel agents in Phase III development include CPX-351, guadecitabine (SGI-110), quizartinib, crenolanib, sapacitabine, vosaroxin and volasertib.

  1. Chemotherapy of acute myeloid leukaemia in adults: Medical Research Council.

    PubMed Central

    1979-01-01

    Two hundred and fifty patients with acute myeloid leukaemia (AML) were randomized between 2 regimens of chemotherapy: TRAP and BARTS III. Overall, patients randomized to TRAP, which was the more intensive of the 2 regimens, fared slightly better (P = 0.06) than those on BARTS III. However, the improvement in survival associated with more intensive chemotherapy was substantial only for patients who had favourable prognostic features at presentation, such as a normal total leucocyte count, or absence of palpable liver, or, especially, age under 40. Indeed, for patients under 40, those allocated to the more intensive regimen (TRAP) lived considerably longer than those allocated to BARTS III (P less than 0.002) while for patients over 40 there was no material difference in survival between patients on the 2 protocols. It thus appears that intensive chemotherapy is likely to be more effective when favourable prognostic features are recorded. PMID:365212

  2. Primary malignant neoplasms associated with chronic lymphocytic leukaemia.

    PubMed Central

    Lishner, M.; Prokocimer, M.; Ron, E.; Shaklai, M.

    1987-01-01

    The relationship between chronic lymphocytic leukaemia (CLL) and primary malignant neoplasms was evaluated using data from the Hematology Division in Beilinson Medical Center and the Israel Cancer Registry. The study population consisted of 81 patients diagnosed between 1962 and 1984. A total of 16 patients were found to have 21 malignant neoplasms in addition to their CLL. Excluding patients with nonmelanoma skin tumours, a 1.7 increased risk (statistically not significant) for developing second malignant neoplasms in CLL patients was detected. The only tumour which occurred significantly more than expected subsequent to CLL diagnosis was brain cancer. The coexistence of multiple cancers in the same patient was diagnosed in four of the patients. The results of this study further support the hypothesis that patients with CLL are prone to develop second neoplasms. PMID:3684832

  3. Contributions of the TEL-patch Amino Acid Cluster on TPP1 to Telomeric DNA Synthesis by Human Telomerase

    PubMed Central

    Dalby, Andrew B.; Hofr, Ctirad; Cech, Thomas R.

    2015-01-01

    Telomere maintenance is a highly coordinated process, and its misregulation is linked to cancer as well as telomere-shortening syndromes. Recent studies have shown that the TEL-patch – a cluster of amino acids on the surface of the shelterin component TPP1 – is necessary for the recruitment of telomerase to the telomere in human cells. However, there has been only basic biochemical analysis of the role of TPP1 in the telomerase recruitment process. Here we develop an in vitro assay to quantitatively measure the contribution of the TEL-patch to telomerase recruitment – binding and extension of the first telomeric repeat. We also demonstrate that the TEL-patch contributes to the translocation step of the telomerase reaction. Finally, our quantitative observations indicate that the TEL-patch stabilizes the association between telomerase and telomeric DNA substrates, providing a molecular explanation for its contributions to telomerase recruitment and action. PMID:25623306

  4. Impact of the Functional CD5 Polymorphism A471V on the Response of Chronic Lymphocytic Leukaemia to Conventional Chemotherapy Regimens

    PubMed Central

    Delgado, Julio; Bielig, Torsten; Bonet, Lizette; Carnero-Montoro, Elena; Puente, Xose S.; Colomer, Dolors; Bosch, Elena; Campo, Elias; Lozano, Francisco

    2016-01-01

    Summary The CD5 lymphocyte receptor -a bona fide immunohistochemical marker of chronic lymphocytic leukaemia (CLL) cells- is a negative regulator of activation signals from the antigen-specific B-cell receptor (BCR). Given that signalling components of the BCR are important contributors to the variable clinical behaviour of CLL, the relevance of functional variants of CD5 on CLL prognosis was explored. The results show that germline-encoded CD5 variants influence the survival to conventional chemotherapies from CLL patients with unmutated IGVH genes. This result supports the notion that CD5 is not only a phenotypic marker but a relevant player in CLL cell biology. PMID:26991857

  5. Design and implementation of a visual and haptic simulator in a platform for a TEL system in percutaneuos orthopedic surgery.

    PubMed

    Luengo, Vanda; Larcher, Aurelie; Tonetti, Jérôme

    2011-01-01

    Within a research project whose aim is to promote the learning of percutaneous operation in orthopedic surgery we design a Technological Enhanced Learning (TEL) system. This project belongs to a multidisciplinary field including computer, orthopedic surgery, medical imaging, didactic and cognitive sciences. The article presents the design principles of TEL with a particular interest in the development of a simulator. This simulator allows a virtual exercise interacting with the learner in visual, temporal and haptic dimension.

  6. Prolonging microtubule dysruption enhances the immunogenicity of chronic lymphocytic leukaemia cells

    PubMed Central

    Shaha, S P; Tomic, J; Shi, Y; Pham, T; Mero, P; White, D; He, L; Baryza, J L; Wender, P A; Booth, J W; Spaner, D E

    2009-01-01

    Cytotoxic chemotherapies do not usually mediate the expression of an immunogenic gene programme in tumours, despite activating many of the signalling pathways employed by highly immunogenic cells. Concomitant use of agents that modulate and complement stress-signalling pathways activated by chemotherapeutic agents may then enhance the immunogenicity of cancer cells, increase their susceptibility to T cell-mediated controls and lead to higher clinical remission rates. Consistent with this hypothesis, the microtubule inhibitor, vincristine, caused chronic lymphocytic leukaemia (CLL) cells to die rapidly, without increasing their immunogenicity. Protein kinase C (PKC) agonists (such as bryostatin) delayed the death of vincristine-treated CLL cells and made them highly immunogenic, with increased stimulatory abilities in mixed lymphocyte responses, production of proinflammatory cytokines, expression of co-stimulatory molecules and activation of c-Jun N-terminal kinase (JNK), p38 and nuclear factor kappa B (NF-κB) signalling pathways. This phenotype was similar to the result of activating CLL cells through Toll-like receptors (TLRs), which communicate ‘danger’ signals from infectious pathogens. Use of PKC agonists and microtubule inhibitors to mimic TLR-signalling, and increase the immunogenicity of CLL cells, has implications for the design of chemo-immunotherapeutic strategies. PMID:19737143

  7. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    DOE PAGES

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; ...

    2016-02-24

    The cytidine analogues azacytidine and 5-aza-2’-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14 ± 5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents ismore » associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Lastly, our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.« less

  8. Detection of hemizygous deletions in genomic DNA from leukaemia specimens for the diagnosis of patients.

    PubMed

    Kees, Ursula R; Terry, Philippa A; Ford, Jette; Everett, Janet; Murch, Ashleigh; de Klerk, Nick; Baker, David L

    2005-02-01

    Hemizygous deletions in genomic DNA appear to play an important role in tumorigenesis. The loss or inactivation of tumour suppressor genes (TSGs) is of critical importance in most malignancies, and has been shown to affect response to therapy. Here, we report a quantitative real-time polymerase chain reaction (qPCR) designed to detect two TSGs at the CDKN2A locus, p16(INK4A) and p14(ARF) that allows the detection of hemizygous deletions. Testing by qPCR of 18 bone marrow specimens from paediatric acute lymphoblastic leukaemia (ALL) patients at diagnosis revealed nine to be GG, six to be GD and three to be DD for exon 2 of p14(ARF)/p16(INK4A), concordant with Southern blotting analysis. A panel of 13 ALL cell lines was investigated for deletions at the CDKN2A locus and one of the lines, typed as GD for all exons, was further assessed by fluorescence in situ hybridisation, confirming the qPCR findings. The expression levels of p16(INK4A) and p14(ARF) were measured in all cell lines and these quantitative reverse transcriptase PCR results also agreed with the typing by qPCR. The qPCR method described is suitable for detection of hemizygous loss in primary patient material and the accuracy of the method was verified by three independent techniques.

  9. Impact of genomic risk factors on survival after haematopoietic stem cell transplantation for patients with acute leukaemia.

    PubMed

    Pearce, K F; Balavarca, Y; Norden, J; Jackson, G; Holler, E; Dressel, R; Greinix, H; Toubert, A; Gluckman, E; Hromadnikova, I; Sedlacek, P; Wolff, D; Holtick, U; Bickeböller, H; Dickinson, A M

    2016-12-01

    The EBMT risk score is an established tool successfully used in the prognosis of survival post-HSCT and is applicable for a range of haematological disorders. One of its main advantages is that score generation involves summation of clinical parameters that are available pretransplant. However, the EBMT risk score is recognized as not being optimal. Previous analyses, involving patients with various diagnoses, have shown that non-HLA gene polymorphisms influence outcome after allogeneic HSCT. This study is novel as it focuses only on patients having acute leukaemia (N = 458) and attempts to demonstrate how non-HLA gene polymorphisms can be added to the EBMT risk score in a Cox regression model to improve prognostic ability for overall survival. The results of the study found that three genetic factors improved EBMT risk score. The presence of MAL (rs8177374) allele T in the patient, absence of glucocorticoid receptor haplotype (consisting of rs6198, rs33389 and rs33388) ACT in the patient and absence of heat-shock protein 70-hom (+2437) (rs2227956) allele C in the patient were associated with decreased survival time. When compared to the EBMT risk score, the scores combining EBMT risk score with the genetic factors had an improved correlation with clinical outcome and better separation of risk groups. A bootstrapping technique, involving repeated testing of a model using multiple validation sets, also revealed that the newly proposed model had improved predictive value when compared to the EBMT risk score alone. Results support the view that non-HLA polymorphisms could be useful for pretransplant clinical assessment and provide evidence that polymorphisms in the recipient genotype may influence incoming donor cells, suppressing the initiation of the graft versus leukaemia effect and reducing survival.

  10. A meta-analysis of leukaemia risk from protracted exposure to low-dose gamma radiation

    PubMed Central

    Schubauer-Berigan, M K

    2010-01-01

    Context More than 400 000 workers annually receive a measurable radiation dose and may be at increased risk of radiation-induced leukaemia. It is unclear whether leukaemia risk is elevated with protracted, low-dose exposure. Objective We conducted a meta-analysis examining the relationship between protracted low-dose ionising radiation exposure and leukaemia. Data sources Reviews by the National Academies and United Nations provided a summary of informative studies published before 2005. PubMed and Embase databases were searched for additional occupational and environmental studies published between 2005 and 2009. Study selection We selected 23 studies that: (1) examined the association between protracted exposures to ionising radiation and leukaemia excluding chronic lymphocytic subtype; (2) were a cohort or nested case–control design without major bias; (3) reported quantitative estimates of exposure; and (4) conducted exposure–response analyses using relative or excess RR per unit exposure. Methods Studies were further screened to reduce information overlap. Random effects models were developed to summarise between-study variance and obtain an aggregate estimate of the excess RR at 100 mGy. Publication bias was assessed by trim and fill and Rosenthal's file drawer methods. Results We found an ERR at 100 mGy of 0.19 (95% CI 0.07 to 0.32) by modelling results from 10 studies and adjusting for publication bias. Between-study variance was not evident (p=0.99). Conclusions Protracted exposure to low-dose gamma radiation is significantly associated with leukaemia. Our estimate agreed well with the leukaemia risk observed among exposed adults in the Life Span Study (LSS) of atomic bomb survivors, providing increased confidence in the current understanding of leukaemia risk from ionising radiation. However, unlike the estimates obtained from the LSS, our model provides a precise, quantitative summary of the direct estimates of excess risk from studies of

  11. Temporal trends in childhood leukaemia incidence following exposure to radioactive fallout from atmospheric nuclear weapons testing.

    PubMed

    Wakeford, Richard; Darby, Sarah C; Murphy, Michael F G

    2010-05-01

    Notably raised rates of childhood leukaemia incidence have been found near some nuclear installations, in particular Sellafield and Dounreay in the United Kingdom, but risk assessments have concluded that the radiation doses estimated to have been received by children or in utero as a result of operations at these installations are much too small to account for the reported increases in incidence. This has led to speculation that the risk of childhood leukaemia arising from internal exposure to radiation following the intake of radioactive material released from nuclear facilities has been substantially underestimated. The radionuclides discharged from many nuclear installations are similar to those released into the global environment by atmospheric nuclear weapons testing, which was at its height in the late-1950s and early-1960s. Measurements of anthropogenic radionuclides in members of the general public resident in the vicinity of Sellafield and Dounreay have found levels that do not differ greatly from those in persons living remote from nuclear installations that are due to ubiquitous exposure to the radioactive debris of nuclear weapons testing. Therefore, if the leukaemia risk to children resulting from deposition within the body of radioactive material discharged from nuclear facilities has been grossly underestimated, then a pronounced excess of childhood leukaemia would have been expected as a consequence of the short period of intense atmospheric weapons testing. We have examined childhood leukaemia incidence in 11 large-scale cancer registries in three continents for which data were available at least as early as 1962. We found no evidence of a wave of excess cases corresponding to the peak of radioactive fallout from atmospheric weapons testing. The absence of a discernible increase in the incidence of childhood leukaemia following the period of maximum exposure to the radioactive debris of this testing weighs heavily against the suggestion that

  12. Radioisotope x-ray fluorescence analysis of ancient pottery from Tel Kouzama site in Damascus, Syria.

    PubMed

    Bakraji, Elias Hanna; Romeié, Mouhammad; Issa, Haissam

    2006-01-01

    The radioisotope X-ray fluorescence method has been utilized in the analysis of thirty nine archaeological pottery fragment samples from Tel Kouzama site, Damascus city, Syria. The samples were irradiated by a 109Cd radioisotope source (-9 10(8) Bq) for 1000 s. 17 chemical elements were determined. These elemental concentrations have been processed using two multivariate statistical methods, cluster and factor analysis in order to determine similarities and correlation between the various samples. Factor analysis confirms that samples were correctly classified by cluster analysis. These two methods suggest that samples can be considered to be manufactured using four different sources of raw material.

  13. Myeloperoxidase deficient polymorphonuclear leucocytes in leukaemia and allied disorders.

    PubMed

    Bendix-Hansen, K

    1988-12-01

    This thesis is a survey of nine previously published articles on MPO deficient PMN. The incidences in leukaemia and allied disorders of the presence of this abnormal subpopulation of mature neutrophils and the relationship to clinical course in AML, susceptibility to infections in AML, FAB classification in AML and MDS, cytogenetically defined aberrations in MDS and morphometrical characteristics were investigated. The aims of the studies were to examine the diagnostic as well as the prognostic value of the parameter, to examine the usefulness of the parameter as an predictive indicator of CR and relapse in AML and to examine the concept that MPO deficient PMN may originate from leukaemic precursors. MPO deficient PMN were found to occur in a minor number (less than 4% of the total number of PMN) in normal humans and the incidences of an abnormal number (greater than 4%) were found to be about 40% in AML (I, II, III, IV, VIII), 60% in CML (I, VII), 30% in MPD other than CML (VII) and 30% in MDS (V). The highest incidences in AML were found in the FAB subtypes possessing the most myeloid differentiation potential i.e. FAB M2 and FAB M4 (IV). In ALL, CLL, HCL, Hodgkin's disease, anaemia not related to leukaemia and leukaemoid reactions the incidences all were 0% (I, unpublished data). The abnormal MPO deficient PMN subpopulation, if present, disappeared when CR was achieved and reappeared when relapse eventually was developed (II, VIII). In both situations serial determinations showed that the change occurred before the usual routine blood examinations predicted CR and relapse; several days and several months prior, respectively (VIII). The probability of obtaining CR was lower in the AML patients with the abnormal subpopulation and the risk of developing relapse higher than in AML patients without the anomaly (II, VIII). These differences were not statistically significant, however. AML patients, showing an increased number of MPO deficient PMN, revealed a

  14. Circulating tight junction proteins mirror blood-brain barrier integrity in leukaemia central nervous system metastasis.

    PubMed

    Zhu, Jing-Cheng; Si, Meng-Ya; Li, Ya-Zhen; Chen, Huan-Zhu; Fan, Zhi-Cheng; Xie, Qing-Dong; Jiao, Xiao-Yang

    2016-03-21

    The aim of this study was to evaluate the clinical significance of circulating tight junction (TJ) proteins as biomarkers reflecting of leukaemia central nervous system (CNS) metastasis. TJs [claudin5 (CLDN5), occludin (OCLN) and ZO-1] concentrations were measured in serum and cerebrospinal fluid (CSF) samples obtained from 45 leukaemia patients. Serum ZO-1 was significantly higher (p < 0.05), but CSF ZO-1 levels were not significantly higher in the CNS leukaemia (CNSL) compared to the non-CNSL. The CNSL patients also had a lower CLDN5/ZO1 ratio in both serum and CSF than in non-CNSL patients (p < 0.05). The TJ index was negatively associated with WBCCSF , ALBCSF and BBB values in leukaemia patients. Among all of the parameters studied, CLDN5CSF had the highest specificity in discriminating between CNSL and non-CNSL patients. Therefore, analysing serum and CSF levels of CLDN5, OCLN and the CLDN5/ZO1 ratio is valuable in evaluating the potential of leukaemia CNS metastasis. Copyright © 2016 John Wiley & Sons, Ltd.

  15. The relation of immune response to pathogenesis, vaccination and epidemiology in virus induced leukaemia.

    PubMed

    Jarrett, W F

    1975-03-01

    The antigenic systems of oncornaviruses and particularly feline leukaemia virus (FeLV) are reviewed briefly. The use of immunological methods in studying the epidemiology of the disease is described. The incidence of FeLV infection as judged by a serological survey is at least 100 times greater than that of leukaemia in the cat population. Horizontal transmission, due to virus replication in respiratory and alimentary epithelial cells, is common. A method of producing high titres of antibody against membrane antigens of virus infected cells is described; the use of such vaccination is discussed in relation to several epidemiological facets of feline leukaemia virus infection. Leukaemia viruses are well known to cause immunodepression to heterologous antigens. The hypothesis is advanced that depression of the humoral antibody response to leukaemia virus antigens and cell membrane antigens may be an early event allowing establishment and replication of virus in haemic and the lymphatic tissues. Subsequent depression of cell mediated immunity through direct action of thymic cells is known to take place in the cat system. This may allow further spread of the virus with replication in epithelial cells which are not susceptible to cytotoxic action. Thus the primary events leading to leukaemogenesis may be an interplay between immunostimulation and immunodepression.

  16. The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia.

    PubMed

    Emerenciano, Mariana; Meyer, Claus; Mansur, Marcela B; Marschalek, Rolf; Pombo-de-Oliveira, Maria S

    2013-04-01

    Acute leukaemia in early childhood - and mainly infant leukaemia (IL) - is characterized by acquired genetic alterations, most commonly by the presence of distinct MLL rearrangements (MLL-r). The aim of this study was to investigate possible correlations between clinical features and molecular analyses of a series of 545 childhood leukaemia (≤24 months of age) cases: 385 acute lymphoblastic leukaemia (ALL) and 160 acute myeloid leukaemia (AML). The location of the genomic breakpoints was determined in a subset of 30 MLL-r cases. The overall survival of the investigated cohort was 60·5%, as determined by the Kaplan-Meier method. Worse outcomes were associated with age at diagnosis ≤6 months (P < 0·001), high white blood cell count (P = 0·001), and MLL-r (P = 0·002) in ALL, while children with AML displayed a poorer outcome (P = 0·009) regardless of their age strata. Moreover, we present first evidence that MLL-r patients with poor outcome preferentially displayed chromosomal breakpoints within MLL intron 11. Based on the literature, most MLL-r IL display a breakpoint localization towards intron 11, which in turn may explain their worse clinical course. In summary, the MLL breakpoint localization is of clinical importance and should be considered as a novel outcome predictor for MLL-r patients.

  17. The role of multiparametric flow cytometry in the detection of minimal residual disease in acute leukaemia.

    PubMed

    Lee, Denise; Grigoriadis, George; Westerman, David

    2015-12-01

    Flow cytometry is the most accessible method for minimal residual disease (MRD) detection due to its availability in most haematological centres. Using a precise combination of different antibodies, immunophenotypic detection of MRD in acute leukaemia can be performed by identifying abnormal combinations or expressions of antigens on malignant cells at diagnosis, during and post treatment. These abnormal phenotypes, referred to as leukaemia-associated immunophenotypes (LAIPs) are either absent or expressed at low frequency in normal bone marrow (BM) cells and are used to monitor the behaviour and quantitate the amount of residual disease following treatment. In paediatric acute lymphoblastic leukaemia (ALL), the level of MRD by multiparametric flow cytometry (MPFC) during therapy is recognised as an important predictor of outcome. Although less extensively studied, adult ALL and adult and paediatric acute myeloid leukaemia (AML) have also demonstrated similar findings. The challenge now is incorporating this information for risk-stratification so that therapy can be tailored individually and ultimately improve outcome while also limiting treatment-related toxicity. In this review we will elaborate on the current and future role of MPFC in MRD in acute leukaemia while also addressing its limitations.

  18. Living with cancer: a qualitative report of the experiences of leukaemia patients in Lagos, Nigeria.

    PubMed

    Adejoh, Samuel Ojima; Temilola, Olusegun Moses; Olayiwola, Bolutife

    2013-12-01

    The study examined the qualitative, cognitive and psychosocial experiences of those living with leukaemia undergoing treatment at a teaching hospital. Twenty respondents who consented to participate were purposively selected from the cancer patients with leukaemia receiving treatment in the said teaching hospital. The in-depth interview method was used to collect data. The data was analysed using manual content analysis. Data showed that patients lack basic knowledge about leukaemia and had no beliefs regarding leukaemia. Some patients believed in God and a medical breakthrough for a cure, while for some, the hope of living was not certain. The ill-health condition had brought about financial predicament to both patients and family members and has limited their productivity in terms of income-generating activities. Good interpersonal relationships and support from their care providers aided their compliance to treatment regime and provided hope for living positively with their condition. The study concludes that there is a need to educate the patients on the causes of their condition. Financial supports should be rendered to those living with leukaemia, while health care providers should be encouraged to continue to maintain good interpersonal relationships with their patients.

  19. Acute disseminated encephalomyelitis mimicking late CNS relapse of acute lymphoblastic leukaemia: case report

    PubMed Central

    Kumar, Ram; Nijalingappa, Shobha; Grainger, John; Ismayl, Omar

    2007-01-01

    Background Acute encephalomyelopathy occurring after an allogeneic bone marrow transplant for leukaemia is a diagnostic emergency. The diagnosis can be challenging since there is a wide set of alternative diagnoses, including opportunistic infections and relapse of the leukaemia. Case presentation A 13-year old girl presented with a severe acute myelopathy and encephalopathy. She was in prolonged remission from a central nervous system and bone marrow relapse of an acute lymphoblastic leukaemia, treated with allogeneic bone marrow transplantation. Neuroimaging showed multifocal grey and white matter lesions of demyelinating appearance in the brain and entire spine. Immunophenotyping and cytogenetic investigations of the girl's cerebrospinal fluid lymphocytosis excluded a late central nervous system relapse of her leukaemia. The diagnosis was acute disseminated encephalomyelitis. With standard immunosuppressive therapy, the girl had early cerebral recovery but a prolonged period of recovery from her myelopathy. Conclusion Acute disseminated encephalomyelitis should be considered in the differential diagnosis of acute encephalomyelopathy after bone marrow transplantation for leukaemia. Demyelinating syndromes such as acute disseminated encephalomyelitis may be late sequelae of bone marrow transplantation. PMID:17411447

  20. Living with the Diagnosis and Treatment of Leukaemia in a Child with Down's Syndrome: A Mother's Reflection

    ERIC Educational Resources Information Center

    Self, Donna

    2008-01-01

    In this article I will discuss the impact of my 2-year-old son's diagnosis and treatment of leukaemia. I will outline the background to being told he had leukaemia before describing the family dynamics that emerged during this time for me, my husband and our other child. My story will focus on managing the practicalities of a long stay in hospital…

  1. Frequency of acute myeloid leukaemia-associated mouse chromosome 2 deletions in X-ray exposed immature haematopoietic progenitors and stem cells☆

    PubMed Central

    Olme, C.-H.; Brown, N.; Finnon, R.; Bouffler, S.D.; Badie, C.

    2013-01-01

    Exposure to ionising radiation can lead to an increased risk of cancer, particularly leukaemia. In radiation-induced acute myeloid leukaemia (rAML), a partial hemizygous deletion of mouse chromosome 2 is a common feature in several susceptible strains. The deletion is an early event detectable 24 h after exposure in bone marrow cells using cytogenetic techniques. Expanding clones of bone marrow cells with chromosome 2 deletions can be detected less than a year after exposure to ionising radiation in around half of the irradiated mice. Ultimately, 15–25% of exposed animals develop AML. It is generally assumed that leukaemia originates in an early progenitor cell or haematopoietic stem cell, but it is unknown whether the original chromosome damage occurs at a similar frequency in committed progenitors and stem cells. In this study, we monitored the frequency of chromosome 2 deletions in immature bone marrow cells (Lin−) and haematopoietic stem cells/multipotent progenitor cells (LSK) by several techniques, fluorescent in situ hybridisation (FISH) and through use of a reporter gene model, flow cytometry and colony forming units in spleen (CFU-S) following ex vivo or in vivo exposure. We showed that partial chromosome 2 deletions are present in the LSK subpopulation, but cannot be detected in Lin− cells and CFU-S12 cells. Furthermore, we transplanted irradiated Lin− or LSK cells into host animals to determine whether specific irradiated cell populations acquire an increased proliferative advantage compared to unirradiated cells. Interestingly, the irradiated LSK subpopulation containing cells carrying chromosome 2 deletions does not appear to repopulate as well as the unirradiated population, suggesting that the chromosomal deletion does not provide an advantage for growth and in vivo repopulation, at least at early stages following occurrence. PMID:23665297

  2. Silver nanoparticles exhibit size-dependent differential toxicity and induce expression of syncytin-1 in FA-AML1 and MOLT-4 leukaemia cell lines.

    PubMed

    Alqahtani, Sultan; Promtong, Pawika; Oliver, Anthony W; He, Xiaotong T; Walker, Thomas D; Povey, Andrew; Hampson, Lynne; Hampson, Ian N

    2016-11-01

    Human endogenous retrovirus (HERV) sequences make up ~8% of the human genome and increased expression of some HERV proteins has been observed in various pathologies including leukaemia and multiple sclerosis. However, little is known about the function of these HERV proteins or environmental factors which regulate their expression. Silver nanoparticles (AgNPs) are used very extensively as antimicrobials and antivirals in numerous consumer products although their effect on the expression of HERV gene products is unknown. Cell proliferation and cell toxicity assays were carried out on human acute T lymphoblastic leukaemia (MOLT-4) and Fanconi anaemia associated acute myeloid leukaemia (FA-AML1) cells treated with two different sizes of AgNPs (7nm and 50nm diameter). Reverse-transcriptase polymerase chain reaction and western blotting were then used to the assess expression of HERV-W syncytin-1 mRNA and protein in these cells. FA-AML1 cells were more sensitive overall than MOLT-4 to treatment with the smaller 7nm sized AgNp's being the most toxic in these cells. MOLT-4 cell were more resistant and showed no evidence of differential toxicity to the different sized particles. Syncytin-1 mRNA and protein were induced by both 7 and 50nm AgNPs in both cell types yet with different kinetics. In summary, the observation that AgNPs induce expression of syncytin-1 in FA-AML1 and MOLT-4 cells at doses as little as 5 µg/ml is grounds for concern since this protein is up-regulated in both malignant and neurodegenerative diseases. Considering the widespread use of AgNPs in the environment it is clear that their ability to induce syncytin-1 should be investigated further in other cell types.

  3. Hairy cell leukaemia and occupational exposure to benzene.

    PubMed Central

    Clavel, J; Conso, F; Limasset, J C; Mandereau, L; Roche, P; Flandrin, G; Hémon, D

    1996-01-01

    OBJECTIVES: The role of occupational exposures in hairy cell leukaemia (HCL) was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to benzene in HCL. METHODS: A population of 226 male cases of HCL and 425 matched controls were included in the study. Benzene exposure was evaluated by expert review of the detailed data on occupational exposures generated by case-control interviews. RESULTS: No association was found between HCL and employment in a job exposed to benzene (odds ratio (OR) 0.9 (95% confidence interval (95% CI) 0.6-1.3)). The sample included 125 subjects, 34 cases (15%), and 91 controls (21%) who had been exposed to benzene, as individually assessed by the experts, for at least one hour a month during one of their jobs. Benzene exposure was not associated with a risk of HCL (OR 0.8 (0.5-1.2)). No trend towards an increase in OR was detected for increasing exposures, the percentage of work time involving exposure to > 1 ppm, or the duration of exposure. No findings suggested a particular risk period, when the OR associated with the time since first or last exposure, or since the end of exposure, were examined. CONCLUSIONS: In conclusion, with the low exposures prevalent in the sample, the study did not show any association between benzene exposure and HCL. PMID:8983464

  4. Prevalence of feline leukaemia provirus DNA in feline lymphomas.

    PubMed

    Weiss, Alexander Th A; Klopfleisch, Robert; Gruber, Achim D

    2010-12-01

    A significant drop in the prevalence of feline leukaemia virus (FeLV) antigenaemic cats and antigen-associated lymphomas has been observed after the introduction of FeLV vaccination and antigen-testing with removal of persistently antigenaemic cats. However, recent reports have indicated that regressively infected cats may contain FeLV provirus DNA and that lymphoma development may be associated with the presence of provirus alone. In the present study, we investigated the presence of FeLV antigen and provirus DNA in 50 lymphomas by immunohistochemistry and semi-nested polymerase chain reaction, respectively. Interestingly, almost 80% of T-cell lymphomas and 60% of B-cell lymphomas contained provirus DNA while only 21% of T-cell lymphomas and 11% of B-cell lymphomas expressed FeLV antigen. In conclusion, our results support previous hypotheses that vaccination and removal of persistently antigenaemic cats have led to a drop in FeLV antigen-expressing lymphomas. However, FeLV provirus DNA is still present in a high percentage of feline lymphomas.

  5. Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia.

    PubMed

    Jackson, Rosanna K; Irving, Julie A E; Veal, Gareth J

    2016-04-01

    Dexamethasone is a key component in the treatment of childhood acute lymphoblastic leukaemia (ALL). Despite playing a key role in the improved survival of ALL over several decades, intensification of dexamethasone therapy has also contributed to the increased toxicity associated with treatment, which is now seen to be at unacceptable levels given the favourable disease prognosis. Therefore the focus for treatment is now shifting towards reducing toxicity whilst maintaining current survival rates. As approximately 50% of patients were successfully treated on less intensive protocols of the 1980s, it has been questioned whether therapy intensification is necessary in all patients. Furthermore, there remains a subset of children who are still not cured of their disease. New strategies are therefore needed to identify patients who could benefit from dose reduction or intensification. However, adjusting a potentially life threatening therapy is a challenging task, particularly given the heterogeneous nature of ALL. This review focuses on the potential for patient stratification based on our current knowledge of dexamethasone pharmacokinetics, pharmacogenetics and the action of dexamethasone at the cellular level. A carefully designed, combined approach is needed if we are to achieve the aim of improved personalization of dexamethasone therapy for future patients.

  6. Longitudinal language outcomes following intrathecal chemotherapy for acute lymphoblastic leukaemia.

    PubMed

    Lewis, Fiona M; Perry, Meghan L; Murdoch, Bruce E

    2013-04-01

    Intrathecal chemotherapy (ITC) is the treatment option for acute lymphoblastic leukaemia (ALL). Neurocognitive deficits have been described following ITC, but language status post-treatment is yet to be clarified. This study examined the language skills of nine children following ITC for ALL (mean age 7;8 years and 3;2 years post-diagnosis at baseline measurement) and nine age- and sex-matched controls, at baseline then 2 years later, using a battery of tests assessing general language skills. An assessment of cognitively-demanding high level language skills was undertaken on a sub-group of the children (n =12). Statistical analysis revealed no significant difference between children treated with ITC and controls when comparing change in performance scores from baseline measurement to 2 years post-baseline measurement. Descriptive analysis of three of the ALL participants in the Intermediate Stage survivorship at language re-assessment indicated no clinically-significant change in performance over 2 years for all measures except receptive language skills, which improved over the time for two of the children. As language skills continue to develop into late adolescence, the need for the monitoring of language abilities of children treated at a young age with ITC as they enter the Intermediate and Late Stages of survivorship is discussed.

  7. Non-coding recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Beà, Silvia; Valdés-Mas, Rafael; Villamor, Neus; Gutiérrez-Abril, Jesús; Martín-Subero, José I; Munar, Marta; Rubio-Pérez, Carlota; Jares, Pedro; Aymerich, Marta; Baumann, Tycho; Beekman, Renée; Belver, Laura; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier; Ferrando, Adolfo A; Gelpí, Josep L; González, Blanca; González, Santiago; González, Marcos; Gut, Marta; Hernández-Rivas, Jesús M; López-Guerra, Mónica; Martín-García, David; Navarro, Alba; Nicolás, Pilar; Orozco, Modesto; Payer, Ángel R; Pinyol, Magda; Pisano, David G; Puente, Diana A; Queirós, Ana C; Quesada, Víctor; Romeo-Casabona, Carlos M; Royo, Cristina; Royo, Romina; Rozman, María; Russiñol, Nuria; Salaverría, Itziar; Stamatopoulos, Kostas; Stunnenberg, Hendrik G; Tamborero, David; Terol, María J; Valencia, Alfonso; López-Bigas, Nuria; Torrents, David; Gut, Ivo; López-Guillermo, Armando; López-Otín, Carlos; Campo, Elías

    2015-10-22

    Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

  8. Predicting relapse risk in childhood acute lymphoblastic leukaemia.

    PubMed

    Teachey, David T; Hunger, Stephen P

    2013-09-01

    Intensive multi-agent chemotherapy regimens and the introduction of risk-stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia (ALL). Current risk allocation schemas are imperfect, as some children are classified as lower-risk and treated with less intensive therapy relapse, while others deemed higher-risk are probably over-treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease (MRD). Other than age and white blood cell count (WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk-stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response-based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk-stratify therapy.

  9. Acute myeloid leukaemia: optimal management and recent developments.

    PubMed

    Villela, Luis; Bolaños-Meade, Javier

    2011-08-20

    The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30-40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients' outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used '7+3' regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients.

  10. Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia.

    PubMed

    Gaynon, Paul S; Sun, Weili

    2016-06-01

    New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post-remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure.

  11. Telomere elongation (Tel), a new mutation in Drosophila melanogaster that produces long telomeres.

    PubMed Central

    Siriaco, Giorgia M; Cenci, Giovanni; Haoudi, Abdelali; Champion, Larry E; Zhou, Chun; Gatti, Maurizio; Mason, James M

    2002-01-01

    In most eukaryotes telomeres are extended by telomerase. Drosophila melanogaster, however, lacks telomerase, and telomere-specific non-LTR retrotransposons, HeT-A and TART, transpose specifically to chromosome ends. A Drosophila strain, Gaiano, that has long telomeres has been identified. We extracted the major Gaiano chromosomes into an Oregon-R genetic background and examined the resulting stocks after 60 generations. In situ hybridization using HeT-A and TART sequences showed that, in stocks carrying either the X or the second chromosome from Gaiano, only the Gaiano-derived chromosomes display long telomeres. However, in stocks carrying the Gaiano third chromosome, all telomeres are substantially elongated, indicating that the Gaiano chromosome 3 carries a factor that increases HeT-A and TART addition to the telomeres. We show that this factor, termed Telomere elongation (Tel), is dominant and localizes as a single unit to 69 on the genetic map. The long telomeres tend to associate with each other in both polytene and mitotic cells. These associations depend on telomere length rather than the presence of Tel. Associations between metaphase chromosomes are resolved during anaphase, suggesting that they are mediated by either proteinaceous links or DNA hydrogen bonding, rather than covalent DNA-DNA bonds. PMID:11805059

  12. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity

    PubMed Central

    Nandakumar, Jayakrishnan; Bell, Caitlin F.; Weidenfeld, Ina; Zaug, Arthur J.; Leinwand, Leslie A.; Cech, Thomas R.

    2012-01-01

    Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase1–3. Shelterin includes the heterodimeric POT1-TPP1 protein, which binds the telomeric single-stranded DNA tail4–9. TPP1 has been implicated both in recruiting telomerase to telomeres and in stimulating telomerase processivity (the addition of multiple DNA repeats after a single primer-binding event)9–14. Determining the mechanisms of these activities has been difficult, especially because genetic perturbations also tend to affect the essential chromosome end-protection function of TPP115–17. Here we identify separation-of-function mutants of TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding telomerase. The seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these two activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a new target for anti-cancer drug development. PMID:23103865

  13. Thermoelectric-Driven Liquid-Metal Plasma-Facing Structures (TELS)

    NASA Astrophysics Data System (ADS)

    Andruczyk, Daniel; Xu, Wenyu; Jung, Soonwook; Fiflis, Peter; Curreli, Davide; Ruzic, David N.

    2012-10-01

    CPMI is embarking on the development of a new, innovative liquid divertor PFC that can withstand heat fluxes above 15 MWm-2. It will be based on the lithium-metal infused trenches (LIMIT) concept which has been demonstrated at Illinois and HT-7. TELS will extend the work that has been done at CPMI is four ways: 1. Develop, refine and test new geometries for thermoelectrically driven structures 2. Expansion of the Illinois pulsed and continuous systems so that pulsed plasma heat loads impinge on a surface that already has a continuous heat load on it 3. Increase the magnetic field so that a broader range of ``fusion type environments'' can be studied 4. Include other PFC materials such as tin and tin-lithium eutectics. The importance of testing with a pulsed plasma heat load is clear since magnetic fusion devices surfaces are subject to ELMs, disruptions, start-up and a variety of other plasma incursions and a PFC needs to show that it is robust under these extreme conditions. Plans for building TELS using the flowing lithium experiment (SLiDE), LiMIT and a pulsed-plasma theta pinch (DEVeX) will be presented. Thus heat removal systems can be systematically investigated and prototypes designed for installation on major fusion experiments around the world.

  14. Thermoelectric-Driven Liquid-Metal Plasma-Facing Structures (TELS) Final Report

    SciTech Connect

    Ruzic, David

    2016-12-17

    The Thermoelectric-Driven Liquid-Metal Plasma-Facing Structures (TELS) project was able to establish the experimental conditions necessary for flowing liquid metal surfaces in order to be utilized as surfaces facing fusion relevant energetic plasma flux. The work has also addressed additional developments along with progressing along the timeline detailed in the proposal. A no-cost extension was requested to conduct other relevant experiment- specifically regarding the characterization droplet ejection during energetic plasma flux impact. A specially designed trench module, which could accommodate trenches with different aspect ratios was fabricated and installed in the TELS setup and plasma gun experiments were performed. Droplet ejection was characterized using high speed image acquisition and also surface mounted probes were used to characterize the plasma. The Gantt chart below had been provided with the original proposal, indicating the tasks to be performed in the third year of funding. These tasks are listed above in the progress report outline, and their progress status is detailed below.

  15. Childhood leukaemia in Europe after Chernobyl: 5 year follow-up.

    PubMed Central

    Parkin, D. M.; Clayton, D.; Black, R. J.; Masuyer, E.; Friedl, H. P.; Ivanov, E.; Sinnaeve, J.; Tzvetansky, C. G.; Geryk, E.; Storm, H. H.; Rahu, M.; Pukkala, E.; Bernard, J. L.; Carli, P. M.; L'Huilluier, M. C.; Ménégoz, F.; Schaffer, P.; Schraub, S.; Kaatsch, P.; Michaelis, J.; Apjok, E.; Schuler, D.; Crosignani, P.; Magnani, C.; Bennett, B. G.

    1996-01-01

    The European Childhood Leukaemia - Lymphoma Incidence Study (ECLIS) is designed to address concerns about a possible increase in the risk of cancer in Europe following the nuclear accident in Chernobyle in 1986. This paper reports results of surveillance of childhood leukaemia in cancer registry populations from 1980 up to the end of 1991. There was a slight increase in the incidence of childhood leukaemia in Europe during this period, but the overall geographical pattern of change bears no relation to estimated exposure to radiation resulting from the accident. We conclude that at this stage of follow-up any changes in incidence consequent upon the Chernobyl accident remain undetectable against the usual background rates. Our results are consistent with current estimates of the leukaemogenic risk of radiation exposure, which, outside the immediate vicinity of the accident, was small. PMID:8611419

  16. Chronic neutrophilic leukaemia and plasma cell-related neutrophilic leukaemoid reactions.

    PubMed

    Bain, Barbara J; Ahmad, Shahzaib

    2015-11-01

    Many cases reported as 'chronic neutrophilic leukaemia' have had an associated plasma cell neoplasm. Recent evidence suggests that the great majority of such cases represent a neutrophilic leukaemoid reaction to the underlying multiple myeloma or monoclonal gammopathy of undetermined significance. We have analysed all accessible reported cases to clarify the likely diagnosis and to ascertain whether toxic granulation, Döhle bodies and an increased neutrophil alkaline phosphatase score were useful in making a distinction between chronic neutrophilic leukaemia and a neutrophilic leukaemoid reaction. We established that all these changes occur in both conditions. Toxic granulation and Döhle bodies are more consistently present in leukaemoid reactions but also occur quite frequently in chronic neutrophilic leukaemia. The neutrophil alkaline phosphatase score is increased in both conditions and is of no value in making a distinction.

  17. Childhood leukaemia incidence around French nuclear installations using geographic zoning based on gaseous discharge dose estimates

    PubMed Central

    Evrard, A-S; Hémon, D; Morin, A; Laurier, D; Tirmarche, M; Backe, J-C; Chartier, M; Clavel, J

    2006-01-01

    The present study investigated for the first time the incidence of childhood leukaemia (1990–2001) around French nuclear installations using a geographic zoning based on estimated doses to the red bone marrow due to gaseous radioactive discharges. The observed number of cases of acute leukaemia (O=750) in 40 km2 centred on 23 French nuclear installations between 1990 and 2001 was lower than expected (E=795.01), although not significantly so (standardised incidence ratio SIR=0.94, 95% confidence interval=(0.88–1.01)). In none of the five zones defined on the basis of the estimated doses was the SIR significantly >1. There was no evidence of a trend in SIR with the estimated doses for all the children or for any of the three age groups studied. This study confirmed that there was no evidence of an increased incidence of childhood leukaemia around the 23 French nuclear sites. PMID:16622448

  18. A Rare Case of Acute Lymphoblastic Leukaemia in Pregnancy- Unique Maternal-Fetal Challenges

    PubMed Central

    Munshi, Shabana

    2014-01-01

    Leukaemia in pregnancy is rare and lethal. Its incidence is estimated to be 1 in 75,000 pregnancies. Use of chemotherapeutic agents during pregnancy can give rise to maternal and fetal adversity; resulting in dilemma regarding proper management plan. A 25-year-old pregnant lady was presented at 24 wk of gestational age with cervical and inguinal lymphadenopathy and bicytopenia in complete blood counts. Diagnosis of acute lymphoblastic leukaemia was confirmed by bone marrow biopsy. Treated with appropriate chemotherapeutic regimen with some modification in the standard protocol due to pregnancy and delivered successfully by lower segment caesarean section at 34 wk of gestational age. Diagnosis of acute leukaemia during pregnancy need high index of suspicion and need prompt management with the proper chemotherapeutic regimen. Clinical judgement regarding the risk benefit ratio of using chemotherapeutic drugs ensures better mother and fetal outcome. PMID:25478417

  19. Analysis of candidate genes for macular telangiectasia type 2

    PubMed Central

    Parmalee, Nancy L.; Schubert, Carl; Merriam, Joanna E.; Allikmets, Kaija; Bird, Alan C.; Gillies, Mark C.; Peto, Tunde; Figueroa, Maria; Friedlander, Martin; Fruttiger, Marcus; Greenwood, John; Moss, Stephen E.; Smith, Lois E.H.; Toomes, Carmel; Inglehearn, Chris F.

    2010-01-01

    Purpose To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach. Methods Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they co-segregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts. Results We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism. Conclusions We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel. PMID:21179236

  20. Opinion: how patients have benefited from mouse models of acute promyelocytic leukaemia.

    PubMed

    Lallemand-Breitenbach, Valérie; Zhu, Jun; Kogan, Scott; Chen, Zhu; de Thé, Hugues

    2005-10-01

    One of the challenges of studying anticancer therapies is that effects observed in cell lines or mouse models are not always good indicators of clinical trial results. The mouse model of acute promyelocytic leukaemia has bucked this trend, as targeted therapies such as retinoic acid and arsenic induce differentiation and clearance of leukaemia cells in both mice and humans. This mouse model has also provided important mechanistic insights into the combinatorial effects of these agents and has promoted combined therapies that have shown recent success in the clinic.

  1. A four-point clinical criteria distinguishes immune thrombocytopenia from acute lymphoblastic leukaemia.

    PubMed

    Lum, S H; How, S J; Ariffin, H; Krishnan, S

    2016-02-01

    Immune thrombocytopenia is the most common diagnosis of isolated thrombocytopenia. The dilemma encountered by paediatricians is missing diagnosis of acute leukaemia in children with isolated thrombocytopenia. We demonstrated childhood ITP could be diagnosed using a four point clinical criteria without missing a diagnosis of acute leukaemia. Hence, bone marrow examination is not necessary in children with typical features compatible with ITP prior to steroid therapy. This can encourage paediatricians to choose steroid therapy, which is cheaper and non-blood product, as first line platelet elevating therapy in children with significant haemorrhage.

  2. Tailored therapy of adult acute leukaemia in Jehovah's Witnesses: unjustified reluctance to treat.

    PubMed

    Laszlo, Daniele; Agazzi, Alberto; Goldhirsch, Aron; Cinieri, Saverio; Bertolini, Francesco; Rabascio, Cristina; Pruneri, Giancarlo; Calabrese, Liliana; Cocquio, Angela; Martinelli, Giovanni

    2004-04-01

    Treatment of acute leukaemia in adult Jehovah's Witnesses (JW) is challenging because of 'a priori' refusal of most physicians to apply diagnostic and therapeutic procedures to haematological abnormalities resembling acute leukaemia. Rejection of blood transfusions by individuals of this faith is usually blamed to justify this attitude, thus leading to severe personal, medical and psychological distress related to the lack of care. We therefore intended to verify whether a standard (tailored) chemotherapy, without the use of prophylactic blood product transfusions, could be applied during treatment of acute leukaemia under such circumstances. Eleven consecutive JW adult patients with acute leukaemia, all of whom had been denied care in other institutions, were treated at the European Institute of Oncology (EIO) in Milan, Italy. Five had acute lymphoblastic leukaemia (ALL) (one bcr/abl positive), six had acute myeloid leukaemia (AML) with immunophenotype and/or cytogenetic intermediate-high risk features, except one patient with acute promyelocytic leukaemia (APML). Standard induction chemotherapy [cytosine arabinoside (ARA-C) and daunorubicin (DNR) for AML, vincristine (VCR), DNR and prednisone (PDN) for ALL, all-trans retinoic acid (ATRA) and DNR for APML] with the antracycline dose of at least 30 mg/sqm were used. All patients experienced severe anaemia after induction chemotherapy despite erythropoietin. Median haemoglobin nadir for patients with ALL and AML was 4.5 g/dL (range 1.3-6.9) and 5.1 g/dL (range 2.6-6.8), respectively. Median platelet nadir counts for all patients was 14.5 x 10(9))/L (range 1-24). One patient died during induction probably due to haemorrhage. Four of five patients with ALL achieved a complete remission (CR) (including the bcr/abl case) while among patients with AML only the one with APML achieved CR. Three patients (APML = 1 and ALL = 2) are still alive and disease-free. This small series of adult patients with leukaemia illustrates

  3. Glioblastoma multiforme following cranial irradiation and chemotherapy for acute lymphocytic leukaemia. Report of 3 cases.

    PubMed

    Menon, R; Muzumdar, D; Shah, A; Goel, A

    2007-01-01

    The most common secondary neoplasms which occur following cranial radiation therapy are sarcoma and meningioma. The occurrence of glioblastoma multiforme following radiation and chemotherapy in acute lymphocytic leukaemia (ALL) is rare. We report 3 cases of glioblastoma multiforme in children developing 11-72 months following completion of chemotherapy/radiotherapy for ALL. The exact cause for the development of glioblastoma multiforme following therapy for ALL is not clear. A genetic predisposition may be essential for the occurrence of such a highly malignant primary brain tumour in leukaemia patients, irrespective of radiation and/or chemotherapy. The pathogenesis and surgical management are discussed, and the literature on the subject is reviewed.

  4. Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.

    PubMed

    Irving, Julie A E

    2016-03-01

    Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse.

  5. Preliminary Clinical Assessment of I.C.R.F. 159 in Acute Leukaemia and Lymphosarcoma

    PubMed Central

    Hellmann, K.; Newton, K. A.; Whitmore, D. N.; Hanham, I. W. F.; Bond, Jane V.

    1969-01-01

    I.C.R.F. 159, a new antitumour agent, has been assessed in six patients with acute leukaemia and three with lymphosarcoma. In all but two there was a considerable fall in circulating primitive cells, and in one there was bone-marrow evidence of a partial remission. Severe toxic effects were seen in only one case; they consisted of alopecia and gastroenteritis. It is suggested that I.C.R.F. 159 is worth further examination in all forms of acute leukaemia and lymphosarcoma. PMID:5251696

  6. Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia.

    PubMed

    Ridinger-Saison, M; Evanno, E; Gallais, I; Rimmelé, P; Selimoglu-Buet, D; Sapharikas, E; Moreau-Gachelin, F; Guillouf, C

    2013-09-01

    Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression.

  7. Interleukin-3 priming in acute myeloid leukaemia patients.

    PubMed

    Tafuri, A; de Felice, L; Goodacre, A; Fenu, S; Petrucci, M T; Valentini, T; Alimena, G; Petti, M C; Meloni, G; Mandelli, F

    1995-09-01

    Several studies have demonstrated that G-CSF, GM-CSF and, in particular, IL-3 can effectively recruit acute myeloid leukaemia (AML) blasts into the cell cycle, resulting in a significant increase in cytosine-arabinoside (Ara-C) mediated cytotoxicity in vitro. Since IL-3 has shown biological and clinical activity, we investigated the cell kinetic effects of rIL-3 and high-dose Ara-C/idarubicin in three patients with refractory AML selected for the presence of chromosome 7 monosomy; this enabled differentiation between the effects of IL-3 on leukaemic and on normal cells. The in vivo administration of rhIL-3 (250 micrograms/m2d s.c. for 6-10d) recruited AML blasts into the cell cycle in two of the three patients, and this effect resulted in an increase in in vitro growth of clonogenic cells (CFU-L) and of their S-phase fraction. The percentage of leukaemic cells with monosomy 7 increased only in the two cases who showed a proliferative response. Normal cells were not recruited, even when rhIL-3 was administered for up to 10 d. In vitro studies showed an increased Ara-C cytotoxicity on clonogenic AML cells, in particular with IL-3 plus GM-CSF, thus confirming the priming effects of IL-3 in the two responding cases. The results of this study suggest that rhIL-3 can selectively recruit leukaemic cells into the cell cycle. Although leukaemic blasts can be sensitized to Ara-C, other mechanisms of primary blast resistance may limit the clinical benefit of kinetic-based approaches.

  8. Improved outcome of acute myeloid leukaemia in Down's syndrome

    PubMed Central

    Craze, J; Harrison, G; Wheatley, K; Hann, I; Chessells, J

    1999-01-01

    OBJECTIVE—To review the clinical features, treatment, and outcome of children in the UK with Down's syndrome and acute myeloid leukaemia (AML).
DESIGN—A retrospective study of 59 children with Down's syndrome and AML presenting between 1987 and 1995. Data were obtained from hospital case notes, trial records, and by questionnaire.
RESULTS—The patients were unusually young (median age, 23 months) with a predominance of megakaryoblastic AML. Two of the seven infants who presented with abnormal myelopoesis aged 2 months or younger achieved complete spontaneous remission. Most of the older children with AML (32 of 52) were treated on recognised intensive protocols but 13 received individualised treatment and seven symptomatic treatment alone. Only four received a bone marrow transplant (BMT) in first remission. For the 45 older children who received chemotherapy the overall survival was 55% (median follow up 4.5 years). Patients on individualised protocols had a similar overall survival and toxic death rate but marginally higher relapse rate than those on standard (intensive) protocols. Children with Down's syndrome treated on the national AML 10 trial had a similar overall survival (70% v 59%) at five years to children of comparable age without Down's syndrome: their improved relapse risk (12% v 38%) offset the slight increase in deaths as a result of treatment toxicity (19% v 11%).
CONCLUSION—Neonates with Down's syndrome and abnormal myelopoesis may achieve spontaneous remission, and older children with Down's syndrome and AML can be treated successfully with intensive chemotherapy, without BMT.

 PMID:10373130

  9. Clinicopathological analysis of near-tetraploidy/tetraploidy acute myeloid leukaemia

    PubMed Central

    Pang, Changlee S; Pettenati, Mark J; Pardee, Timothy S

    2016-01-01

    Aims Near-tetraploidy/tetraploidy (NT/T) is a rare cytogenetic alteration in acute myeloid leukaemia (AML). NT/T-AML is categorised as complex cytogenetics and therefore, presumed to have an unfavourable prognosis. Our aim is to further characterise the clinical, morphological, cytogenetic and prognostic features of NT/T-AML. Methods We searched our cytogenetic laboratory database from 1991 to 2012 to reveal 13 cases of NT/T-AML. Each case was evaluated with regard to its demographics, morphology, immunophenotype and prognosis. Specific morphological features included blast size, irregularity of nuclear contours, cytoplasmic vacuoles, and presence and lineage of dysplasia. Results Eleven men and two women had a median age of 68 years. Blasts were predominately large (11/13). Eight of 13 patients had AML with myelodysplasia-related changes. Sixty-nine per cent of patients achieved complete remission (CR). Median overall survival (OS) was 8.6 months. CR rate and median OS in cases with ≥5 cytogenetic abnormalities were 71% and 6 months, compared with 67% and 18.1 months in cases with <5 abnormalities. Conclusions NT/T-AML occurs in older males, exhibits large blast size and is associated with myelodysplasia. Unlike previously reported data, our study reveals an overall better prognosis in this older population with NT/T-AML than was expected for a complex karyotype AML. Cytogenetic complexity independent of ploidy status did not greatly affect the high CR rates, but did appear to be a better estimation of prognostic risk in terms of median OS. PMID:25563333

  10. Simian T cell leukaemia virus type I subtype B in a wild-caught gorilla (Gorilla gorilla gorilla) and chimpanzee (Pan troglodytes vellerosus) from Cameroon.

    PubMed

    Nerrienet, Eric; Meertens, Laurent; Kfutwah, Anfumbom; Foupouapouognigni, Yacouba; Ayouba, Ahidjo; Gessain, Antoine

    2004-01-01

    A serological survey for human T cell leukaemia virus (HTLV)/simian T cell leukaemia virus (STLV) antibodies was performed in 61 wild-caught African apes, including five gorillas and 56 chimpanzees originating from south Cameroon. Two young animals, a gorilla (Gorilla gorilla gorilla) and a chimpanzee (Pan troglodytes vellerosus), exhibited a pattern of complete HTLV-I seroreactivity. Sequence comparison and phylogenetic analyses using the complete LTR (750 bp) and a 522 bp fragment of the env gene indicated the existence of two novel STLV-I strains, both of which belonged to HTLV-I/STLV-I molecular clade subtype B, specific to central Africa. These first STLV-I strains to be characterized in gorilla and chimpanzee were closely related to each other as well as to several HTLV-I strains originating from inhabitants of south Cameroon, including pygmies. Such findings reinforce the hypothesis of interspecies transmission of STLV-I to humans, leading to the present day distribution of HTLV-I in central African inhabitants.

  11. In-Q-Tel, the strategic investment firm for the U.S. Intelligence Community

    NASA Astrophysics Data System (ADS)

    Ulvick, S. J.; Tighe, D. W.

    2008-04-01

    In-Q-Tel is a strategic investment firm that works to identify, adapt, and deliver innovative technology solutions to support the missions of the Central Intelligence Agency and the broader U.S. Intelligence Community (IC). Launched by the CIA in 1999 as a private, independent, not-for-profit organization, IQT's mission is to identify and partner with companies developing cutting-edge technologies that serve the national security interests of the United States. Working from an evolving strategic blueprint defining the Intelligence Community's critical technology needs, IQT engages with entrepreneurs, growth companies, researchers, and venture capitalists to deliver technologies that provide superior capabilities for the CIA and the broader IC. To date, IQT has reviewed more than 6,300 business proposals, invested in more than 100 companies, and delivered more than 140 technology solutions to the U.S. Intelligence Community.

  12. Hypereosinophilia in childhood acute lymphoblastic leukaemia at diagnosis: report of 2 cases and review of the literature.

    PubMed

    Parasole, Rosanna; Petruzziello, Fara; De Matteo, Antonia; Maisto, Giovanna; Castelli, Luisa; Errico, Maria Elena; Menna, Giuseppe; Poggi, Vincenzo

    2014-04-10

    Hypereosinophilia as first clinical presentation has rarely been reported in paediatric acute lymphoblastic leukaemia. It is commonly associated with specific cytogenetic abnormalities. Although eosinophilia is considered a reactive, non-neoplastic epiphenomenon, it adversely affects patient outcomes, both in children and adults. We describe herewith two paediatric patients who had marked eosinophilia at onset of acute lymphoblastic leukaemia. We point out the importance of a correct differential diagnosis in persistent, unexplained peripheral hypereosinophilia. Clinicians should keep in mind that eosinophilia can be part of the overall pattern of acute leukaemia and therefore needs to be properly investigated. We also provide some recommendations for an appropriate approach to hypereosinophilia - related morbidities.

  13. Space–time clustering patterns in childhood leukaemia support a role for infection

    PubMed Central

    Birch, J M; Alexander, F E; Blair, V; Eden, O B; Taylor, G M; McNally, R J Q

    2000-01-01

    Previous studies of space–time clustering in childhood leukaemia have produced equivocal and inconsistent results. To address this issue we have used Manchester Children's Tumour Registry leukaemia data in space–time clustering analyses. Knox tests for space–time interactions between cases were applied with fixed thresholds of close in space, < 5 km and close in time < 1 year apart. Addresses at birth as well as diagnosis were utilized. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. All methods showed highly significant evidence of space–time clustering based on place of birth and time of diagnosis, particularly for all leukaemias aged 0–14 and 0–4 years, and acute lymphoblastic leukaemia (ALL) 0–4 years. Some results based on location at diagnosis were significant but mainly gave larger P -values. The results are consistent with an infectious hypothesis. Furthermore, we found an excess of male cases over females involved in space–time pairs. We suggest this may be related to genetic differences in susceptibility to infection between males and females. These findings provide the basis for future studies to identify possible infectious agents. © 2000 Cancer Research Campaign PMID:10789727

  14. Diagnosis and management of B cell chronic lymphocytic leukaemia in a cat.

    PubMed

    Tebb, A J; Cave, T; Barron, R; Brown, A L; Martineau, H M; Willett, B J; Hosie, M J

    2004-04-03

    A four-year-old, female neutered domestic shorthair cat had a history of chronic intermittent vomiting and lymphocytosis. B cell chronic lymphocytic leukaemia was diagnosed by flow cytometry, which revealed abnormally large numbers of mature B lymphocytes in the peripheral blood. The cat was treated conservatively with antiemetic drugs and remained stable without chemotherapy for over a year.

  15. The inherent metastasis of leukaemia and its exploitation by sonodynamic therapy.

    PubMed

    Trendowski, Matthew

    2015-05-01

    Nearly all cancers are linked by the inexorable phenotype of metastasis as malignant growths have the capability to spread from their place of origin to distant sites throughout the body. While different cancers may have various propensities to migrate towards specific locations, they are all linked by this unifying principal. Unlike most neoplasms, leukaemia has inherent cell motility as leukocytes are required to move throughout the vascular system, suggesting that no mutations are required for anchorage independent growth. As such, it seems likely that leukaemias are inherently metastatic, endowed with the deadliest phenotype of cancer simply due to cell of origin. This article presents the biology of metastasis development and how leukaemia cells are inherently provided these phenotypic characteristics. It is then proposed how clinicians may be able to exploit the motility of leukaemia and metastatic emboli of other cancer types through an approach known as sonodynamic therapy (SDT), a treatment modality that combines chemotherapeutic agents with ultrasound to preferentially damage malignant cells. As experimental evidence has indicated, SDT is a promising therapeutic approach in need of clinical testing for further validation.

  16. Gemtuzumab-induced orchitis in a patient with refractory acute promyelocytic leukaemia.

    PubMed

    Jalil-ur-Rehman; Kelta, Muhammad; Awad, Khalid; Beirouti, Basim Al; Nasser, Shahzad; Aslam, Muhammad

    2012-09-01

    We report the case of a 22-year-old Saudi male patient who was treated extensively in the past with various regimens for acute promyelocytic leukaemia that was refractory to all standard treatments. He was ultimately administered Gemtuzumab to induce remission and subjected to an allogeneic bone marrow transplant. However, he developed orchitis, which has not been previously reported with this agent.

  17. Rothia dentocariosa septicaemia in a patient with chronic lymphocytic leukaemia and toxic granulocytopenia.

    PubMed

    Pers, C; Kristiansen, J E; Jønsson, V; Hansen, N E

    1987-12-01

    Rothia dentocariosa is part of the human oral flora and has only rarely been reported as a cause of clinical infection. We report the isolation of Rothia dentocariosa from the blood of a septicaemic patient with chronic lymphocytic leukaemia and bone marrow depression following treatment with clomipramine and zuclopentixol.

  18. Childhood leukaemia risks: from unexplained findings near nuclear installations to recommendations for future research.

    PubMed

    Laurier, D; Grosche, B; Auvinen, A; Clavel, J; Cobaleda, C; Dehos, A; Hornhardt, S; Jacob, S; Kaatsch, P; Kosti, O; Kuehni, C; Lightfoot, T; Spycher, B; Van Nieuwenhuyse, A; Wakeford, R; Ziegelberger, G

    2014-09-01

    Recent findings related to childhood leukaemia incidence near nuclear installations have raised questions which can be answered neither by current knowledge on radiation risk nor by other established risk factors. In 2012, a workshop was organised on this topic with two objectives: (a) review of results and discussion of methodological limitations of studies near nuclear installations; (b) identification of directions for future research into the causes and pathogenesis of childhood leukaemia. The workshop gathered 42 participants from different disciplines, extending widely outside of the radiation protection field. Regarding the proximity of nuclear installations, the need for continuous surveillance of childhood leukaemia incidence was highlighted, including a better characterisation of the local population. The creation of collaborative working groups was recommended for consistency in methodologies and the possibility of combining data for future analyses. Regarding the causes of childhood leukaemia, major fields of research were discussed (environmental risk factors, genetics, infections, immunity, stem cells, experimental research). The need for multidisciplinary collaboration in developing research activities was underlined, including the prevalence of potential predisposition markers and investigating further the infectious aetiology hypothesis. Animal studies and genetic/epigenetic approaches appear of great interest. Routes for future research were pointed out.

  19. The Dimeric Architecture of Checkpoint Kinases Mec1ATR and Tel1ATM Reveal a Common Structural Organization.

    PubMed

    Sawicka, Marta; Wanrooij, Paulina H; Darbari, Vidya C; Tannous, Elias; Hailemariam, Sarem; Bose, Daniel; Makarova, Alena V; Burgers, Peter M; Zhang, Xiaodong

    2016-06-24

    The phosphatidylinositol 3-kinase-related protein kinases are key regulators controlling a wide range of cellular events. The yeast Tel1 and Mec1·Ddc2 complex (ATM and ATR-ATRIP in humans) play pivotal roles in DNA replication, DNA damage signaling, and repair. Here, we present the first structural insight for dimers of Mec1·Ddc2 and Tel1 using single-particle electron microscopy. Both kinases reveal a head to head dimer with one major dimeric interface through the N-terminal HEAT (named after Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR1) repeat. Their dimeric interface is significantly distinct from the interface of mTOR complex 1 dimer, which oligomerizes through two spatially separate interfaces. We also observe different structural organizations of kinase domains of Mec1 and Tel1. The kinase domains in the Mec1·Ddc2 dimer are located in close proximity to each other. However, in the Tel1 dimer they are fully separated, providing potential access of substrates to this kinase, even in its dimeric form.

  20. The relationship between plasma effects and cosmic radiation with TriTel-LMP common measurement in the ESEO mission

    NASA Astrophysics Data System (ADS)

    Zabori, Balazs; Hirn, Attila; Bencze, Pal

    The development of the European Student Earth Orbiter (ESEO) was announced by the Eu-ropean Space Agency for young students interested in the space exploration. The Budapest University of Technology and Economics (BUTE) joined this international cooperation with a technological innovation (Electrical Power System) and two scientific experiments, called TriTel and Langmuir Probe (LMP). The development of the TriTel 3D silicon detector telescope began in the KFKI Atomic Energy Research Institute several years ago in order to determine the av-erage radiation quality factor of the cosmic radiation for dosimetric purposes. The design of the LMP got under way at BUTE some years ago to determine the electron temperature, electron density, and electric potential of plasma. The common use of the TriTel and LMP instruments enables the simultaneous study of effects of interplanetary and magnetospheric phenomena (Tri-Tel), as well as observation of variations in the topside ionosphere (LMP). The paper presents those effects and characteristics of the magnetosphere and ionosphere that might be studied with these two instrument originally developed for different measurement goals. From the results of the experiments we expect to identify the relationship between plasma effects and cosmic radiation especially in polar regions and the South Atlantic Anomaly (SAA).

  1. 76 FR 13438 - AccessTel, Inc., American Asset Management Corp., DME Interactive Holdings, Inc., DocuPort, Inc...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-11

    ... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION AccessTel, Inc., American Asset Management Corp., DME Interactive Holdings, Inc., DocuPort, Inc... is a lack of current and accurate information concerning the securities of DME Interactive...

  2. The Dimeric Architecture of Checkpoint Kinases Mec1ATR and Tel1ATM Reveal a Common Structural Organization*

    PubMed Central

    Sawicka, Marta; Wanrooij, Paulina H.; Darbari, Vidya C.; Tannous, Elias; Hailemariam, Sarem; Bose, Daniel; Makarova, Alena V.; Burgers, Peter M.; Zhang, Xiaodong

    2016-01-01

    The phosphatidylinositol 3-kinase-related protein kinases are key regulators controlling a wide range of cellular events. The yeast Tel1 and Mec1·Ddc2 complex (ATM and ATR-ATRIP in humans) play pivotal roles in DNA replication, DNA damage signaling, and repair. Here, we present the first structural insight for dimers of Mec1·Ddc2 and Tel1 using single-particle electron microscopy. Both kinases reveal a head to head dimer with one major dimeric interface through the N-terminal HEAT (named after Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR1) repeat. Their dimeric interface is significantly distinct from the interface of mTOR complex 1 dimer, which oligomerizes through two spatially separate interfaces. We also observe different structural organizations of kinase domains of Mec1 and Tel1. The kinase domains in the Mec1·Ddc2 dimer are located in close proximity to each other. However, in the Tel1 dimer they are fully separated, providing potential access of substrates to this kinase, even in its dimeric form. PMID:27129217

  3. Organizing the Library to Suit the Undergraduates' Information Gathering Behavior at the Tel-Hai Academic College in Israel

    ERIC Educational Resources Information Center

    Chai, Iris

    2007-01-01

    The study examined the factors influencing information gathering behavior of undergraduates at Tel-Hai Academic College, so that library services can cope effectively with this behavior. Related to the findings, we changed our circulation desk to become a "one stop shop" for directions to all library information.

  4. Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis

    PubMed Central

    Chaudry, Sabah F.

    2017-01-01

    Acute myeloid leukaemia (AML) is a haematological malignancy characterized by clonal stem cell proliferation and aberrant block in differentiation. Dysfunction of epigenetic modifiers contributes significantly to the pathogenesis of AML. One frequently mutated gene involved in epigenetic modification is DNMT3A (DNA methyltransferase-3-alpha), a DNA methyltransferase that alters gene expression by de novo methylation of cytosine bases at CpG dinucleotides. Approximately 22% of AML and 36% of cytogenetically normal AML cases carry DNMT3A mutations and around 60% of these mutations affect the R882 codon. These mutations have been associated with poor prognosis and adverse survival outcomes for AML patients. Advances in whole-exome sequencing techniques have recently identified a large number of DNMT3A mutations present in clonal cells in normal elderly individuals with no features of haematological malignancy. Categorically distinct from other preleukaemic conditions, this disorder has been termed clonal haematopoiesis of indeterminate potential (CHIP). Further insight into the mutational landscape of CHIP may illustrate the consequence of particular mutations found in DNMT3A and identify specific “founder” mutations responsible for clonal expansion that may contribute to leukaemogenesis. This review will focus on current research and understanding of DNMT3A mutations in both AML and CHIP. PMID:28286768

  5. New germline mutations in the hypervariable minisatellite CEB1 in the parents of children with leukaemia

    PubMed Central

    Davies, B G; Hussain, A; Ring, S M; Birch, J M; Eden, T O B; Reeves, M; Dubrova, Y E; Taylor, G M

    2007-01-01

    Gardner and co-workers advanced the hypothesis that the Seascale leukaemia cluster could have been caused by new mutations in germ cells, induced by paternal preconceptional irradiation (PPI) exposure at the Sellafield nuclear installation. Since evidence has shown that PPI can increase the de novo germline mutation rate in hypervariable minisatellite loci, we investigated the hypothesis that sporadic childhood leukaemia might be associated with an increased parental germline minisatellite mutation rate. To test this hypothesis, we compared de novo germline mutation rates in the hypervariable minisatellite locus, CEB1, in family trios (both parents and their child) of children with leukaemia (n=135) compared with unaffected control families (n=124). The majority of case and control germline mutations were paternal (94%); the mean paternal germline mutation rates of children with leukaemia (0.083) and control children (0.156) were not significantly different (odds ratio, 95% confidence interval: 0.50, 0.23–1.08; P=0.11). There were no significant differences in case and control parental allele sizes, case and control germline mutation progenitor allele sizes (2.74 vs 2.54 kb; P=0.56), case and control mutant allele sizes (2.71 vs 2.67 kb; P=0.90), mutant allele size changes (0.13 vs 0.26 kb; P=0.10), or mutational spectra. Within the limitation of the number of families available for study, we conclude that childhood leukaemia is unlikely to be associated with increased germline minisatellite instability. PMID:17387343

  6. Leukaemia in young children living in the vicinity of German nuclear power plants.

    PubMed

    Kaatsch, Peter; Spix, Claudia; Schulze-Rath, Renate; Schmiedel, Sven; Blettner, Maria

    2008-02-15

    A case control study was conducted where cases were children younger than 5 years (diseased between 1980 and 2003) registered at the german childhood cancer registry (GCCR). Population-based matched controls (1:3) were selected from the corresponding registrar's office. Residential proximity to the nearest nuclear power plant was determined for each subject individually (with a precision of about 25 m). The report is focused on leukaemia and mainly on cases in the inner 5-km zone around the plants. The study includes 593 leukaemia cases and 1,766 matched controls. All leukaemia combined show a statistically significant trend for 1/distance with a positive regression coefficient of 1.75 [lower 95%-confidence limit (CL): 0.65]; for acute lymphoid leukaemia 1.63 (lower 95%-CL: 0.39), for acute nonlymphocytic leukaemia 1.99 (lower 95%-CL: -0.41). This indicates a negative trend for distance. Cases live closer to nuclear power plants than the randomly selected controls. A categorical analysis shows a statistically significant odds ratio of 2.19 (lower 95%-CL: 1.51) for residential proximity within 5 km compared to residence outside this area. This result is largely attributed to cases in previous studies of the GCCR (especially in the inner zone) as there is clearly some overlap between those studies. The result was not to be expected under current radiation-epidemiological knowledge. Considering that there is no evidence of relevant accidents and that possible confounders could not be identified, the observed positive distance trend remains unexplained.

  7. High-dose gallium-67 therapy in patients with relapsed acute leukaemia: a feasibility study.

    PubMed Central

    Jonkhoff, A. R.; Plaizier, M. A.; Ossenkoppele, G. J.; Teule, G. J.; Huijgens, P. C.

    1995-01-01

    Gallium-67 (67Ga) accumulates in malignant tissues via the transferrin receptor without need for a monoclonal antibody and emits cytotoxic low-energy electrons. In this study we investigated the feasibility, pharmacokinetics, toxicity and preliminary efficiency of high-dose 67Ga injected intravenously (i.v.) in patients with acute leukaemia not responding to conventional therapy. Twelve doses of 36-105 mCi of Gallium67 citrate were administered as a push injection to eight patients with resistant leukaemia in a pilot study. All five patients with acute myeloid leukaemia (AML) and three patients with acute lymphoblastic leukaemia (ALL) had resistant disease or resistant relapse. No (sub)acute toxicity was observed. Independent of the administered dose, whole-blood radioactivity levels 10 min after administration measured only 1.25 +/- 1.39 microCi ml-1, indicating a large volume of distribution. Urine excretion in the first 24 h ranged from 18% to 51.5% (median 29.5%) of the administered dose. Cellular uptake of 67Ga was less than in previous in vitro studies. Whole-body radiation dose was estimated to be 0.25 +/- 0.03 cGy mCi-1. Red marrow dose was estimated to be between 0.18 +/- 0.02 and 0.97 +/- 0.12 cGy mCi-1. One definite response was observed in an ALL patient with disappearance of skin lesions, normalisation of the enlarged spleen and profound leucopenia. Three other patients showed transient reductions in white blood cell counts without disappearance of blasts from the peripheral blood. We conclude that high-dose i.v. 67Ga can be safely administered but that the uptake of 67Ga in blast cells must increase to make 67Ga therapeutically useful in patients with relapsed leukaemia. Images Figure 2 PMID:8519674

  8. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus.

    PubMed

    Schmiegelow, Kjeld; Attarbaschi, Andishe; Barzilai, Shlomit; Escherich, Gabriele; Frandsen, Thomas Leth; Halsey, Christina; Hough, Rachael; Jeha, Sima; Kato, Motohiro; Liang, Der-Cherng; Mikkelsen, Torben Stamm; Möricke, Anja; Niinimäki, Riitta; Piette, Caroline; Putti, Maria Caterina; Raetz, Elizabeth; Silverman, Lewis B; Skinner, Roderick; Tuckuviene, Ruta; van der Sluis, Inge; Zapotocka, Ester

    2016-06-01

    Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment.

  9. Genesis of Kirsten murine sarcoma virus: sequence analysis reveals recombination points and potential leukaemogenic determinant on parental leukaemia virus genome.

    PubMed Central

    Norton, J D; Connor, J; Avery, R J

    1984-01-01

    The genome of Kirsten murine sarcoma virus was formed by recombination between Kirsten murine leukaemia virus sequences, and rat sequences derived from a retrovirus-like '30S' (VL30) genetic element encompassing the Kras oncogene. Using cloned DNAs we have determined the nucleotide sequences of the long terminal repeats and adjacent regions, extending across the points of recombination on the sarcoma and leukaemia virus genomes. Our results suggest that discrete regions of homology and other cryptic sequence features, may have constituted recombinational hot-spots involved in the genesis of the Kirsten murine sarcoma virus genome. We have also compared the sequence of the Kirsten murine leukaemia virus p15 env and adjacent long terminal repeat with the corresponding regions of the AKV and Gross A murine leukaemia virus genomes. This comparison has identified a leukaemogenic determinant in the U3 domain of the long terminal repeat, possibly within a enhancer-like sequence element. PMID:6091040

  10. Co-occurrence of biphenotypic acute leukaemia, glucose 6-phosphate dehydrogenase deficiency and haemoglobin E trait in a single child.

    PubMed

    Mallick, Debkrishna; Thapa, Rajoo; Biswas, Biswajit

    2016-02-01

    Acute leukaemias occur as the result of clonal expansion subsequent to transformation and arrest at a normal differentiation stage of haematopoietic precursors, which commit to a single lineage, such as myeloid or B-lymphoid or T-lymphoid cells. Biphenotypic acute leukaemia (BAL) constitutes a biologically different group of leukaemia arising from a precursor stem cell and co-expressing more than one lineage specific marker. The present report describes a child with unusual co-occurrence of biphenotypic (B-precursor cell and Myeloid) acute leukaemia, haemoglobin E trait and glucose 6-phosphate dehydrogenase (G6-PD) deficiency. To the best of our knowledge, this constellation of haematological conditions in a single child has never been described before.

  11. [Prognostic value of absolute monocyte count in chronic lymphocytic leukaemia].

    PubMed

    Szerafin, László; Jakó, János; Riskó, Ferenc

    2015-04-01

    Bevezetés: Az alacsony perifériás lymphocyta- és magas monocytaszám kedvezőtlen prognózisra utal különböző típusú lymphomákban és egyéb daganatos megbetegedésekben. Krónikus lymphoid leukaemiában azonban az abszolút monocytaszám prognosztikus értékéről csak kevés adat ismert. Célkitűzés: A szerzők krónikus lymphoid leukaemiás betegeik diagnóziskor mért abszolút monocytaszámának hatását vizsgálták a kezelésig eltelt időre és a túlélésre. Módszer: 2005. január 1. és 2012. december 31. között diagnosztizált 223 krónikus lymphoid leukaemiás beteg adatait rögzítették. Értékelték a kezelést igénylő betegek arányát, a kezelésig eltelt idő és a túlélés relatív kockázatát, valamint a halálokokat a Rai-stádiumtól függően, a CD38-, ZAP-70-pozitivitásnak és az abszolút monocytaszámnak megfelelően. Eredmények: Rai 0, I., II., III. és IV. stádiumban a betegek 21,1%-a, 57,4%-a, 88,9%-a, 88,9%-a és 100%-a, CD38-, illetve ZAP-70-pozitivitás esetén a betegek 61,9%-a, illetve 60,8%-a, továbbá, ha az abszolút monocytaszámuk <0,25 G/l, 0,25–0,75 G/l és >0,75 G/l volt, akkor a betegek 76,9%-a, 21,2%-a és 66,2%-a szorult kezelésre. A kezelés elkezdéséig tartó medián idő, illetve a túlélés medián ideje a monocytaszámtól függően 19,5, 65 és 35,5 hónap, illetve 41,5, 65 és 49,5 hónap volt. A kezelésmegkezdés szükségességének relatív kockázata, RR = 1,62 (p<0,01) volt a 0,25 G/l alatti vagy 0,75 G/l feletti és a 0,25–0,75 G/l abszolút monocytaszámú betegek összehasonlításakor, míg a túlélésé RR = 2,41 (p<0,01) volt, ha a 0,25 G/l alatti és feletti abszolút monocytaszámú betegeket hasonlították össze. A relatív kockázatok Rai 0 stádiumú betegekben vizsgálva is szignifikánsak maradtak. A fő halálokok alacsony abszolút monocytaszám esetén fertőzések (41,7%) és a krónikus lymphoid leukaemia (58,3%), míg közepes és magas monocytasz

  12. Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study

    PubMed Central

    Leuraud, Klervi; Richardson, David B; Cardis, Elisabeth; Daniels, Robert D; Gillies, Michael; O'Hagan, Jacqueline A; Hamra, Ghassan B; Haylock, Richard; Laurier, Dominique; Moissonnier, Monika; Schubauer-Berigan, Mary K; Thierry-Chef, Isabelle; Kesminiene, Ausrele

    2015-01-01

    Summary Background There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. Methods We assembled a cohort of 308 297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8·22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. Findings Doses were accrued at very low rates (mean 1·1 mGy per year, SD 2·6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2·96 per Gy (90% CI 1·17–5·21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10·45, 90% CI 4·48–19·65). Interpretation This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. Funding Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England. PMID:26436129

  13. Trends in childhood leukaemia in the Nordic countries in relation to fallout from atmospheric nuclear weapons testing.

    PubMed Central

    Darby, S. C.; Olsen, J. H.; Doll, R.; Thakrar, B.; Brown, P. D.; Storm, H. H.; Barlow, L.; Langmark, F.; Teppo, L.; Tulinius, H.

    1992-01-01

    OBJECTIVE--To obtain further information about the risks of childhood leukaemia after exposure to ionising radiation at low doses and low dose rates before or after birth or to the father's testes shortly before conception. DESIGN--Observational study of trends in incidence of childhood leukaemia in relation to estimated radiation exposures due to fallout from atmospheric nuclear weapons testing during the 1950s and 1960s. SETTING--Nordic countries. SUBJECTS--Children aged under 15 years. MAIN OUTCOME MEASURES--Incidence rates of leukaemia by age at diagnosis, sex, country, and calendar year of diagnosis or year of birth; exposure category; relation between leukaemia and exposure for children aged 0-14 and 0-4 separately. RESULTS--During the high fallout period the average estimated dose equivalent to the fetal red bone marrow was around 140 mu Sv and the average annual testicular dose 140 mu Sv. There was little evidence of increased incidence of leukaemia among children born in these years. Doses to the red bone marrow of a child after birth were higher, and during the high exposure period children would have been subjected to an additional dose equivalent of around 1500 mu Sv, similar to doses received by children in several parts of central and eastern Europe owing to the Chernobyl accident and about 50% greater than the annual dose equivalent to the red bone marrow of a child from natural radiation. leukaemia incidence and red marrow dose was not related overall, but rates of leukaemia in the high exposure period were slightly higher than in the surrounding medium exposure period (relative risk for ages 0-14: 1.07, 95% confidence interval 1.00 to 1.14; for ages 0-4: 1.11, 1.00 to 1.24). CONCLUSIONS--Current predicted risks of childhood leukaemia after exposure to radiation are not greatly underestimated for low dose rate exposures. PMID:1586779

  14. Soil properties in urban parks and city population in Tel Aviv-Jaffa: Mutual effects

    NASA Astrophysics Data System (ADS)

    Oz, A.; Sarah, P.; Zhevelev, H.

    2012-04-01

    Urban parks are man-made open spaces, located in the city area and having two major functions: conservation of natural resources and optimization of the physical and social environment. This study aimed to investigate the relations between the soil properties and the socioeconomic profile of the populations in the parks in Tel Aviv. The city of Tel Aviv was divided into three geographical regions: South, Central and North. This division reflects the course of development of the city from south to north, and encompasses differing socio-economic levels of residents. In each geographical region 15 parks were randomly chosen, and were divided into three groups by size (2-10, 10-20 and 20-50 acres). In each park soil was sampled in two microenvironments (lawn and path), from three points and from three depth layers (0-2, 5-10 and 10-20 cm) in July-August 2011. Before the sampling, penetration depth was determined at all the points. Each of the soil samples was analyzed for organic matter content, pH, electrical conductivity, and sodium and chlorine contents. For each type of microenvironment, the results were analyzed with respect to three factors: size of park, region of city, and soil depth. It was found that the urban park soil properties varied widely: sodium and chlorine contents from 1.8 to 12 and from 1.9 to 7.8 meq/kg, respectively; and electrical conductivity from 0.40 to 1.47 dS/m. In the lawn microenvironment, electrical conductivity, chlorine and sodium increased in all depths with park size. This trend was significant only in the upper layer. In the path microenvironment no such trend was seen. In the center of the city lower values of soil properties than in the other regions were found at all depths. Soil properties decreased with depth in all three geographical regions, in all three sizes of park, and in both microenvironments. For all sizes of park, in all geographical regions, and in both microenvironments, penetration depths were found be similar. We

  15. Are the children of fathers whose jobs involve contact with many people at an increased risk of leukaemia?

    PubMed Central

    Fear, N. T.; Roman, E.; Reeves, G.; Pannett, B.

    1999-01-01

    OBJECTIVES: To investigate the hypothesis that children of men whose jobs involve contact with many people (particularly children) are at an increased risk of leukaemia. METHODS: A population based dataset obtained from routinely collected death certificates involving 14,168 cancer deaths occurring before the age of 15 years registered in England and Wales between 1959-63 and 1970-90. Associations were assessed with the proportional cancer mortality ratio (PCMR), with all childhood cancer deaths forming the standard for comparison. The PCMRs were adjusted, by stratification, for age and year of death (in 1-year bands) and paternal social class (nine categories). Analyses were performed by estimated level of paternal occupational social contact (high, medium, and low) for all leukaemias, leukaemia subtype, age at death, year of death, and individual occupation. RESULTS: Out of 223 occupations, 36 (16%) were identified as having potentially high levels of social contact, and 27 (12%) as having potentially medium levels of social contact. No associations were found between paternal occupational social contact and death during childhood from leukaemia (high social contact: PCMR 94, 95% confidence interval (95% CI) 87 to 102; medium social contact: 101, 95 to 106). No associations were found when the data were analysed by leukaemia subtype, age at death, year of death, or individual occupation. CONCLUSION: The findings presented here do not support the suggestion that childhood leukaemia is related to the amount of social contact that fathers experience at work.   PMID:10472313

  16. Leukaemia and non-Hodgkin's lymphoma in children and young adults: are prenatal and neonatal factors important determinants of disease?

    PubMed Central

    Roman, E.; Ansell, P.; Bull, D.

    1997-01-01

    A medical record-based study of leukaemia and non-Hodgkin's lymphoma diagnosed before the age of 30 years was carried out at three hospitals in the south of England. Findings for 177 cases and 354 age- and sex-matched controls are presented here. For documented viral infection in pregnancy, the odds ratio (OR) was 6.0 [95% confidence interval (CI) 1.2-29.7] for leukaemia and infinity (95% CI 1.24-infinity) for non-Hodgkin's lymphoma. Mothers of leukaemic cases were more likely to be anaemic, the OR for a pregnancy haemoglobin below 10 g being 3.8 (95% CI 1.3-11.1). An association with birthweight was found for acute myeloid leukaemia, the OR for birthweights > 3500 g being 6.2 (95% CI 1.3-29.8). Further, the preceding siblings of those diagnosed with any form of leukaemia were also more likely to weigh > 3500 g at birth (OR 2.2; 95% CI 1.1-4.4). Overall, leukaemic cases appeared to be comparatively robust at birth with respect to other indicators of well-being, the ORs for jaundice, phototherapy, admission to special care nursery and neonatal intensive care all being less than 1.0. Further, no relation between childhood leukaemia and neonatal administration of intramuscular vitamin K was noted (OR 0.6, 95% CI 0.3-1.4; for acute lymphoblastic leukaemia diagnosed between the ages of 1 and 6 years). PMID:9252212

  17. Allogeneic haematopoietic stem cell transplantation for infant acute lymphoblastic leukaemia with KMT2A (MLL) rearrangements: a retrospective study from the paediatric acute lymphoblastic leukaemia working group of the Japan Society for Haematopoietic Cell Transplantation.

    PubMed

    Kato, Motohiro; Hasegawa, Daiichiro; Koh, Katsuyoshi; Kato, Keisuke; Takita, Junko; Inagaki, Jiro; Yabe, Hiromasa; Goto, Hiroaki; Adachi, Souichi; Hayakawa, Akira; Takeshita, Yasufumi; Sawada, Akihisa; Atsuta, Yoshiko; Kato, Koji

    2015-02-01

    Allogeneic haematopoietic stem cell transplantation (HSCT) is still considered to play an important role as a consolidation therapy for high-risk infants with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed outcomes of HSCT in infants with ALL based on nationwide registry data of the Japan Society for Haematopoietic Cell Transplantation. A total of 132 allogeneic HSCT for infant ALL with KMT2A (MLL) gene rearrangements, which were performed in first complete remission (CR1), were analysed. The 5-year overall survival rate after transplantation was 67·4 ± 4·5%). Although recent HSCT (after 2004) had a trend toward better survival, no statistical correlation was observed between outcomes and each factor, including age at diagnosis, initial leucocyte count, cytogenetics, donor types or conditioning of HSCT. Myeloablative conditioning with total body irradiation did not provide a better survival (60·7 ± 9·2%) over that with busulfan (BU; 67·8 ± 5·7%). Two of the 28 patients treated with irradiation, but none of the 90 BU-treated patients, developed a secondary malignant neoplasm. In conclusion, allogeneic HSCT using BU was a valuable option for infant ALL with KMT2A rearrangements in CR1.

  18. TriTel 3 dimensional space dosimetric telescope in the European Student Earth Orbiter project of ESA

    NASA Astrophysics Data System (ADS)

    Zábori, Balázs; Hirn, Attila

    2012-02-01

    The development of the European Student Earth Orbiter (ESEO) was announced in the year of 2008 by the European Space Agency for students interested in the space exploration. The Budapest University of Technology and Economics joined this international cooperation with three student groups among other participating European universities. One of them is the ESEO-TriTel team. The development of the TriTel 3D silicon detector telescope began in the KFKI Atomic Energy Research Institute several years ago in order to determine the average radiation quality factor of the space radiation field for dosimetric purposes. In the year 2011—before the start of the ESEO mission—it will be operated on board the European Columbus module of the International Space Station (ISS) and will be installed in the Russian segment of the ISS as well. The ESEO version of TriTel will fly higher than the ISS version, at an altitude of 520 km. At this altitude the Earth's geomagnetic field is much lower and the spectrum of the radiation field is also different. In the ESEO-TriTel experiment the anisotropies in the radiation field, the effects of the Earth shadow and the South Atlantic Anomaly (SAA) will be analysed and the results will be compared with the fluxes calculated with the standard AP-8 and AE-8 trapped proton and electron models. In the near future the frequency of manned space flights will probably increase, we can think of the continuous human presence in the near-Earth region (low Earth orbits) or the proposed human Mars expedition. That is why the cosmic radiation field is interesting not only in the near-Earth region but at higher altitudes or in the interplanetary field as well. The present paper addresses the optimal shielding of the dosimetric telescopes of TriTel in order to avoid the saturation of the electronics. The amount of optimal shielding is equivalent to the effective thickness of astronaut's space suit, which means that the same dose will be measured as what the

  19. Fallout from Chernobyl and incidence of childhood leukaemia in Finland, 1976-92.

    PubMed Central

    Auvinen, A.; Hakama, M.; Arvela, H.; Hakulinen, T.; Rahola, T.; Suomela, M.; Söderman, B.; Rytömaa, T.

    1994-01-01

    OBJECTIVE--To assess effects of fallout from Chernobyl on incidence of childhood leukaemia in Finland. DESIGN--Nationwide cohort study. External exposure measured for 455 Finnish municipalities with instruments driven 19,000 km throughout the country. Values specific to municipalities corrected for shielding due to houses and fallout from A bomb testing. Internal exposure estimated from whole body measurements on a random sample of 81 children. Mean effective dose for two years after incident calculated from these measurements. Data on childhood leukaemia obtained from Finnish cancer registry and verified through hospitals treating childhood cancers. SETTING--Finland, one of the countries most heavily contaminated by the Chernobyl accident; the population was divided into fifths by exposure. SUBJECTS--Children aged 0-14 years in 1976-92. MAIN OUTCOME MEASURES--Standardised incidence ratio of childhood leukaemia and relative excess risk of childhood leukaemia per mSv. From incidence data of Finnish cancer registry for 1976-85, expected numbers specific to sex and age group (0-4, 5-9, and 10-14 years) were calculated for each municipality for three periods (1976-85, 1986-8, and 1989-92) and pooled as exposure fifths. Dose response was estimated as regression slope of standardised incidence ratios on mean doses for fifths for each period. RESULTS--Population weighted mean effective doses for first two years after the accident were 410 microSv for the whole country and 970 microSv for the population fifth with the highest dose. In all Finland the incidence of childhood leukaemia did not increase 1976-92. The relative excess risk 1989-92 was not significantly different from zero (7% per mSv; 95% confidence interval -27% to 41%). CONCLUSIONS--An important increase in childhood leukaemia can be excluded. Any effect is smaller than eight extra cases per million children per year in Finland. The results are consistent with the magnitude of effect expected. PMID:8044092

  20. Diffusion tensor imaging and neurocognition in survivors of childhood acute lymphoblastic leukaemia.

    PubMed

    Edelmann, Michelle N; Krull, Kevin R; Liu, Wei; Glass, John O; Ji, Qing; Ogg, Robert J; Sabin, Noah D; Srivastava, Deo Kumar; Robison, Leslie L; Hudson, Melissa M; Reddick, Wilburn E

    2014-11-01

    Survivors of childhood acute lymphoblastic leukaemia are at risk for neurocognitive impairment, though little information is available on its association with brain integrity, particularly for survivors treated without cranial radiation therapy. This study compares neurocognitive function and brain morphology in long-term adult survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy alone (n = 36) to those treated with cranial radiation therapy (n = 39) and to healthy control subjects (n = 23). Mean (standard deviation) age at evaluation was 24.9 (3.6) years for the chemotherapy group and 26.7 (3.4) years for the cranial radiation therapy group, while time since diagnosis was 15.0 (1.7) and 23.9 (3.1) years, respectively. Brain grey and white matter volume and diffusion tensor imaging was compared between survivor groups and to 23 healthy controls with a mean (standard deviation) age of 23.1 (2.6) years. Survivors treated with chemotherapy alone had higher fractional anisotropy in fibre tracts within the left (P < 0.05), but not in the right, hemisphere when compared to controls. Survivors of acute lymphoblastic leukaemia, regardless of treatment, had a lower ratio of white matter to intracranial volume in frontal and temporal lobes (P < 0.05) compared with control subjects. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone performed worse in processing speed (P < 0.001), verbal selective reminding (P = 0.01), and academics (P < 0.05) compared to population norms and performed better than survivors treated with cranial radiation therapy on verbal selective reminding (P = 0.02), processing speed (P = 0.05) and memory span (P = 0.009). There were significant associations between neurocognitive performance and brain imaging, particularly for frontal and temporal white and grey matter volume. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone demonstrated significant long-term differences in

  1. Sapphirine and fluid inclusions in Tel Thanoun mantle xenoliths,Syria

    NASA Astrophysics Data System (ADS)

    Bilal, Ahmad

    2016-04-01

    Volcanoes along the Syrian rift, which extend a distance of about 1000 km, brought to the surface mantle xenoliths within erupted basalts, during multiples periods of volcanic activity. Xenoliths in early Cretaceous volcanoes originate in the garnet peridotite field of the subcontinental mantle, whereas those in recent Cenozoic volcanoes, the prime object of this study, are issued from shallower levels (spinel peridotite field). The recent discovery of sapphirine-bearing websterite in Tel Thanoun, a small volcanic diatreme inside the larger Quaternary volcanic field (Djebel Al Arab), allows us to estimate the P-T evolution and fluid-rock interaction at the volcanic source. Harzburgites and lherzolites are equilibrated at a temperature of about 1000 °C at a depth of 35-40 km. Sapphirine appears to have formed during cooling, at depth at a temperature of about 900 °C, at a time where spinel exsolution occurred in harzburgite and lherzolite pyroxenes. This occurred in the presence of a high-density pure CO2 fluid phase, still present in primary fluid inclusions. The highly-aluminous sapphirine-bearing protolith might be former garnet websterite (possibly uplifted during cretaceous magmatism), which resided and cooled in the spinel peridotite stability field, and was then dragged and brought to the surface by quaternary basalts.

  2. Mesenchymal stromal cells primed with Paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia-bearing mice.

    PubMed

    Pessina, Augusto; Coccè, Valentina; Pascucci, Luisa; Bonomi, Arianna; Cavicchini, Loredana; Sisto, Francesca; Ferrari, Maura; Ciusani, Emilio; Crovace, Antonio; Falchetti, Maria Laura; Zicari, Sonia; Caruso, Arnaldo; Navone, Stefania; Marfia, Giovanni; Benetti, Anna; Ceccarelli, Piero; Parati, Eugenio; Alessandri, Giulio

    2013-03-01

    Current leukaemia therapy focuses on increasing chemotherapy efficacy. Mesenchymal stromal cells (MSCs) have been proposed for carrying and delivery drugs to improve killing of cancer cells. We have shown that MSCs loaded with Paclitaxel (PTX) acquire a potent anti-tumour activity. We investigated the effect of human MSCs (hMSCs) and mouse SR4987 loaded with PTX (hMSCsPTX and SR4987PTX) on MOLT-4 and L1210, two leukaemia cell (LCs) lines of human and mouse origin, respectively. SR4987PTX and hMSCsPTX showed strong anti-LC activity. hMSCsPTX, co-injected with MOLT-4 cells or intra-tumour injected into established subcutaneous MOLT-4 nodules, strongly inhibited growth and angiogenesis. In BDF1-mice-bearing L1210, the intraperitoneal administration of SR4987PTX doubled mouse survival time. In vitro, both hMSCs and hMSCsPTX released chemotactic factors, bound and formed rosettes with LCs. In ultrastructural analysis of rosettes, hMSCsPTX showed no morphological alterations while the attached LCs were apoptotic and necrotic. hMSCs and hMSCsPTX released molecules that reduced LC adhesion to microvascular endothelium (hMECs) and down-modulated ICAM1 and VCAM1 on hMECs. Priming hMSCs with PTX is a simple procedure that does not require any genetic cell manipulation. Once the effectiveness of hMSCsPTX on established cancers in mice is proven, this procedure could be proposed for leukaemia therapy in humans.

  3. Constitutional trisomy 8p11.21-q11.21 mosaicism: a germline alteration predisposing to myeloid leukaemia.

    PubMed

    Ripperger, Tim; Tauscher, Marcel; Praulich, Inka; Pabst, Brigitte; Teigler-Schlegel, Andrea; Yeoh, Allen; Göhring, Gudrun; Schlegelberger, Brigitte; Flotho, Christian; Niemeyer, Charlotte M; Steinemann, Doris

    2011-10-01

    Juvenile myelomonocytic leukaemia (JMML) is a unique myeloproliferative disorder of early childhood. Frequently, mutations in NRAS, KRAS, PTPN11, NF1 or CBL are found in these patients. Monosomy 7 is the most common cytogenetic aberration. To identify submicroscopic genomic copy number alterations, 20 JMML samples were analysed by comparative genomic hybridization. Ten out of 20 samples displayed additional submicroscopic alterations. In two patients, an almost identical gain of chromosome 8 was identified. In both patients, fluorescence in situ hybridization confirmed a constitutional partial trisomy 8 mosaic (cT8M). A survey on 27 cT8M patients with neoplasms showed that 21 had myeloid malignancies, and five of these had a JMML. Notably, the region gained in our cases is the smallest gain of chromosome 8 reported in cT8M cases with malignancies so far. Our results dramatically reduce the critical region to 8p11.21q11.21 harbouring 31 protein coding genes and two non-coding RNAs, e.g. MYST3, IKBKB, UBE2V2, GOLGA7, FNTA and MIR486--a finding with potential implications for the role of somatic trisomy 8 in myeloid malignancies. Further investigations are required to more comprehensively determine how constitutional partial trisomy 8 mosaicisms may contribute to leukaemogenesis in different mutational subtypes of JMML and other myeloid malignancies.

  4. PU.1 downregulation in murine radiation-induced acute myeloid leukaemia (AML): from molecular mechanism to human AML

    PubMed Central

    Verbiest, Tom; Bouffler, Simon; Nutt, Stephen L.; Badie, Christophe

    2015-01-01

    The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the −14kb SPI1 upstream regulatory element were described previously in human primary AML, although they are rare events. Other mechanisms linked to PU.1 downregulation in human AML include TP53 deletion, FLT3-ITD mutation and the recurrent AML1-ETO [t(8;21)] and PML-RARA [t(15;17)] translocations. This review provides an up-to-date overview on our current understanding of the involvement of PU.1 in the initiation and development of radiation-induced AML, together with recommendations for future murine and human studies. PMID:25750172

  5. Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma.

    PubMed

    Smeets, Monique F M A; Chan, Angela C; Dagger, Samantha; Bradley, Cara K; Wei, Andrew; Izon, David J

    2013-01-01

    The Ets transcription factor Fli-1 is preferentially expressed in hematopoietic tissues and cells, including immature T cells, but the role of Fli-1 in T cell development has not been closely examined. To address this we retrovirally overexpressed Fli-1 in various in vitro and in vivo settings and analysed its effect on T cell development. We found that Fli-1 overexpression perturbed the DN to DP transition and inhibited CD4 development whilst enhancing CD8 development both in vitro and in vivo. Surprisingly, Fli-1 overexpression in vivo eventuated in development of pre-T cell lymphoblastic leukaemia/lymphoma (pre-T LBL). Known Fli-1 target genes such as the pro-survival Bcl-2 family members were not found to be upregulated. In contrast, we found increased NOTCH1 expression in all Fli-1 T cells and detected Notch1 mutations in all tumours. These data show a novel function for Fli-1 in T cell development and leukaemogenesis and provide a new mouse model of pre-T LBL to identify treatment options that target the Fli-1 and Notch1 signalling pathways.

  6. Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

    PubMed Central

    Rumjanek, Vivian M.; Vidal, Raphael S.; Maia, Raquel C.

    2013-01-01

    The hallmark of CML (chronic myeloid leukaemia) is the BCR (breakpoint cluster region)–ABL fusion gene. CML evolves through three phases, based on both clinical and pathological features: a chronic phase, an accelerated phase and blast crisis. TKI (tyrosine kinase inhibitors) are the treatment modality for patients with chronic phase CML. The therapeutic potential of the TKI imatinib is affected by BCR–ABL dependent an independent mechanisms. Development of MDR (multidrug resistance) contributes to the overall clinical resistance. MDR involves overexpression of ABC -transporters (ATP-binding-cassette transporter) among other features. MDR studies include the analysis of cancer cell lines selected for resistance. CML blast crisis is accompanied by increased resistance to apoptosis. This work reviews the role played by the influx transporter OCT1 (organic cation transporter 1), by efflux ABC transporters, molecules involved in the modulation of apoptosis (p53, Bcl-2 family, CD95, IAPs (inhibitors of apoptosis protein)], Hh and Wnt/β-catenin pathways, cytoskeleton abnormalities and other features described in leukaemic cells of clinical samples and CML cell lines. An MDR cell line, Lucena-1, generated from K562 by stepwise exposure to vincristine, was used as our model and some potential anticancer drugs effective against the MDR cell line and patients’ samples are presented. PMID:24070327

  7. A Study of Haemostatic Parameters in Patients of Chronic Myeloid Leukaemia

    PubMed Central

    Gupta, Naresh; Singh, Tejinder; Agarwal, Sunita

    2016-01-01

    Introduction Chronic Myeloid Leukaemia (CML) is characterized by derangement of various components of the haemostatic system resulting in thrombo-haemorrhagic complications. Although less common than other myeloproliferative neoplasms, derangement of various components of the haemostatic system is observed in CML. Haemostatic abnormalities have been described in relation to hyperleucostasis and drugs used to treat CML. However, the correlation between haemostatic derangements and phase of CML is unclear in the literature. Aim The purpose of this cross-sectional study was to assay various haemostatic parameters in patients of CML receiving Imatinib and to determine any correlation between them and phases of disease as well as the status of remission. Materials and Methods The study included 30 patients with CML (17 males, 13 females, mean age of 35.53 ± 8.92 years) receiving imatinib mesylate. Haemostatic parameters including platelet counts, Prothrombin Time (PT), activated Partial Thromboplastin Time (APTT), fibrinogen, D-dimers and Factor VIII levels were assayed for all patients using standard methods. Bcr-abl gene product (quantitative) was determined on the peripheral blood by reverse transcriptase polymerase chain reaction (RT-PCR). Patients were grouped into phases of disease (chronic, accelerated and blast) and their response to imatinib was determined in the form of remission (clinical, haematological and molecular). Correlations were drawn between them using spearman’s coefficient. Results A significant positive correlation was found between PT (p=0.002), fibrinogen (p=0.011), D-dimers (p=0.050), Factor VIII levels (p=0.006) with the phase of CML and a significant negative correlation was observed between PT (p=0.003, 0.006), fibrinogen (p=0.010, 0.005), D-dimers (p=0.035, 0.017), Factor VIII levels (p=0.005, 0.001) and clinical and haematological remission respectively. No significant correlation of platelet counts and APTT was seen with the phase of

  8. Core binding factor acute myeloid leukaemia and c-KIT mutations.

    PubMed

    Riera, Ludovica; Marmont, Filippo; Toppino, Daniela; Frairia, Chiara; Sismondi, Francesca; Audisio, Ernesta; Di Bello, Cristiana; D'Ardia, Stefano; Di Celle, Paola Francia; Messa, Emanuela; Inghirami, Giorgio; Vitolo, Umberto; Pich, Achille

    2013-05-01

    Core binding factor (CBF) acute myeloid leukaemia (AML) represents 5-8% of all AMLs and has a relatively favourable prognosis. However, activating c-KIT mutations are reported to be associated with higher risk of relapse and shorter survival. To verify the incidence and prognostic value of c-KIT mutations in CBF AML, we retrospectively analysed bone marrow samples of 23 consecutive adult patients with de novo CBF AML [14 inv(16) and 9 t(8;21)] treated at a single institution from 2000 to 2011. All patients received standard induction chemotherapy with cytarabine, idarubicin and etoposide; 13 underwent allogeneic stem cell transplantation. c-KIT mutations in exons 8, 9, 10, 11, 13, 14 and 17 were assessed by PCR amplification in combination with direct sequencing. c-KIT mutations (3 in exon 10 and 4 in exon 17) were detected in 7/23 (30.4%) patients, 3 with t(8;21) and 4 with inv(16). No difference in c-KIT mutation status was observed between cases with inv(16) or t(8;21) alone and cases with additional cytogenetic abnormalities. No association between gender, age, white blood cell and platelet count, peripheral blood and bone marrow blast cells at diagnosis, achievement of complete remission, cytogenetic risk groups and Wilms tumour gene 1 (WT1) levels was found. On the contrary, lactate dehydrogenase (LDH) values were higher in mutated than in non-mutated patients (p=0.01). Overall survival (OS) rates were longer in CBF compared to the other types of AML and disease-free survival (DFS) was longer in inv(16) than in t(8;21) AML. OS and DFS were similar in mutated and non-mutated CBF AML patients. Our results confirm a better prognosis for CBF AML than all other AML categories, and for inv(16) than t(8;21) AML. However, no prognostic value for c-KIT mutational status was found in our series. The association between LDH levels and c-KIT mutation would indicate a more active proliferation for mutated CBF AML.

  9. miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia

    SciTech Connect

    Zhu, Hong; Miao, Mei-hua; Ji, Xue-qiang; Xue, Jun; Shao, Xue-jun

    2015-04-03

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. - Highlights: • miR-664 mimics promote the proliferation and invasion of T-ALL cells. • miR-664 inhibitors inhibit the proliferation and invasion of T-ALL cells. • miR-664 targets 3′ UTR of PLP2 in T-ALL cells. • miR-664 negatively regulates PLP2 in T-ALL cells.

  10. Significant Haematogone Proliferation Mimicking Relapse in Acute Lymphoblastic Leukaemia on Therapy

    PubMed Central

    Misra, Ruchira; Dorwal, Pranav; Sharma, Rashi; Sachdev, Ritesh

    2017-01-01

    Haematogones are benign B lymphoid precursors which may mimic neoplastic lymphoblasts and pose diagnostic difficulty especially when the percentage of haematogones exceeds 10% in the bone marrow. Flow cytometric analysis with combination of CD19/CD10/CD20/CD34/CD38/CD58 can be used to differentiate the two depending upon the difference in the fluorescence intensity between blasts and haematogones. We hereby present a case of Common Acute Lymphoblastic Leukaemia Associated Antigen (CALLA) positive Acute Lymphoblastic Leukaemia (ALL), in which patient presented with haematogone proliferation in bone marrow after 6 months of chemotherapy mimicking relapse. The distinction was made on flow cytometric immunophenotyping by using optimal antibody combination. Distinction of benign haematogones from neoplastic lymphoblasts is essential for disease management in cases of post chemotherapy or post marrow transplant, especially in patients of ALL. Flow cytometric immunophenotyping is reliable to distinguish haematogones from residual lymphoblasts in almost all cases when optimal antibody combinations are used. PMID:28384870

  11. Chronic myelogenous leukaemia with persistent neutrophilia, eosinophilia and basophilia in a cat.

    PubMed

    Mochizuki, Hiroyuki; Seki, Takahiro; Nakahara, Yoshitaka; Tomita, Akitada; Takahashi, Masashi; Fujino, Yasuhito; Ohno, Koichi; Tsujimoto, Hajime

    2014-06-01

    Chronic myelogenous leukaemia was diagnosed in a 7-year-old male neutered domestic shorthair cat. Leukocytosis (74,900/µl)--mature neutrophilia, eosinophilia and basophilia--was observed. Bone marrow aspiration revealed hypercellularity with proliferation of cells of myeloid lineage. An underlying condition leading to leukocytosis was not identified. The severe leukocytosis did not respond to antibiotic therapy. Based on these findings, chronic myelogenous leukaemia was diagnosed. Because of the absence of clinical signs, the cat was monitored without treatment until 7 months after diagnosis, when it developed pruritic skin lesions. Pruritus was controlled with oral prednisolone. Forty-two months after diagnosis, the cat developed nasal lymphoma, which was treated with radiation therapy, resulting in complete remission. The cat was still in good physical condition 63 months after diagnosis, despite the persistence of marked neutrophilia, eosinophilia and basophilia.

  12. Plastic isolators for treatment of acute leukaemia patients under "germ-free" conditions.

    PubMed Central

    Trexler, P C; Spiers, A S; Gaya, H

    1975-01-01

    A gnotobiotic isolation system based on those developed in veterinary research has been constructed for hospital use. Fifteen patients with leukaemia and neutropenia spent a total of 110 weeks in plastic isolators, and none acquired any infection. Endogenous flora was effectively suppressed by topical antiseptics and gastrointestinal decontamination effected with nonabsorbable antibiotics. The isolator system was acceptable to patients and staff and much cheaper than the use of sterile rooms. Other advantages of the system are portability, easy storage, and use on ordinary open wards without prejudice to the microbiological protection afforded. It is as yet uncertain whether protective environments of this type will substantially improve the outcome of treatment for the acute leukaemias. PMID:1203666

  13. Combination chemotherapy for marrow relapse in children and adolescents with acute lymphocytic leukaemia.

    PubMed

    Amadori, S; Spiriti, M A; Meloni, G; Pacilli, L; Papa, G; Mandelli, F

    1981-04-01

    38 children with acute lymphocytic leukaemia (ALL) in haematologic relapse were retreated with vincristine, daunomycin and prednisone (VPD) together with intrathecal methotrexate and prednisone, followed by asparaginase in those patients not in complete remission after 4 weeks. The overall complete remission (CR) rate was 79%; asparaginase was needed to achieve CR in 7 of the 30 responding patients. The median duration of second remission was only 36 weeks, but 6 out of 15 children receiving the COAP-POMP-CART consolidation regimen remain in continuous second remission after 37-260 weeks; 3 of them are currently off all therapy. It is concluded that a prolonged second remission can be achieved in children with ALL in bone marrow relapse by combining intensive chemotherapy with the prevention of meningeal leukaemia.

  14. Acute sinusitis and blindness as the first presentation of chronic lymphocytic leukaemia.

    PubMed

    Lim, K H; Thomas, G; van Beers, E J; Hosman, A E; Mourits, M P; van Noesel, C J M; Kater, A P; Reinartz, S M

    2014-12-01

    Chronic lymphocytic leukaemia (CLL) is the most frequent form of leukaemia among adults in the Western world, presenting at a median age of 65 years. The diagnosis is usually made incidentally during routine blood examination while the disease is still in its early phase. We report a case of blindness of 24 hours due to acute sinusitis based on CLL localisation in a patient with undiagnosed CLL. Emergency endoscopic sinus surgery and intra- and extra-ocular orbital decompression were performed. The sinusitis resolved after surgery and intravenous antibiotics. Her vision improved within 24 hours and eventually recovered completely after six months. Her CLL remained in an indolent state, needing no active treatment. This case illustrates that blindness from a lymphoproliferative disorder may be treated with emergency endoscopic sinus surgery instead of conventional chemotherapy in order to salvage the vision first, even if the vision is lost for more than 24 hours.

  15. Monoclonal cryoimmunoglobulin with anti-cytomegalovirus activity associated with T cell chronic lymphocytic leukaemia.

    PubMed Central

    Seigneurin, J M; Renversez, J C; Baccard, M; Seigneurin, D; Micouin, C

    1980-01-01

    A patient with chronic T cell lymphocytic leukaemia developed a monoclonal immunoglobulin (IgG3 kappa = 14 g/l) which was in part cryoprecipitable. At the same time, a subclinical CMV infection occurred which was associated with a neutropenia and thrombocytopenia, and which led to a rise in anti-CMV antibodies. The F(ab')2 fragment of IgG3 kappa, obtained by enzymatic cleavage, was examined for several antiviral activities and it was found to have a strong anti-CMV activity using the immunofluorescence test with anti-kappa conjugate. This is one of the few examples of a cryoglobulin with specific antiviral activity. The leukaemia, possibly together with immunosuppressive therapy, may have been responsible for the uncontrolled proliferation of the clone producing the cryoimmunoglobulin. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:6254708

  16. Acute myelomonocytic leukaemia with short-term spontaneous remission in a cat.

    PubMed

    Mylonakis, M E; Petanides, T A; Valli, V E; Vernau, W; Koytinas, A F; Michael, R S

    2008-06-01

    A 2-year-old, spayed female domestic shorthair cat was referred with a history of anorexia and depression of 1 week duration. On physical examination, the cat was lethargic and febrile, with splenomegaly, anisocoria and ulcerative stomatitis. A complete blood count (CBC) and a biochemistry profile showed leukocytosis, numerous blast cells in the peripheral blood, thrombocytopenia, hyperglobulinaemia and a positive test for feline leukaemia virus antigen. A diagnosis of acute myelomonocytic leukaemia was made on the basis of the results of bone marrow cytology, histopathology, and immunochemistry (CD3, CD79a, lysozyme, and myeloperoxidase) tests. Following an unexpected 1-month period of clinical and clinicopathological remission without chemotherapy, the cat relapsed and died 1 week later.

  17. Pooled analysis of recent studies on magnetic fields and childhood leukaemia

    PubMed Central

    Kheifets, L; Ahlbom, A; Crespi, C M; Draper, G; Hagihara, J; Lowenthal, R M; Mezei, G; Oksuzyan, S; Schüz, J; Swanson, J; Tittarelli, A; Vinceti, M; Wunsch Filho, V

    2010-01-01

    Background: Previous pooled analyses have reported an association between magnetic fields and childhood leukaemia. We present a pooled analysis based on primary data from studies on residential magnetic fields and childhood leukaemia published after 2000. Methods: Seven studies with a total of 10 865 cases and 12 853 controls were included. The main analysis focused on 24-h magnetic field measurements or calculated fields in residences. Results: In the combined results, risk increased with increase in exposure, but the estimates were imprecise. The odds ratios for exposure categories of 0.1–0.2 μT, 0.2–0.3 μT and ⩾0.3 μT, compared with <0.1 μT, were 1.07 (95% CI 0.81–1.41), 1.16 (0.69–1.93) and 1.44 (0.88–2.36), respectively. Without the most influential study from Brazil, the odds ratios increased somewhat. An increasing trend was also suggested by a nonparametric analysis conducted using a generalised additive model. Conclusions: Our results are in line with previous pooled analyses showing an association between magnetic fields and childhood leukaemia. Overall, the association is weaker in the most recently conducted studies, but these studies are small and lack methodological improvements needed to resolve the apparent association. We conclude that recent studies on magnetic fields and childhood leukaemia do not alter the previous assessment that magnetic fields are possibly carcinogenic. PMID:20877339

  18. Specific aquaporins facilitate Nox-produced hydrogen peroxide transport through plasma membrane in leukaemia cells.

    PubMed

    Vieceli Dalla Sega, Francesco; Zambonin, Laura; Fiorentini, Diana; Rizzo, Benedetta; Caliceti, Cristiana; Landi, Laura; Hrelia, Silvana; Prata, Cecilia

    2014-04-01

    In the last decade, the generation and the role of reactive oxygen species (ROS), particularly hydrogen peroxide, in cell signalling transduction pathways have been intensively studied, and it is now clear that an increase of ROS level affects cellular growth and proliferation pathways related to cancer development. Hydrogen peroxide (H2O2) has been long thought to permeate biological membranes by simple diffusion since recent evidence challenged this notion disclosing the role of aquaporin water channels (AQP) in mediating H2O2 transport across plasma membranes. We previously demonstrated that NAD(P)H oxidase (Nox)-generated ROS sustain glucose uptake and cellular proliferation in leukaemia cells. The aim of this study was to assess whether specific AQP isoforms can channel Nox-produced H2O2 across the plasma membrane of leukaemia cells affecting downstream pathways linked to cell proliferation. In this work, we demonstrate that AQP inhibition caused a decrease in intracellular ROS accumulation in leukaemia cells both when H2O2 was produced by Nox enzymes and when it was exogenously added. Furthermore, AQP8 overexpression or silencing resulted to modulate VEGF capacity of triggering an H2O2 intracellular level increase or decrease, respectively. Finally, we report that AQP8 is capable of increasing H2O2-induced phosphorylation of both PI3K and p38 MAPK and that AQP8 expression affected positively cell proliferation. Taken together, the results here reported indicate that AQP8 is able to modulate H2O2 transport through the plasma membrane affecting redox signalling linked to leukaemia cell proliferation.

  19. Childhood infectious diseases and risk of leukaemia in an adult population.

    PubMed

    Parodi, Stefano; Crosignani, Paolo; Miligi, Lucia; Nanni, Oriana; Ramazzotti, Valerio; Rodella, Stefania; Costantini, Adele Seniori; Tumino, Rosario; Vindigni, Carla; Vineis, Paolo; Stagnaro, Emanuele

    2013-10-15

    Our study is aimed at investigating the association between common childhood infectious diseases (measles, chickenpox, rubella, mumps and pertussis) and the risk of developing leukaemia in an adult population. A reanalysis of a large population-based case-control study was carried out. Original data included 1,771 controls and 649 leukaemia cases from 11 Italian areas. To contain recall bias, the analysis was restricted to subjects directly interviewed and with a good quality interview (1,165 controls and 312 cases). Odds ratios (ORs) and their related 95% confidence intervals (95% CIs) were estimated by unconditional polychotomous logistic regression model adjusting for age, gender and occupational and lifestyle exposures. A protective effect of at least one infection (OR = 0.66, 95% CI: 0.45-0.97), measles (OR = 0.57, 95% CI: 0.39-0.82) and pertussis (OR = 0.66, 95% CI: 0.45-0.98) was observed for chronic lymphoid leukaemia (CLL). The number of infections was strongly inversely associated with the risk of CLL (p = 0.002, test for trend). With regard to the other types of leukaemia, only a protective effect of pertussis was observed for AML (OR = 0.52, 95% CI: 0.32-0.87). Our results pointed out a protective role of childhood infectious diseases on the risk of CLL in adults. Although a specific antioncogenic effect of some infectious disease, especially measles, cannot be ruled out, the observed decrease of risk with increasing number of infections suggests that a more general "hygiene hypothesis" could be the most likely explanation of the detected association. The protective role of pertussis remains to be elucidated.

  20. Case report: late aggressive meningioma following prophylactic cranial irradiation for acute lymphoblastic leukaemia.

    PubMed

    Stein, M E; Drumea, K; Guilbord, J N; Ben-Itzhak, O; Kuten, A

    1995-10-01

    The clinical, radiological and pathological findings in a 28-year-old female patient who developed aggressive meningioma 20 years after prophylatic cranial irradiation (PCI) for acute lymphoblastic leukaemia (ALL) are described here. Only four cases of late atypical/aggressive meningioma following PCI were detected in a thorough search of the literature. The high cure rate in childhood ALL, attributable to aggressive chemotherapy and PCI, is capable of inducing secondary brain tumour, including aggressive meningioma.

  1. Tumour lysis syndrome after treatment of chronic lymphocytic leukaemia with fludarabine.

    PubMed Central

    Montalban, C.; Liaño, F.; Aguilera, A.

    1994-01-01

    Fludarabine is one of the most recent and promising therapeutic agents for chronic lymphocytic leukaemia. We describe a patient who developed tumour lysis syndrome after the first course of treatment with fludarabine and call attention to this uncommon but potentially lethal complication that has not been previously taken into account in this neoplasia. It should always be anticipated when patients are treated with new and effective drugs. PMID:7971632

  2. The mechanism of recurrence of mouse myeloid leukaemia after total body irradiation and bone marrow transplantation.

    PubMed

    Poljak-Blazi, M; Popović, M; Majić, T

    1994-01-01

    RFM mice were X-irradiated (9.5 Gy) 3, 4, 5, 6 or 7 days after inoculation of a transplantable strain-specific myeloid leukaemia (ML) and were reconstituted or not with syngeneic or allogeneic bone marrow cells. Recurrent leukaemia was observed in mice with either type of the bone marrow transplant, indicating that ML cells survived the dose of 9.5 Gy of X-rays. ML cells exposed in vitro to high doses of X-rays (20, 30, 40, 50, 60 Gy) and injected into lethally irradiated syngeneic recipients were still capable of forming leukaemic colonies on the spleens. Higher doses (70, 80, 90 and 100 Gy) abolished the colony formation completely. Irradiated ML cells were also capable of causing leukaemia (hepatosplenomegaly) if inoculated into lethally irradiated CBA mice reconstituted with bone marrow cells of CBA or RFM mice. That was attributed to the release of a leukaemogenic factor from the ML cells, capable of transforming transplanted normal cells.

  3. Incidence of persistent viraemia and latent feline leukaemia virus infection in cats with lymphoma.

    PubMed

    Stützer, Bianca; Simon, Karin; Lutz, Hans; Majzoub, Monir; Hermanns, Walter; Hirschberger, Johannes; Sauter-Louis, Carola; Hartmann, Katrin

    2011-02-01

    In the past, feline leukaemia virus (FeLV) infection, and also latent FeLV infection, were commonly associated with lymphoma and leukaemia. In this study, the prevalence of FeLV provirus in tumour tissue and bone marrow in FeLV antigen-negative cats with these tumours was assessed. Seventy-seven diseased cats were surveyed (61 antigen-negative, 16 antigen-positive). Blood, bone marrow, and tumour samples were investigated by two polymerase chain reaction (PCR) assays detecting deoxyribonucleic acid (DNA) sequences of the long terminal repeats (LTR) and the envelope (env) region of the FeLV genome. Immunohistochemistry (IHC) was performed in bone marrow and tumour tissue. None of the antigen-negative cats with lymphoma was detectably infected with latent FeLV. The prevalence of FeLV viraemia in cats with lymphoma was 20.8%. This suggests that causes other than FeLV play a role in tumorigenesis, and that latent FeLV infection is unlikely to be responsible for most feline lymphomas and leukaemias.

  4. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

    PubMed Central

    Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

    2013-01-01

    FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan–Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients. PMID:23929599

  5. A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity

    PubMed Central

    Fuentes-Garí, María; Misener, Ruth; García-Munzer, David; Velliou, Eirini; Georgiadis, Michael C.; Kostoglou, Margaritis; Pistikopoulos, Efstratios N.; Panoskaltsis, Nicki; Mantalaris, Athanasios

    2015-01-01

    Acute myeloid leukaemia is characterized by marked inter- and intra-patient heterogeneity, the identification of which is critical for the design of personalized treatments. Heterogeneity of leukaemic cells is determined by mutations which ultimately affect the cell cycle. We have developed and validated a biologically relevant, mathematical model of the cell cycle based on unique cell-cycle signatures, defined by duration of cell-cycle phases and cyclin profiles as determined by flow cytometry, for three leukaemia cell lines. The model was discretized for the different phases in their respective progress variables (cyclins and DNA), resulting in a set of time-dependent ordinary differential equations. Cell-cycle phase distribution and cyclin concentration profiles were validated against population chase experiments. Heterogeneity was simulated in culture by combining the three cell lines in a blinded experimental set-up. Based on individual kinetics, the model was capable of identifying and quantifying cellular heterogeneity. When supplying the initial conditions only, the model predicted future cell population dynamics and estimated the previous heterogeneous composition of cells. Identification of heterogeneous leukaemia clones at diagnosis and post-treatment using such a mathematical platform has the potential to predict multiple future outcomes in response to induction and consolidation chemotherapy as well as relapse kinetics. PMID:26040591

  6. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia.

    PubMed

    Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-Aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

    2013-09-01

    FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients.

  7. Multi-loci diagnosis of acute lymphoblastic leukaemia with high-throughput sequencing and bioinformatics analysis.

    PubMed

    Ferret, Yann; Caillault, Aurélie; Sebda, Shéhérazade; Duez, Marc; Grardel, Nathalie; Duployez, Nicolas; Villenet, Céline; Figeac, Martin; Preudhomme, Claude; Salson, Mikaël; Giraud, Mathieu

    2016-05-01

    High-throughput sequencing (HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow-up. As part of an immunoglobulin/T cell receptor-based minimal residual disease (MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci (TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients.

  8. Quercus Suber L. Cork Extracts Induce Apoptosis in Human Myeloid Leukaemia HL-60 Cells.

    PubMed

    Bejarano, Ignacio; Godoy-Cancho, Belén; Franco, Lourdes; Martínez-Cañas, Manuel A; Tormo, María A

    2015-08-01

    Quercus suber L. cork contains a diversity of phenolic compounds, mostly low molecular weight phenols. A rising number of reports support with convergent findings that polyphenols evoke pro-apoptotic events in cancerous cells. However, the literature related to the anti-cancer bioactivity of Q. suber L. cork extractives (QSE) is still limited. Herein, we aim to describe the antitumor potential displayed by cork extractives obtained by different extraction methods in the human promyelocytic leukaemia cells. In order to quantify the effects of QSE on cancer cells viability, phosphatidylserine exposure, caspase-3 activity, mitochondrial membrane potential and cell cycle were evaluated. The results indicated that the QSE present a time-dependent and dose-dependent cytotoxicity in the human promyelocytic leukaemia cells. Such a noxious effect leads these leukaemia cells to their death through apoptotic processes by altering the mitochondrial outer membrane potential, activating caspase-3 and externalizing phosphatidylserine. However, cells cycle progression was not affected by the treatments. This study contributes to open a new way to use this natural resource by exploiting its anti-cancer properties. Moreover, it opens new possibilities of application of cork by-products, being more efficient in the sector of cork-based agriculture. Copyright © 2015 John Wiley & Sons, Ltd.

  9. Childhood leukaemia and non-Hodgkin's lymphoma in relation to proximity to railways.

    PubMed

    Dickinson, H O; Hammal, D M; Dummer, T J B; Parker, L; Bithell, J F

    2003-03-10

    We investigated whether living close to railway lines is a risk factor for childhood leukaemia and non-Hodgkin's lymphoma in electoral wards in England and Wales, 1966-1987. The national rail network, 1966-1987, was digitised and the numbers of cases in each ward were related to two measures of environmental exposure to railways: a proximity and a density function, contributions to these functions being weighted by the frequency of use and time in use of each stretch of railway. Poisson regression was used to derive rate ratios in relation to these measures of exposure to railways, both unadjusted and adjusted for population mixing. We found no association between risk of leukaemia and railway proximity (unadjusted rate ratio for trend from the lowest to the median value=1.006, 95% CI: 0.998 - 1.013, P=0.14) and a very small association with railway density, of marginal statistical significance (rate ratio for trend=1.001, 95% CI: 1.000 - 1.003, P=0.05). This effect depended on two deprived, urban wards with high railway density and high population mixing and became nonsignificant (P=0.09) after allowing for population mixing. The very weak association between railway density and risk of childhood leukaemia is likely to be a consequence of the association between population mixing and proximity to railways in very deprived, urban wards.

  10. Outcomes of a telemonitoring-based program (telEPOC) in frequently hospitalized COPD patients

    PubMed Central

    Esteban, Cristóbal; Moraza, Javier; Iriberri, Milagros; Aguirre, Urko; Goiria, Begoña; Quintana, José M; Aburto, Myriam; Capelastegui, Alberto

    2016-01-01

    Background The increasing prevalence of chronic diseases requires changes in health care delivery. In COPD, telemedicine appears to be a useful tool. Our objective was to evaluate the efficacy (in improving health care-resource use and clinical outcomes) of a telemonitoring-based program (telEPOC) in COPD patients with frequent hospitalizations. Materials and methods We conducted a nonrandomized observational study in an intervention cohort of 119 patients (Galdakao-Usansolo Hospital) and a control cohort of 78 patients (Cruces Hospital), followed up for 2 years (ClinicalTrials.gov identifier: NCT02528370). The inclusion criteria were two or more hospital admissions in the previous year or three or more admissions in the previous 2 years. The intervention group received telemonitoring plus education and controls usual care. Results Most participants were men (13% women), and the sample had a mean age of 70 years, forced expiratory volume in 1 second of 45%, Charlson comorbidity index score of 3.5, and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index score of 4.1. In multivariate analysis, the intervention was independently related to lower rates of hospital admission (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.27–0.54; P<0.0001), emergency department attendance (OR 0.56, 95% CI 0.35–0.92; P<0.02), and 30-day readmission (OR 0.46, 95% CI 0.29–0.74; P<0.001), as well as cumulative length of stay (OR 0.58, 95% CI 0.46–0.73; P<0.0001). The intervention was independently related to changes in several clinical variables during the 2-year follow-up. Conclusion An intervention including telemonitoring and education was able to reduce the health care-resource use and stabilize the clinical condition of frequently admitted COPD patients. PMID:27920519

  11. Multi-disciplinary study for the exploration of deep low enthalpy geothermal reservoirs, Neuchâtel, Switzerland

    NASA Astrophysics Data System (ADS)

    Mauri, G.; Abdelfettah, Y.; Negro, F.; Schill, E.; Vuataz, F.

    2011-12-01

    The authorities of the canton of Neuchâtel, in the Western part of Switzerland, are willing to develop geothermal energy for district heating in the two main cities of the canton: Neuchâtel, located along the Lake of Neuchâtel, and La Chaux-de-Fonds situated in a high valley of the Jura Massif. The geology of both areas is linked to the Jura Range and present complex structures, where the landscape is composed of anticlines associated with overthrust faults, which are overcut by strike-slip fault and secondary faulting events. The rock formations go from the Trias, which forms the detachment layer, up to the Quaternary rock. Bedrocks are mainly composed of limestones and marls, which can reach a thickness of several hundreds meters. The three main deep aquifers investigated in this area, from the shallowest (≤ 400 m below surface) to deepest (< 2000 m), are the Malm, the Dogger and the Muschelkalk. The estimated temperatures, based on previous studies, should range between 20 to 65 oC, which are function of depth, elevation and groundwater velocity. The expected low temperature is mainly due to the presence of karstic systems, which drains the heat towards the low elevation of the basin. The present study is based on gravimetry surveys, 3D geological models and 3D gravimetry models to best characterize the underground structures and to find areas where the rock properties would be favourable to geothermal exploitation. This means targets where permeability and porosity are high in the potential aquifers, allowing a significant flow at the future production wells. The results indicate that gravity anomalies are associated with both shallow and deep geological structures in the two exploration sites and that high resolution of dense grid gravity measurements combined with realistic 3D models of the geological structures allow to characterize interesting features for deep geothermal exploration. Gravity corrections were carried out with a computing code using

  12. Transformation of cytogenetically normal chronic myelomonocytic leukaemia to an acute myeloid leukaemia and the emergence of a novel +13, +15 double trisomy resulting in an adverse outcome.

    PubMed

    McGrattan, Peter; Humphreys, Mervyn; Hull, Donald; McMullin, Mary F

    2007-09-01

    A 58-year-old man was admitted with symptoms of lethargy and easy bruising for four months duration. Peripheral blood (PB) analysis revealed a white blood cell count (WBC) of 15.9 x 10(9)/l with monocytes 5.4 x 10(9)/l. Bone marrow (BM) was hypercellular with 15% blasts, monocytosis and trilineage dysplasia. Conventional cytogenetic analysis (G-banding) detected an apparently normal male karyotype (46,XY). A diagnosis of chronic myelomonocytic leukaemia (CMML) was made. After 3 years, PB analysis revealed a WBC count of 22 x 10(9)/l and a predominance of blasts. BM aspirate analysis also revealed 89% myeloid blasts and G-banding detected the emergence of an abnormal clone harbouring an extra copy of chromosomes 13 and 15. A diagnosis of disease transformation to acute myeloid leukaemia (AML) was made. Post chemotherapy BM aspirate was very hypocellular and the abnormal +13, +15 clone was still present suggesting primary refractory disease. A second course of chemotherapy was only administered for 24 hours due to complications. The abnormal +13, +15 clone was still present and it was decided that no further treatment apart from palliative care could be offered. The patient died 11 weeks later, five months after AML transformation. This is the first description of a cytogenetically normal CMML patient transforming to AML with the emergence of a unique +13, +15 double trisomy resulting in an adverse outcome.

  13. Out come of induction of remission in undernourished children with acute lymphoblastic leukaemia.

    PubMed

    Begum, M; Jahan, S; Tawfique, M; Mannan, M A

    2012-10-01

    Acute lymphoblastic leukaemia (ALL) is the most common childhood leukaemia. On the other hand under-nutrition is a common problem in our country. This prospective study was conducted to see the outcome of induction of remission in undernourished children with acute lymphoblastic leukaemia. This study was carried out in the department of Paediatric hematology and oncology of Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period from November 2002 to October 2004. A total of sixty (60) children who were diagnosed as acute lymphoblastic leukaemia in 1 to 15 years of age were included in this study. But the children with previous history of congenital disease and that of chemotherapy or steroid were excluded from this study. Patients were divided into two groups on the basis of Z score of weight for age. Thirty (30) children those with Z score- 2 or less were classified as undernourished and was labeled as Group A and another thirty (30) patient those Z score above-2 were classified as well nourished and was placed in Group B, After inclusion into the study, completion of induction of remission was monitored by physical examination and laboratory investigations. The result showed that mean age in Group A was 77.16 ± 7.07 months and that in Group B was 74.13 ± 5.09 months with male preponderance in both the groups. Mean body weight in Group A was 14.55 ± 0.76 Kg and that in Group B was 21.40 ± 1.05 kg (p<0.001). Children in Group A required 39.06 ± 0.72 days to complete induction but in Group B it required 31.63 ± 0.17 days (p<0.04). Hospital stay in Group A children was 52.10 ± 1.08 days and in Group B 42.37 ± 0.50 (p<0.002). The result suggested that under nutrition has an influence on the out come of induction of remission in undernourished children with acute lymphoblastic leukaemia. So appropriate measures are essential to improve nutritional status of children for successful management of ALL in children.

  14. Residential exposure to extremely low-frequency magnetic fields and risk of childhood leukaemia, CNS tumour and lymphoma in Denmark

    PubMed Central

    Pedersen, Camilla; Johansen, Christoffer; Schüz, Joachim; Olsen, Jørgen H; Raaschou-Nielsen, Ole

    2015-01-01

    Background: We previously reported that children exposed to elevated extremely low-frequency magnetic fields (ELF-MF) had a five to six times higher risk of leukaemia, central nervous system (CNS) tumour and malignant lymphoma. Here we extend the study from 1968 to 1986 through 2003. Methods: We included 3277 children with leukaemia, CNS tumour or malignant lymphoma during 1968–2003 recorded in the Danish Cancer Registry and 9129 controls randomly selected from the Danish childhood population. ELF-MF from 50 to 400 kV facilities were calculated at the residences. Results: For recently diagnosed cases (1987–2003), the relative risk (RR) was 0.88 (95% confidence interval (CI): 0.32–2.42), while for the total period (1968–2003) it was 1.63 (95% CI: 0.77–3.46) for leukaemia, CNS tumour and malignant lymphoma combined for exposures ⩾0.4 μT compared with <0.1 μT. These results were based on five cases (recent period) and 11 cases (total period) in the highest exposure group. Conclusions: We did not confirm the previous finding of a five- to six-fold higher risk for leukaemia, CNS tumour and malignant lymphoma when including data from the more recent time period. For the total time period, the results for childhood leukaemia were in line with large pooled analyses showing RRs between 1.5 and 2. PMID:26484412

  15. In vivo expansion of the endogenous B-cell compartment stimulated by radiation and serial bone marrow transplantation induces B-cell leukaemia in mice.

    PubMed

    Holyoake, T L; Freshney, M G; Samuel, K; Ansell, J; Watson, G E; Wright, E G; Graham, G J; Pragnell, I B

    2001-07-01

    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5(+) B cells. This B-cell lineage is established during ontogeny and replenished by the process of self-renewal. Spontaneous and induced leukaemias that frequently affect this lineage are thought to arise as a result of the frequent cell division required to maintain the population throughout adulthood and in response to repeated exposure to environmental antigens. In a series of bone marrow transplant (BMT) experiments performed in B6D2F1 mice, B-cell leukaemia occurred in recipients of serially transplanted syngeneic bone marrow. This study was therefore designed to determine the frequency and phenotype of the observed leukaemia. Male donor cells were initially transplanted into lethally irradiated female hosts and secondary (2 degrees ) BMT was performed at 3 months. At 1, 2, 3 and 16 months following primary (1 degrees ) BMT, and when 2 degrees BMT recipients developed leukaemia, animals were sacrificed and their tissues extensively examined. These analyses confirmed a host-derived CD5(+) transplantable B-cell leukaemia that was initiated in 50% of 1 degrees BMT recipients. With serial passage, the leukaemia became more aggressive and lost CD5 expression, suggesting transformation to a high-grade leukaemia/lymphoma. This previously unreported observation suggests that the combination of radiation and subsequent serial transplantation induces a proliferative stress to the host B-cell compartment that is causative in leukaemic transformation.

  16. Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia.

    PubMed

    Mavrakis, Konstantinos J; Wolfe, Andrew L; Oricchio, Elisa; Palomero, Teresa; de Keersmaecker, Kim; McJunkin, Katherine; Zuber, Johannes; James, Taneisha; Khan, Aly A; Leslie, Christina S; Parker, Joel S; Paddison, Patrick J; Tam, Wayne; Ferrando, Adolfo; Wendel, Hans-Guido

    2010-04-01

    MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the miR-17-92 cluster, containing six individual miRNAs, is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo. Clinical use of these findings hinges on isolating the oncogenic activity within the 17-92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1-induced T-cell acute lymphoblastic leukaemia (T-ALL) in vivo. In concord with the pathogenic importance of this interaction in T-ALL, we report a novel translocation that targets the 17-92 cluster and coincides with a second rearrangement that activates Notch1. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short hairpin RNA screen for genes whose knockdown can phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and include Bim (Bcl2L11), AMP-activated kinase (Prkaa1) and the phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clampdown on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukaemogenic miR-19.

  17. Park size and disturbance: impact on soil heterogeneity - a case study Tel-Aviv- Jaffa.

    NASA Astrophysics Data System (ADS)

    Zhevelev, Helena; Sarah, Pariente; Oz, Atar

    2015-04-01

    Parks and gardens are poly-functional elements of great importance in urban areas, and can be used for optimization of physical and social components in these areas. This study aimed to investigate alteration of soil properties with land usages within urban park and with area size of park. Ten parks differed by size (2 - 50 acres) were chosen, in random, in Tel-Aviv- Jaffa city. Soil was sampled in four microenvironments ((lawn, path, picnic and peripheral area (unorganized area) of each the park)), in three points and three depth (0-2, 5-10 and 10-20 cm). Penetration depth was measured in all point of sampling. For each soil sample electrical conductivity and organic matter content were determined. Averages of penetration depth drastically increased from the most disturbed microenvironments (path and picnic) to the less disturbed ones (lawn and peripheral). The maximal heterogeneity (by variances and percentiles) of penetration depth was found in the peripheral area. In this area, penetration depth increased with increasing park size, i.e., from 2.6 cm to 3.7 cm in the small and large parks, respectively. Averages of organic matter content and electrical conductivity decreased with soil depth in all microenvironments and increased with decreasing disturbance of microenvironments. Maximal heterogeneity for both of these properties was found in the picnic area. Increase of park size was accompanied by increasing of organic matter content in the upper depth in the peripheral area, i.e., from 2.4% in the small parks to 4.5% in the large ones. In all microenvironments the increasing of averages of all studied soil properties was accompanied by increasing heterogeneity, i.e., variances and upper percentiles. The increase in the heterogeneity of the studied soil properties is attributed to improved ecological soil status in the peripheral area, on the one hand, and to the high anthropogenic pressure in the picnic area, on the other. This means that the urban park offers

  18. The significance of visitors' pressure for soil status in an urban park in Tel-Aviv

    NASA Astrophysics Data System (ADS)

    Zhevelev, Helena; Sarah, Pariente; Oz, Atar

    2010-05-01

    A park is one of the most important elements of sustainable development and optimization of the urban environment. The equilibrium within the complex of natural and anthropogenic factors defines the status of a park's ecosystem. The seasonal dynamics and spatial variations of soil properties in areas under differing levels of visitors' pressure were studied in a park in Tel-Aviv. Soil was sampled twice a year, in wet (March) and dry (July) seasons, from three types of areas, subjected to differing levels of visitors' pressure: high, low and none (control). In each type of area samples were taken from two depths (0-2 cm and 5-10 cm), at 14-39 points. In total, 268 soil samples were taken. Before the soil sampling, penetration depth was determined at each point. In addition, the numbers of barbecue fires in each of the three areas were counted. Gravimetric soil moisture, organic matter, pH, electrical conductivity, and soluble ions were measured in 1:1 water extraction. Penetration depth and electrical conductivity, and organic matter, sodium, potassium and chlorite contents differed under differing levels of visitors' pressure, whereas soil moisture, pH and calcium content exhibited only minor differences. Soil moisture, electrical conductivity, and magnesium and chlorite contents exhibited strong seasonal changes, whereas the organic matter, potassium and pH levels were unaffected by seasonal dynamics. Calcium, organic matter, magnesium and chlorite contents, and electrical conductivity were significantly affected by the depth of soil sampling, whereas pH was not so affected. The seasonal changes in soil properties in the area subjected to high visitors' pressure were higher than in the one under low visitors' pressure. In most cases, visitors' pressure led to increases in variance and coefficient of variation. Different soil properties were differently affected by visitors' pressure, seasonal dynamics and soil depth. The surface of the soil was more sensitive to

  19. [Cerebral sinovenous thrombosis in a girl with acute lymphoblastic leukaemia carrying the prothrombin G20210A variant].

    PubMed

    González García, H; Sacoto Erazo, G; Moreno Gómez, E; Blanco Quirós, A; Fernández Abril, M C; Alvarez Guisasola, F J

    2013-04-01

    Although cerebral venous thrombosis is rare, it is more commonly associated with children suffering from acute lymphoblastic leukaemia. We report the case of a 7-year-old girl who developed massive cerebral sinovenous thrombosis on day 22 of induction therapy for high-risk acute lymphoblastic leukaemia. Clinical symptoms were gradual onset of headache, decreasing consciousness, and ensuing left hemiplegia. A subsequent prothrombotic study revealed a heterozygous prothrombin G20210A variant in the child and mother. We analysed the prothrombotic factors found in the case before and after thrombosis. We confirm the importance of early exploration of patients for clinical predisposing risk factors of thrombosis and primary prothrombotic states in children with acute lymphoblastic leukaemia. This might help identify patients at particular risk from thrombosis and so administer thromboprophylaxis.

  20. Evidence for an infective cause of childhood leukaemia: comparison of a Scottish new town with nuclear reprocessing sites in Britain.

    PubMed

    Kinlen, L

    1988-12-10

    Increases of leukaemia in young people that cannot be explained in terms of radiation have been recorded near both of Britain's nuclear reprocessing plants at Dounreay and Sellafield. These were built in unusually isolated places where herd immunity to a postulated widespread virus infection (to which leukaemia is a rare response) would tend to be lower than average. The large influxes of people in the 1950s to those areas might have been conducive to epidemics. The hypothesis has been tested in Scotland in an area identified at the outset as the only other rural area that received a large influx at the same time, when it was much more cut off from the nearest conurbation than at present--the New Town of Glenrothes. A significant increase of leukaemia below age 25 was found (10 observed, expected 3.6), with a greater excess below age 5 (7 observed, expected 1.5).

  1. Mobile health for early retention in HIV care: a qualitative study in Kenya (WelTel Retain).

    PubMed

    Smillie, Kirsten; Van Borek, Natasha; van der Kop, Mia L; Lukhwaro, Abigael; Li, Neville; Karanja, Sarah; Patel, Anik R; Ojakaa, David; Lester, Richard T

    2014-01-01

    Many people newly diagnosed with HIV are lost to follow-up before timely initiation of antiretroviral therapy (ART). A randomised controlled trial (RCT), WelTel Kenya1, demonstrated the effectiveness of the WelTel text messaging intervention to improve clinical outcomes among patients initiating ART. In preparation for WelTel Retain, an RCT that will evaluate the effect of the intervention to retain patients in care immediately following HIV diagnosis, we conducted an informative qualitative study with people living with HIV (n = 15) and healthcare providers (HCP) (n = 5) in October 2012. Study objectives included exploring the experiences of people living with HIV who have attempted to engage in HIV care, the use of cell phones in everyday life, and perceptions of communicating via text message with HCP. Participants were recruited through convenience sampling. Semi-structured, qualitative interviews were conducted and recorded, transcribed verbatim and analysed using NVivo software. Analysis was guided by the Theory of Reasoned Action and the Technology Acceptance Model. Results indicate that while individuals have many motivators for engaging in care after diagnosis, structural and individual barriers including poverty, depression and fear of stigma prevent them from doing so. All participants had access to a mobile phone, and most were comfortable communicating through text messages, or were willing to learn. Both people living with HIV and HCP felt that increased communication via the text messaging intervention has the potential to enable early identification of problems, leading to timely problem solving that may improve retention and engagement in care during the first year after diagnosis.

  2. Gene expression signatures in lymphoid tumours.

    PubMed

    Kees, Ursula R

    2004-04-01

    Lymphoid tumours comprise the acute and chronic leukaemias, the broad spectrum of lymphomas, including Hodgkin's disease, and multiple myeloma. The subdivision of the acute leukaemias according to the proliferating type of white blood cells has had a major impact on the care of these patients. More recently, specific chromosomal translocations have been used to identify patients who may benefit from more intensive therapies. The novel high-throughput genomic technologies, such as microarrays, provide new avenues for the molecular diagnosis of the haematological malignancies. Rapid advances in genome sequencing and gene expression profiling provide unprecedented opportunities to identify specific genes involved in complex biological processes, including tumorigenesis. The features of microarray technology and the variety of experimental approaches to elucidate lymphoid malignancies are discussed. Microarray technology has the potential to lead to more accurate prognostic assessment for patients and is expected to ultimately allow the clinician to select therapies optimally suited to each patient.

  3. Rapidly progressing, fatal and acute promyelocytic leukaemia that initially manifested as a painful third molar: a case report

    PubMed Central

    2009-01-01

    Introduction Acute promyelocytic leukaemia, an uncommon and devastating subtype of leukaemia, is highly prevalent in Latin American populations. The disease may be detected by a dentist since oral signs are often the initial manifestation. However, despite several cases describing oral manifestations of acute promyelocytic leukaemia and genetic analysis, reports of acute promyelocytic leukaemia in Hispanic populations are scarce. The identification of third molar pain as an initial clinical manifestation is also uncommon. This is the first known case involving these particular features. Case presentation A 24-year-old Latin American man without relevant antecedents consulted a dentist for pain in his third molar. After two dental extractions, the patient experienced increased pain, poor healing, jaw enlargement and bleeding. A physical examination later revealed that the patient had pallor, jaw enlargement, ecchymoses and gingival haemorrhage. Laboratory findings showed pancytopaenia, delayed coagulation times, hypoalbuminaemia and elevated lactate dehydrogenase. Splenomegaly was detected on ultrasonography. Peripheral blood and bone marrow analyses revealed a hypercellular infiltrate of atypical promyelocytic cells. Cytogenetic analysis showing genetic translocation t(15;17) further confirmed acute promyelocytic leukaemia. Despite early chemotherapy, the patient died within one week due to intracranial bleeding secondary to disseminated intravascular coagulation. Conclusion The description of this unusual presentation of acute promyelocytic leukaemia, the diagnostic difficulties and the fatal outcome are particularly directed toward dental surgery practitioners to emphasise the importance of clinical assessment and preoperative evaluation as a minimal clinically-oriented routine. This case may also be of particular interest to haematologists, since the patient's cytogenetic analysis, clinical course and therapeutic response are well documented. PMID:19946580

  4. Report of the Second International Symposium on Molecular Epidemiology in Childhood Leukaemia and Embryonal Tumours, Rio de Janeiro, Brazil

    PubMed Central

    Pombo de Oliveira, MS; Ferman, S; de Camargo, B

    2008-01-01

    The recent International Symposium on Molecular epidemiology in Embryonal Tumours and Paediatric Leukaemia was held on 4–6 March 2008 in Rio de Janeiro, Brazil. It proved a very productive meeting in which studies relating to genetics, therapeutical trials, identification of risk factors in acute leukaemia neuroblastoma and Wilms’ tumours were presented. Over 120 participants gathered for three days of fruitful discussions, including representatives of paediatrics, haematology, laboratory, epidemiology and pathology. Debates were held about strategies of applications of important biomarkers for clinical trials. Highlights of each of the scientific presentations are summarized below. PMID:22275972

  5. Survival of twenty-two months in a patient with primary plasma cell leukaemia treated with melphalan and prednisolone.

    PubMed Central

    Walker, J. D.; Kaczmarski, R. S.

    1988-01-01

    In the majority of cases plasma cell leukaemia is a rapidly fatal disease with a mean survival time of five months. There have been reports of increased survival using various regimens of chemotherapy although most cases eventually relapse. We describe a patient with primary plasma cell leukaemia who responded to a combination of oral melphalan and prednisolone with control of the disease in the bone marrow but relapsed with extramedullary disease in the central nervous system and testes, and died 22 months after diagnosis. Melphalan poorly penetrates the central nervous system and its testicular penetration is unknown. Images Figure 1 PMID:3174543

  6. Additional cytogenetic abnormalities in adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a study of the Cancer and Leukaemia Group B.

    PubMed

    Wetzler, Meir; Dodge, Richard K; Mrózek, Krzysztof; Stewart, Carleton C; Carroll, Andrew J; Tantravahi, Ramana; Vardiman, James W; Larson, Richard A; Bloomfield, Clara D

    2004-02-01

    We analysed the nature and prognostic significance of secondary cytogenetic changes in 111 newly diagnosed adults with acute lymphoblastic leukaemia (ALL) and t(9;22)(q34;q11.2) or its variants. Secondary aberrations were seen in 75 (68%) patients. They included, in order of descending frequency: +der(22)t(9;22), +21, abnormalities of 9p, high hyperdiploidy (>50 chromosomes), +8, -7, +X and abnormalities resulting in loss of material from 8p, gain of 8q, gain of 1q and loss of 7p. Eighty patients (72%) had > or =1 normal metaphase in their karyotype. There were four balanced and 12 unbalanced translocations previously unreported in ALL with t(9;22). The t(2;7)(p11;p13) and der(18)t(8;18)(q11.2;p11.2) were seen in two cases each, and have never before been reported in haematological malignancy. All but four patients were treated on front-line Cancer and Leukaemia Group B clinical protocols. The presence of -7 as a sole secondary abnormality was associated with a lower complete remission (CR) rate (P = 0.004), while the presence of > or =3 aberrations was associated with a higher CR rate (P = 0.009) and +der(22)t(9;22) with a higher cumulative incidence of relapse (P = 0.02). It will be of interest to see if newly diagnosed t(9;22)-positive adult ALL patients with these and other secondary aberrations respond differently to treatment regimens that include imatinib mesylate.

  7. Evolution of resistance to Aurora kinase B inhibitors in leukaemia cells.

    PubMed

    Failes, Timothy W; Mitic, Gorjana; Abdel-Halim, Heba; Po'uha, Sela T; Liu, Marjorie; Hibbs, David E; Kavallaris, Maria

    2012-01-01

    Aurora kinase inhibitors are new mitosis-targeting drugs currently in clinical trials for the treatment of haematological and solid malignancies. However, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Herein, we developed and characterised an in vitro leukaemia model of resistance to the Aurora B inhibitor ZM447439. Human T-cell acute lymphoblastic leukaemia cells, CCRF-CEM, were selected for resistance in 4 µM ZM447439. CEM/AKB4 cells showed no cross-resistance to tubulin-targeted and DNA-damaging agents, but were hypersensitive to an Aurora kinase A inhibitor. Sequencing revealed a mutation in the Aurora B kinase domain corresponding to a G160E amino acid substitution. Molecular modelling of drug binding in Aurora B containing this mutation suggested that resistance is mediated by the glutamate substitution preventing formation of an active drug-binding motif. Progression of resistance in the more highly selected CEM/AKB8 and CEM/AKB16 cells, derived sequentially from CEM/AKB4 in 8 and 16 µM ZM447439 respectively, was mediated by additional defects. These defects were independent of Aurora B and multi-drug resistance pathways and are associated with reduced apoptosis mostly likely due to reduced inhibition of the catalytic activity of aurora kinase B in the presence of drug. Our findings are important in the context of the use of these new targeted agents in treatment regimes against leukaemia and suggest resistance to therapy may arise through multiple independent mechanisms.

  8. The First European Conference on Infections in Leukaemia - ECIL1: a current perspective.

    PubMed

    Meunier, Françoise; Lukan, Colette

    2008-10-01

    The First European Conference on Infections in Leukaemia - ECIL1 - was organised under the auspices of the Infectious Diseases Group of the European Organisation for Research and Treatment of Cancer (EORTC), the Infectious Diseases Working Party of the European Group for Blood and Bone Marrow Transplantation (EBMT), the Supportive Care Group of the European LeukaemiaNet (ELN) and the International Immunocompromised Host Society (ICHS). The objective of the meeting was to develop evidence-based guidelines for the management of bacterial and fungal infections in high-risk immunocompromised adult leukaemia patients and hematopoietic stem cell transplantation recipients. The conference was held on September 30th and October 1st, 2005 in Juan-les-Pins, France and brought together a panel of 59 expert haematologists, oncologists, microbiologists, infectious disease specialists and clinical trialists from across Europe, Israel and Australia. The ECIL1 Guidelines were formulated after lengthy discussion, debate and panel consensus on the findings from a relevant comprehensive literature search, results of a European current practice questionnaire and other international guidelines, specific to each of the six clinical areas examined. The final recommendations, published in the Supplements of this journal as a series of six manuscripts in 2007, were well received by the medical community. The ECIL1 organisers anticipated the need for regular review of these guidelines and the Second ECIL Conference was held in September 2007. Publication of the updated and expanded ECIL2 Guidelines is forthcoming. This paper provides a concise summary of the methodology and main recommendations of the ECIL1 Guidelines.

  9. Study of clinical, haematological and cytogenetic profile of patients with acute erythroid leukaemia

    PubMed Central

    Linu, Jacob Abraham; Udupa, MS Namratha; Madhumathi, DS; Lakshmaiah, KC; Babu, K Govind; Lokanatha, D; Babu, MC Suresh; Lokesh, KN; Rajeev, LK; Rudresha, AH

    2017-01-01

    Background Acute erythroid leukaemia (AEL) is a rare subtype of acute myeloid leukaemia (AML), constituting <5% of all the cases of AML. The World Health Organization (WHO) in 2001 classified AEL into two types: (1) erythroid/myeloid leukaemia which required ≥50% erythroid precursors with ≥20% of the non-erythroid cells to be myeloid blasts and (2) pure erythroleukemia (pEL) with ≥80% erythroblasts. The WHO 2008 classification kept these subcategories, but made erythroleukemia a diagnosis of exclusion. There are very few studies on the clinico haematological and cytogenetic profile of this disease, considering the rarity of its occurrence and poor prognosis. Materials and methods This study was done by retrospective analysis of data from 32 case files of patients diagnosed with AEL. Clinical details noted down were the demographic profile, peripheral blood smear details and bone marrow examination details: (1) blasts-erythroblasts and myeloblasts, (2) dysplasia in the cell lineages and (3) cytogenetic abnormalities. Results The most common presenting symptom was fever. Pancytopenia at presentation was seen in 81.25% of patients. Dysplasia was observed in bone marrow in 100% of erythroblasts and in 40% of myeloblasts in erythroid/myeloid subtype. In pure myeloid subtype, myeloid and megakaryocytic dysplasias were not obvious. Complex karyotype was noticed only in patients of pEL. Conclusion AEL is a rare group of heterogeneous diseases with many neoplastic and non-neoplastic conditions mimicking the diagnosis. The clinical presentation and cytogenetics are also non-specific, presenting additional challenges to the diagnosis. PMID:28144286

  10. Residential exposure to electromagnetic fields and childhood leukaemia: a meta-analysis.

    PubMed Central

    Angelillo, I. F.; Villari, P.

    1999-01-01

    Although individual epidemiological investigations have suggested associations between residential exposure to electromagnetic fields (EMFs) and childhood leukaemia, overall the findings have been inconclusive. Several of these studies do, however, lend themselves to application of the meta-analysis technique. For this purpose we carried out searches using MEDLINE and other sources, and 14 case-control studies and one cohort study were identified and evaluated for epidemiological quality and included in the meta-analysis. Relative risk estimates were extracted from each of the studies and pooled. Separate meta-analyses were performed on the basis of the assessed EMF exposure (wiring configuration codes, distance to power distribution equipment, spot and 24-h measures of magnetic field strength (magnetic flux density) and calculated magnetic field). The meta-analysis based on wiring configuration codes yielded a pooled relative risk estimate of 1.46 (95% confidence interval (CI) = 1.05-2.04, P = 0.024) and for that for exposure to 24-h measurements of magnetic fields, 1.59 (95% CI = 1.14-2.22, P = 0.006), indicating a potential effect of residential EMF exposure on childhood leukaemia. In most cases, lower risk estimates were obtained by pooling high-quality studies than pooling low-quality studies. There appears to be a clear trend for more recent studies to be of higher quality. Enough evidence exists to conclude that dismissing concerns about residential EMFs and childhood leukaemia is unwarranted. Additional high-quality epidemiological studies incorporating comparable measures for both exposure and outcomes are, however, needed to confirm these findings and, should they prove to be true, the case options for minimizing exposure should be thoroughly investigated to provide definitive answers for policy-makers. PMID:10612886

  11. Geranylated flavanone tomentodiplacone B inhibits proliferation of human monocytic leukaemia (THP-1) cells

    PubMed Central

    Kollár, Peter; Bárta, Tomáš; Závalová, Veronika; Šmejkal, Karel; Hampl, Aleš

    2011-01-01

    BACKGROUND AND PURPOSE Paulownia tomentosa is a rich source of geranylated flavanones, some of which we have previously shown to have cytotoxic activity. To identify members of this class of compounds with cytostatic effects, we assessed the effects of the geranylated flavanone tomentodiplacone B (TOM B) on cell cycle progression and cell cycle regulatory pathways of THP-1 human monocytic leukaemia cells. EXPERIMENTAL APPROACH Cell viability was measured by dye exclusion and proliferation by WST-1 assays; cell cycle was monitored by flow cytometry. Regulatory proteins were assessed by immunoprecipitation and kinase assays, and Western blotting. KEY RESULTS Tomentodiplacone B had no effect during the first 24 h of cell growth at concentrations between 1 and 2.5 µM, but inhibited cell growth in a dose-dependent manner at concentrations of 5 µM or higher. Growth inhibition during the first 24 h of exposure to TOM B was not accompanied by cytotoxicity as cells were accumulated in G1 phase dose-dependently. This G1 phase accumulation was associated with down-regulation of cyclin-dependent kinase 2 activity and also protein levels of cyclins E1 and A2. However, key stress-related molecules (γ-H2AX, p53 and p21) were not induced, suggesting that TOM B acts by directly inhibiting the cyclin-dependent kinase 2 signalling pathway rather than initiating DNA damage or cellular stress. CONCLUSIONS AND IMPLICATIONS Our study provides the first evidence that TOM B directly inhibits proliferation of human monocytic leukaemia cells, and thus is a potential anticancer agent, preventing leukaemia cells from progressing from G1 phase into DNA synthesis. PMID:21175584

  12. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists.

    PubMed

    Prost, Stéphane; Relouzat, Francis; Spentchian, Marc; Ouzegdouh, Yasmine; Saliba, Joseph; Massonnet, Gérald; Beressi, Jean-Paul; Verhoeyen, Els; Raggueneau, Victoria; Maneglier, Benjamin; Castaigne, Sylvie; Chomienne, Christine; Chrétien, Stany; Rousselot, Philippe; Leboulch, Philippe

    2015-09-17

    Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally

  13. Transcriptional mechanism of vascular endothelial growth factor-induced expression of protein kinase CβII in chronic lymphocytic leukaemia cells

    PubMed Central

    Al-Sanabra, Ola; Duckworth, Andrew D.; Glenn, Mark A.; Brown, Benjamin R. B.; Angelillo, Piera; Lee, Kelvin; Herbert, John; Falciani, Francesco; Kalakonda, Nagesh; Slupsky, Joseph R.

    2017-01-01

    A key feature of chronic lymphocytic leukaemia (CLL) cells is overexpressed protein kinase CβII (PKCβII), an S/T kinase important in the pathogenesis of this and other B cell malignancies. The mechanisms contributing to enhanced transcription of the gene coding for PKCβII, PRKCB, in CLL cells remain poorly described, but could be important because of potential insight into how the phenotype of these cells is regulated. Here, we show that SP1 is the major driver of PKCβII expression in CLL cells where enhanced association of this transcription factor with the PRKCB promoter is likely because of the presence of histone marks permissive of gene activation. We also show how vascular endothelial growth factor (VEGF) regulates PRKCB promoter function in CLL cells, stimulating PKCβ gene transcription via increased association of SP1 and decreased association of STAT3. Taken together, these results are the first to demonstrate a clear role for SP1 in the up regulation of PKCβII expression in CLL cells, and the first to link SP1 with the pathogenesis of this and potentially other B cell malignancies where PKCβII is overexpressed. PMID:28233872

  14. Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia

    PubMed Central

    Pan, Li-li; Huang, Yuan-mao; Wang, Min; Zhuang, Xiao-e; Luo, Dong-feng; Guo, Shi-cheng; Zhang, Zhi-shun; Huang, Qing; Lin, Sheng-long; Wang, Shao-yuan

    2015-01-01

    An inherited predisposition to acute myeloid leukaemia (AML) is exceedingly rare, but the investigation of these families will aid in the delineation of the underlying mechanisms of the more common, sporadic cases. Three AML predisposition genes, RUNX1, CEBPA and GATA2, have been recognised, but the culprit genes in the majority of AML pedigrees remain obscure. We applied a combined strategy of linkage analysis and next-generation sequencing (NGS) technology in an autosomal-dominant AML Chinese family with 11 cases in four generations. A genome-wide linkage scan using a 500K SNP genotyping array was conducted to identify a previously unreported candidate region on 20p13 with a maximum multipoint heterogeneity LOD (HLOD) score of 3.56 (P=0.00005). Targeted NGS within this region and whole-exome sequencing (WES) revealed a missense mutation in TGM6 (RefSeq, NM_198994.2:c.1550T>G, p.(L517W)), which cosegregated with the phenotype in this family, and was absent in 530 healthy controls. The mutated amino acid was located in a highly conserved position, which may be deleterious and affect the activation of TGM6. Our results strongly support the candidacy of TGM6 as a novel familial AML-associated gene. PMID:24755948

  15. Chronic lymphatic leukaemia and engine exhausts, fresh wood, and DDT: a case-referent study.

    PubMed

    Flodin, U; Fredriksson, M; Persson, B; Axelson, O

    1988-01-01

    The effect of potential risk factors for chronic lymphatic leukaemia was evaluated in a case-referent study encompassing 111 cases and 431 randomised referents, all alive. Information on exposure was obtained by questionnaires posted to the subjects. Crude rate ratios were increased for occupational exposure to solvents. DDT, engine exhausts, fresh wood (lumberjacks, paper pulp workers, and sawmill workers, for example) and also in farming. Further analysis of the material by means of the Miettinen confounder score technique reduced the number of rate ratios significantly exceeding unity to encompass only occupational exposure to engine exhaust, fresh wood, DDT, and contact with horses.

  16. Chronic lymphatic leukaemia and engine exhausts, fresh wood, and DDT: a case-referent study.

    PubMed Central

    Flodin, U; Fredriksson, M; Persson, B; Axelson, O

    1988-01-01

    The effect of potential risk factors for chronic lymphatic leukaemia was evaluated in a case-referent study encompassing 111 cases and 431 randomised referents, all alive. Information on exposure was obtained by questionnaires posted to the subjects. Crude rate ratios were increased for occupational exposure to solvents. DDT, engine exhausts, fresh wood (lumberjacks, paper pulp workers, and sawmill workers, for example) and also in farming. Further analysis of the material by means of the Miettinen confounder score technique reduced the number of rate ratios significantly exceeding unity to encompass only occupational exposure to engine exhaust, fresh wood, DDT, and contact with horses. PMID:2449239

  17. [High-dose radiation-induced meningioma following prophylactic cranial irradiation for acute lymphoblastic leukaemia].

    PubMed

    Matsuda, Ryosuke; Nikaido, Yuji; Yamada, Tomonori; Mishima, Hideaki; Tamaki, Ryo

    2005-03-01

    A 12 year-old girl was treated with prophylatic cranial irradiation for acute lymphoblastic leukaemia (ALL). At the age of 39, she was admitted to our hospital for status epilepticus. Computed tomography demonstrated two, enhancing bilateral sided intracranial tumors. After surgery, this patient presented meningiomas which histologically, were of the meningothelial type. The high cure rate in childhood ALL, attributable to aggressive chemotherapy and prophylatic cranial irradiation, is capable of inducing secondary brain tumor. Twelve cases of high-dose radiation-induced meningioma following ALL are also reviewed.

  18. Therapeutic leukapheresis in hyperleucocytic leukaemias: lack of correlation between degree of cytoreduction and early mortality rate.

    PubMed

    Porcu, P; Danielson, C F; Orazi, A; Heerema, N A; Gabig, T G; McCarthy, L J

    1997-08-01

    The clinical and laboratory data of 48 leukapheresis-treated patients with hyperleucocytic leukaemia (HL) was reviewed to assess the correlation between the degree of leucoreduction and early mortality. Leukapheresis resulted in > 50% leucoreductions and postapheresis WBC counts < 100 x 10(9)/l in most patients (64.5%). Patients presenting with neurological, respiratory or renal complications had higher early mortality rates than patients without such complications, despite similar initial WBC counts and comparable leucoreductions. Thus, in these patients, more efficient leucoreduction was not associated with improved early survival.

  19. Receptor mutation is not a common mechanism of naturally occurring glucocorticoid resistance in leukaemia cell lines.

    PubMed

    Beesley, Alex H; Weller, Renae E; Senanayake, Saranga; Welch, Mathew; Kees, Ursula R

    2009-02-01

    Glucocorticoids (GCs) are among the most important drugs for the treatment of acute lymphoblastic leukaemia (ALL). Cell lines cultured in high GC concentrations typically contain mutated glucocorticoid receptor (GR), something that is rarely found in primary ALL specimens. We studied naturally occurring mechanisms of GC resistance and examined sensitivity to GC in 15 T-ALL cell lines grown without prior exposure to drugs. Resistance could not be attributed to mutations in GR or variations in levels of its expression. We conclude that this panel of cell lines provides a suitable in vitro model since it reflects GC resistance in primary ALL.

  20. Holoprosencephaly and Pure Red Cell Aplasia in a Feline Leukaemia Virus-Positive Kitten.

    PubMed

    Southard, T L; Rodriguez-Ramos Fernandez, J; Priest, H; Stokol, T

    2016-01-01

    A 9-month-old, female, domestic longhair cat with severe anaemia tested positive for feline leukaemia virus (FeLV) and was humanely destroyed and submitted for necropsy examination. Gross findings included a non-divided rostral telencephalon, consistent with semilobar holoprosencephaly. Histological examination of the bone marrow revealed an almost complete absence of erythroid precursor cells, consistent with pure red cell aplasia, and mild to moderate myelofibrosis. This case demonstrates a very unusual central nervous system defect, as well as an atypical presentation of pure red cell aplasia, in a FeLV-positive kitten.

  1. Bradycardia following retinoic acid differentiation syndrome in a patient with acute promyelocytic leukaemia.

    PubMed

    McGregor, Andrew; Hurst, Erin; Lord, Stephen; Jones, Gail

    2012-07-09

    The authors describe a 28-year-old woman with newly diagnosed acute promyelocytic leukaemia (APL), who developed junctional bradycardia after receiving the molecular-targeted therapy all-trans retinoic acid (ATRA) and the anthracycline-based chemotherapeutic agent idarubicin following sepsis and the APL differentiation syndrome. The patient was asymptomatic of the bradycardia. Electrolytes and cardiac imaging were unremarkable. No other cases have been reported in this context and the mechanisms of the sinus node dysfunction are unclear. The patient achieved normal sinus rhythm after ATRA was withheld. The patient recovered and went on to achieve complete remission after re-starting ATRA and idarubicin.

  2. Polyphenols act synergistically with doxorubicin and etoposide in leukaemia cell lines

    PubMed Central

    Mahbub, AA; Le Maitre, CL; Haywood-Small, SL; Cross, NA; Jordan-Mahy, N

    2015-01-01

    The study aimed to assess the effects of polyphenols when used in combination with doxorubicin and etoposide, and to determine whether polyphenols sensitised leukaemia cells, causing inhibition of cell proliferation, cell cycle arrest and induction of apoptosis. This study is based on findings in solid cancer tumours, which have shown that polyphenols can sensitize cells to chemotherapy, and induce apoptosis and/or cell-cycle arrest. This could enable a reduction of chemotherapy dose and off-target effects, whilst maintaining treatment efficacy. Quercetin, apigenin, emodin, rhein and cis-stilbene were investigated alone and in combination with etoposide and doxorubicin in two lymphoid and two myeloid leukaemia cells lines. Measurements were made of ATP levels (using CellTiter-Glo assay) as an indication of total cell number, cell cycle progression (using propidium iodide staining and flow cytometry) and apoptosis (NucView caspase 3 assay and Hoechst 33342/propidium iodide staining). Effects of combination treatments on caspases 3, 8 and 9 activity were determined using Glo luminescent assays, glutathione levels were measured using the GSH-Glo Glutathione Assay and DNA damage determined by anti-γH2AX staining. Doxorubicin and etoposide in combination with polyphenols synergistically reduced ATP levels, induced apoptosis and increased S and/or G2/M phase cell cycle arrest in lymphoid leukaemia cell lines. However, in the myeloid cell lines the effects of the combination treatments varied; doxorubicin had a synergistic or additive effect when combined with quercetin, apigenin, emodin, and cis-stilbene, but had an antagonistic effect when combined with rhein. Combination treatment caused a synergistic downregulation of glutathione levels and increased DNA damage, driving apoptosis via caspase 8 and 9 activation. However, in myeloid cells where antagonistic effects were observed, this was associated with increased glutathione levels and a reduction in DNA damage and

  3. THE GEMINI NICI PLANET-FINDING CAMPAIGN: DISCOVERY OF A CLOSE SUBSTELLAR COMPANION TO THE YOUNG DEBRIS DISK STAR PZ Tel

    SciTech Connect

    Biller, Beth A.; Liu, Michael C.; Wahhaj, Zahed; Dupuy, Trent J.; Ftaclas, Christ; Nielsen, Eric L.; Close, Laird M.; Males, Jared; Skemer, Andrew; Hayward, Thomas L.; Hartung, Markus; Chun, Mark; Clarke, Fraser; Tecza, Matthias; Thatte, Niranjan; Reid, I. Neill; Shkolnik, Evgenya L.; Alencar, Silvia H. P.; Artymowicz, Pawel

    2010-09-01

    We report the discovery of a tight substellar companion to the young solar analog PZ Tel, a member of the {beta} Pic moving group observed with high-contrast adaptive optics imaging as part of the Gemini Near-Infrared Coronagraphic Imager Planet-Finding Campaign. The companion was detected at a projected separation of 16.4 {+-} 1.0 AU (0.''33 {+-} 0.''01) in 2009 April. Second-epoch observations in 2010 May demonstrate that the companion is physically associated and shows significant orbital motion. Monte Carlo modeling constrains the orbit of PZ Tel B to eccentricities >0.6. The near-IR colors of PZ Tel B indicate a spectral type of M7 {+-} 2 and thus this object will be a new benchmark companion for studies of ultracool, low-gravity photospheres. Adopting an age of 12{sup +8} {sub -4} Myr for the system, we estimate a mass of 36 {+-} 6 M {sub Jup} based on the Lyon/DUSTY evolutionary models. PZ Tel B is one of the few young substellar companions directly imaged at orbital separations similar to those of giant planets in our own solar system. Additionally, the primary star PZ Tel A shows a 70 {mu}m emission excess, evidence for a significant quantity of circumstellar dust that has not been disrupted by the orbital motion of the companion.

  4. Indications of stellar prominence oscillations on fast rotating stars: the cases of HK Aqr and PZ Tel

    NASA Astrophysics Data System (ADS)

    Leitzinger, M.; Odert, P.; Zaqarashvili, T. V.; Greimel, R.; Hanslmeier, A.; Lammer, H.

    2016-11-01

    We present the analysis of six nights of spectroscopic monitoring of two young and fast rotating late-type stars, namely the dMe star HK Aqr and the dG/dK star PZ Tel. On both stars, we detect absorption features reminiscent of signatures of corotating cool clouds or prominences visible in Hα. Several prominences on HK Aqr show periodic variability in the prominence tracks which follow a sinusoidal motion (indication of prominence oscillations). On PZ Tel, we could not find any periodic variability in the prominence tracks. By fitting sinusoidal functions to the prominence tracks, we derive amplitudes and periods which are similar to those of large-amplitude oscillations seen in solar prominences. In one specific event, we also derive a periodic variation of the prominence track in the Hβ spectral line which shows an anti-phase variation with the one derived for the Hα spectral line. Using these parameters and estimated mass density of a prominence on HK Aqr, we derive a minimum magnetic field strength of ˜2 G. The relatively low strength of the magnetic field is explained by the large height of this stellar prominence (≥ 0.67 stellar radii above the surface).

  5. An interlocked dimer of the protelomerase TelK distorts DNA structure for the formation of hairpin telomeres

    PubMed Central

    Aihara, Hideki; Huang, Wai Mun; Ellenberger, Tom

    2007-01-01

    Summary The termini of linear chromosomes are protected by specialized DNA structures known as telomeres that also facilitate the complete replication of DNA ends. The simplest type of telomere is a covalently closed DNA hairpin structure found in linear chromosomes of prokaryotes and viruses. Bidirectional replication of a chromosome with hairpin telomeres produces a catenated circular dimer that is subsequently resolved into unit-length chromosomes by a dedicated DNA cleavage-rejoining enzyme known as a hairpin telomere resolvase (protelomerase). Here we report a crystal structure of the protelomerase TelK from Klebseilla oxytoca phage φKO2, in complex with the palindromic target DNA. The structure shows the TelK dimer destabilizes base pairing interactions to promote the refolding of cleaved DNA ends into two hairpin ends. We propose that the hairpinning reaction is made effectively irreversible by a unique protein-induced distortion of the DNA substrate that prevents re-ligation of the cleaved DNA substrate. PMID:17889664

  6. Clostridium difficile-associated diarrhoea, a frequent complication in patients with acute myeloid leukaemia.

    PubMed

    Schalk, Enrico; Bohr, Ulrich R M; König, Brigitte; Scheinpflug, Katrin; Mohren, Martin

    2010-01-01

    Diarrhoea occurs frequently in neutropenic patients with acute leukaemia receiving chemotherapy and may be caused by either infection- or drug-induced cytotoxicity. Since Clostridium difficile is the most common cause of nosocomial infectious diarrhoea in non-haematologic patients, we were interested in its incidence in patients with acute myeloid leukaemia (AML). In this retrospective study, we analysed 134 patients with AML receiving a total of 301 chemotherapy courses. Diarrhoea occurred during 33% of all courses in 58 patients. C. difficile-associated diarrhoea (CDAD) occurred in 18% of all patients and 9% of all treatment courses. Almost one third of diarrhoea episodes were caused by C. difficile. CDAD was associated with older age (58 vs. 50 years), number of antibiotics administered (2 vs. 1), duration of antibiotic therapy (7 vs. 4 days), ceftazidime as the antibiotic of choice (75% vs. 54%) and duration of neutropenia (12 vs. 7 days) prior to onset of diarrhoea. An increased risk for CDAD was seen for prolonged neutropenia. CDAD responded well to oral metronidazole and/or vancomycin and no patient died of this complication. In conclusion, CDAD is common in patients with AML receiving chemotherapy. C. difficile enterotoxin testing of stool specimens should be included in all symptomatic patients.

  7. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.

    PubMed

    Zhao, Chen; Chen, Alan; Jamieson, Catriona H; Fereshteh, Mark; Abrahamsson, Annelie; Blum, Jordan; Kwon, Hyog Young; Kim, Jynho; Chute, John P; Rizzieri, David; Munchhof, Michael; VanArsdale, Todd; Beachy, Philip A; Reya, Tannishtha

    2009-04-09

    Although the role of Hedgehog (Hh) signalling in embryonic pattern formation is well established, its functions in adult tissue renewal and maintenance remain unclear, and the relationship of these functions to cancer development has not been determined. Here we show that the loss of Smoothened (Smo), an essential component of the Hh pathway, impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukaemia (CML) by the BCR-ABL1 oncoprotein. Loss of Smo causes depletion of CML stem cells--the cells that propagate the leukaemia--whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, we show that the cell fate determinant Numb, which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacological inhibition of Hh signalling impairs not only the propagation of CML driven by wild-type BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. These data indicate that Hh pathway activity is required for maintenance of normal and neoplastic stem cells of the haematopoietic system and raise the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway.

  8. Medical neglect death due to acute lymphoblastic leukaemia: an autopsy case report.

    PubMed

    Usumoto, Yosuke; Sameshima, Naomi; Tsuji, Akiko; Kudo, Keiko; Nishida, Naoki; Ikeda, Noriaki

    2014-12-01

    We report the case of 2-year-old girl who died of precursor B-cell acute lymphoblastic leukaemia (ALL), the most common cancer in children. She had no remarkable medical history. She was transferred to a hospital because of respiratory distress and died 4 hours after arrival. Two weeks before death, she had a fever of 39 degrees C, which subsided after the administration of a naturopathic herbal remedy. She developed jaundice 1 week before death, and her condition worsened on the day of death. Laboratory test results on admission showed a markedly elevated white blood cell count. Accordingly, the cause of death was suspected to be acute leukaemia. Forensic autopsy revealed the cause of death to be precursor B-cell ALL. With advancements in medical technology, the 5-year survival rate of children with ALL is nearly 90%. However, in this case, the deceased's parents preferred complementary and alternative medicine (i.e., naturopathy) to evidence-based medicine and had not taken her to a hospital for a medical check-up or immunisation since she was an infant. Thus, if she had received routine medical care, she would have a more than 60% chance of being alive 5 years after diagnosis. Therefore, we conclude that the parents should be accused of medical neglect regardless of their motives.

  9. Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers

    PubMed Central

    Rushton, L; Schnatter, A R; Tang, G; Glass, D C

    2014-01-01

    Background: High benzene exposure causes acute myeloid leukaemia (AML). Three petroleum case–control studies identified 60 cases (241 matched controls) for AML and 80 cases (345 matched controls) for chronic lymphoid leukaemia (CLL). Methods: Cases were classified and scored regarding uncertainty by two haematologists using available diagnostic information. Blinded quantitative benzene exposure assessment used work histories and exposure measurements adjusted for era-specific circumstances. Statistical analyses included conditional logistic regression and penalised smoothing splines. Results: Benzene exposures were much lower than previous studies. Categorical analyses showed increased ORs for AML with several exposure metrics, although patterns were unclear; neither continuous exposure metrics nor spline analyses gave increased risks. ORs were highest in terminal workers, particularly for Tanker Drivers. No relationship was found between benzene exposure and risk of CLL, although the Australian study showed increased risks in refinery workers. Conclusion: Overall, this study does not persuasively demonstrate a risk between benzene and AML. A previously reported strong relationship between myelodysplastic syndrome (MDS) (potentially previously reported as AML) at our study's low benzene levels suggests that MDS may be the more relevant health risk for lower exposure. Higher CLL risks in refinery workers may be due to more diverse exposures than benzene alone. PMID:24357793

  10. Cohort Profile: The French Childhood Cancer Survivor Study For Leukaemia (LEA Cohort)

    PubMed Central

    Berbis, Julie; Michel, Gérard; Baruchel, André; Bertrand, Yves; Chastagner, Pascal; Demeocq, François; Kanold, Justyna; Leverger, Guy; Plantaz, Dominique; Poirée, Marilyne; Stephan, Jean-Louis; Auquier, Pascal; Contet, Audrey; Dalle, Jean-Hugues; Ducassou, Stéphane; Gandemer, Virginie; Lutz, Patrick; Sirvent, Nicolas; Tabone, Marie-Dominique; Thouvenin-Doulet, Sandrine

    2015-01-01

    The main aim of the Leucémies de l’Enfant et l’Adolescent (LEA) project (Childhood and Adolescent Leukaemia) is to study the determinants (medical, socioeconomic, behavioural and environmental) of medium- and long-term outcomes of patients treated for childhood acute leukaemia (AL). The LEA study began in 2004 and is based on a French multicentric prospective cohort. Included are children treated for AL since January 1980 (incident and prevalent cases), surviving at month 24 for myeloblastic AL and lymphoblastic AL grafted in first complete remission or at month 48 for lymphoblastic AL not grafted in first complete remission. Information is collected during specific medical visits and notably includes the following data: socioeconomic data, AL history, physical late effects (such as fertility, cardiac function and metabolic syndrome) and quality of life. Data are collected every 2 years until the patient is 20 years old and has had a 10-year follow-up duration from diagnosis or last relapse. Thereafter, assessments are planned every 4 years. In active centres in 2013, eligible patients number more than 3000. The cohort has already included 2385 survivors, with rate of exhaustiveness of almost 80%. Data access can be requested from principal coordinators and must be approved by the steering committee. PMID:24639445

  11. Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

    PubMed Central

    Koehler, Philipp; Schmidt, Patrick; Hombach, Andreas A.; Hallek, Michael; Abken, Hinrich

    2012-01-01

    B-cell chronic lymphocytic leukaemia (B-CLL) remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR) which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells. PMID:21837241

  12. MRD parameters using immunophenotypic detection methods are highly reliable in predicting survival in acute myeloid leukaemia.

    PubMed

    Feller, N; van der Pol, M A; van Stijn, A; Weijers, G W D; Westra, A H; Evertse, B W; Ossenkoppele, G J; Schuurhuis, G J

    2004-08-01

    Outgrowth of minimal residual disease (MRD) in acute myeloid leukaemia (AML) is responsible for the occurrence of relapses. MRD can be quantified by immunophenotyping on a flow cytometer using the expression of leukaemia-associated phenotypes. MRD was monitored in follow-up samples taken from bone marrow (BM) of 72 patients after three different cycles of chemotherapy and from autologous peripheral blood stem cell (PBSC) products. The MRD% in BM after the first cycle (n=51), second cycle (n=52) and third cycle (n=30), as well as in PBSC products (n=39) strongly correlated with relapse-free survival. At a cutoff level of 1% after the first cycle and median cutoff levels of 0.14% after the second, 0.11% after the third cycle and 0.13% for PBSC products, the relative risk of relapse was a factor 6.1, 3.4, 7.2 and 5.7, respectively, higher for patients in the high MRD group. Also, absolute MRD cell number/ml was highly predictive of the clinical outcome. After the treatment has ended, an increase of MRD% predicted forthcoming relapses, with MRD assessment intervals of < or =3 months. In conclusion, MRD parameter assessment at different stages of disease is highly reliable in predicting survival and forthcoming relapses in AML.

  13. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia

    PubMed Central

    Hirsch, Pierre; Zhang, Yanyan; Tang, Ruoping; Joulin, Virginie; Boutroux, Hélène; Pronier, Elodie; Moatti, Hannah; Flandrin, Pascale; Marzac, Christophe; Bories, Dominique; Fava, Fanny; Mokrani, Hayat; Betems, Aline; Lorre, Florence; Favier, Rémi; Féger, Frédéric; Mohty, Mohamad; Douay, Luc; Legrand, Ollivier; Bilhou-Nabera, Chrystèle; Louache, Fawzia; Delhommeau, François

    2016-01-01

    In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner. PMID:27534895

  14. The relationship between growth in agar, karyotype and prognosis in acute leukaemia.

    PubMed

    Gustavsson, A; Mitelman, F; Olofsson, T; Olsson, I

    1984-04-01

    The growth pattern in agar culture and the karyotype of bone marrow cells were studied in 79 patients with untreated acute non-lymphocytic leukaemia (ANLL). Results were divided into the following groups: (A) colony and cluster formation; (B) growth of less than 600 small clusters per 10(5) cells; (C) growth of more than 600 small clusters; (D) no growth in agar. Cytogenetically, the patients were divided into 3 categories: NN, normal metaphases only; AN, both abnormal and normal metaphases and AA, abnormal metaphases only. An association was seen between growth pattern and karyotype: the majority of NN patients (33/37) belonged to group (A + B) while in group (C + D) 20/24 patients were AN or AA. 37 patients were prognostically evaluable. The growth pattern in agar but not the cytogenetic pattern had prognostic implications. 25 patients with acute lymphocytic leukaemia (ALL) were also studied at diagnosis. Different growth patterns in agar had no impact on prognosis. No relationship was detected between growth pattern and karyotype in ALL.

  15. Indoor residential radon exposure and risk of childhood acute myeloid leukaemia

    PubMed Central

    Steinbuch, M; Weinberg, C R; Buckley, J D; Robison, L L; Sandler, D P

    1999-01-01

    Exposure to radon has been identified as a risk factor for lung cancer in uranium miners, but evidence of adverse health effects due to indoor radon exposure is inconsistent. Ecological studies have suggested a correlation between indoor radon levels and leukaemia incidence. We evaluated the risk associated with indoor residential radon exposure within a larger interview-based case–control study of risk factors for childhood acute myeloid leukaemia (AML). A total of 173 cases and 254 controls met the eligibility criteria, and information was collected through telephone interviews with parents and analysis of alpha-track radon detectors placed in the home for a period of 1 year. No association was observed between radon exposure and risk of AML, with adjusted odds ratios of 1.2 (95% confidence interval (CI) 0.7–1.8) for 37–100 Bq m–3 and 1.1 (95% CI 0.6–2.0) for > 100 Bq m–3 compared with < 37 Bq m–3. Although there was an inverse association between radon level and AML risk among children < 2 years at diagnosis, among children ≥2 years, AML risk was increased among those with higher radon exposure. The observed association after age 2 is most likely due to chance. Overall, there was no association between residential radon and risk of childhood AML. © 1999 Cancer Research Campaign PMID:10555766

  16. Tracer‐Based Metabolic NMR‐Based Flux Analysis in a Leukaemia Cell Line

    PubMed Central

    Carrigan, John B.; Reed, Michelle A. C.; Ludwig, Christian; Khanim, Farhat L.; Bunce, Christopher M.

    2016-01-01

    Abstract High levels of reactive oxygen species (ROS) have a profound impact on acute myeloid leukaemia cells and can be used to specifically target these cells with novel therapies. We have previously shown how the combination of two redeployed drugs, the contraceptive steroid medroxyprogesterone and the lipid‐regulating drug bezafibrate exert anti‐leukaemic effects by producing ROS. Here we report a 13C‐tracer‐based NMR metabolic study to understand how these drugs work in K562 leukaemia cells. Our study shows that [1,2‐13C]glucose is incorporated into ribose sugars, indicating activity in oxidative and non‐oxidative pentose phosphate pathways alongside lactate production. There is little label incorporation into the tricarboxylic acid cycle from glucose, but much greater incorporation arises from the use of [3‐13C]glutamine. The combined medroxyprogesterone and bezafibrate treatment decreases label incorporation from both glucose and glutamine into α‐ketoglutarate and increased that for succinate, which is consistent with ROS‐mediated conversion of α‐ketoglutarate to succinate. Most interestingly, this combined treatment drastically reduced the production of several pyrimidine synthesis intermediates. PMID:27347458

  17. Bioenergetic modulation overcomes glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia.

    PubMed

    Samuels, Amy L; Heng, Jasmin Y; Beesley, Alex H; Kees, Ursula R

    2014-04-01

    Drug-resistant forms of acute lymphoblastic leukaemia (ALL) are a leading cause of death from disease in children. Up to 25% of patients with T-cell ALL (T-ALL) develop resistance to chemotherapeutic agents, particularly to glucocorticoids (GCs), a class of drug to which resistance is one of the strongest indicators of poor clinical outcome. Despite their clinical importance, the molecular mechanisms that underpin GC resistance and leukaemia relapse are not well understood. Recently, we demonstrated that GC-resistance is associated with a proliferative metabolism involving the up-regulation of glycolysis, oxidative phosphorylation and cholesterol biosynthesis. Here we confirm that resistance is directly associated with a glycolytic phenotype and show that GC-resistant T-ALL cells are able to shift between glucose bioenergetic pathways. We evaluated the potential for targeting these pathways in vitro using a glycolysis inhibitor, 2-deoxyglucose (2DG), and the oxidative phosphorylation inhibitor oligomycin in combination with methylprednisolone (MPRED). We found that oligomycin synergized with MPRED to sensitize cells otherwise resistant to GCs. Similarly we observed synergy between MPRED and simvastatin, an inhibitor of cholesterol metabolism. Collectively, our findings suggest that dual targeting of bioenergetic pathways in combination with GCs may offer a promising therapeutic strategy to overcome drug resistance in ALL.

  18. Prognostic significance of ligands belonging to tumour necrosis factor superfamily in acute lymphoblastic leukaemia.

    PubMed

    Bolkun, L; Lemancewicz, D; Jablonska, E; Szumowska, A; Bolkun-Skornicka, U; Moniuszko, M; Dzieciol, J; Kloczko, J

    2015-03-01

    Altered activities of ligands belonging to tumour necrosis factor (TNF) superfamily, namely B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and apoptosis inducing ligand (TRAIL) were demonstrated in several haematological diseases including acute lymphoblastic leukaemia (ALL). BAFF, APRIL and TRAIL provide crucial survival signals to immature, naive and activated B cells. These ligands are capable of activating a broad spectrum of intracellular signalling cascades that can either induce apoptosis or protect from programmed cell death. BAFF and APRIL, which can directly activate the NF-κB pathway, have been identified as crucial survival factors for ALL cells. Here, we have analyzed serum BAFF, APRIL and TRAIL concentrations in 48 patients with newly diagnosed ALL and 44 healthy volunteers. The levels of APRIL and BAFF were significantly higher in ALL patients as compared to healthy volunteers. In contrast, concentrations of TRAIL were significantly lower in ALL patients. Moreover, following induction, the levels of APRIL, but not BAFF or TRAIL, were significantly lower in a group of patients with complete remission (CR) as compared to non-respondent (NR) ALL patients. Furthermore, we demonstrated statistically significant differences in concentrations of APRIL between CR MRD-negative and CR, MRD-positive ALL patients. Notably detection of higher concentrations of APRIL was associated with shorter leukaemia-free survival and overall survival. Altogether, our data indicate that APRIL can play an important role in the pathogenesis of ALL and the measurement of APRIL levels can improve prognostication in ALL patients.

  19. Application of oncoproteomics to aberrant signalling networks in changing the treatment paradigm in acute lymphoblastic leukaemia.

    PubMed

    López Villar, Elena; Wang, Xiangdong; Madero, Luis; Cho, William C

    2015-01-01

    Oncoproteomics is an important innovation in the early diagnosis, management and development of personalized treatment of acute lymphoblastic leukaemia (ALL). As inherent factors are not completely known - e.g. age or family history, radiation exposure, benzene chemical exposure, certain viral exposures such as infection with the human T-cell lymphoma/leukaemia virus-1, as well as some inherited syndromes may raise the risk of ALL - each ALL patient may modify the susceptibility of therapy. Indeed, we consider these unknown inherent factors could be explained via coupling cytogenetics plus proteomics, especially when proteins are the ones which play function within cells. Innovative proteomics to ALL therapy may help to understand the mechanism of drug resistance and toxicities, which in turn will provide some leads to improve ALL management. Most important of these are shotgun proteomic strategies to unravel ALL aberrant signalling networks. Some shotgun proteomic innovations and bioinformatic tools for ALL therapies will be discussed. As network proteins are distinctive characteristics for ALL patients, unrevealed by cytogenetics, those network proteins are currently an important source of novel therapeutic targets that emerge from shotgun proteomics. Indeed, ALL evolution can be studied for each individual patient via oncoproteomics.

  20. Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome

    PubMed Central

    Flores-Lujano, J; Perez-Saldivar, M L; Fuentes-Pananá, E M; Gorodezky, C; Bernaldez-Rios, R; Del Campo-Martinez, M A; Martinez-Avalos, A; Medina-Sanson, A; Paredes-Aguilera, R; De Diego-Flores Chapa, J; Bolea-Murga, V; Rodriguez-Zepeda, M C; Rivera-Luna, R; Palomo-Colli, M A; Romero-Guzman, L; Perez-Vera, P; Alvarado-Ibarra, M; Salamanca-Gómez, F; Fajardo-Gutierrez, A; Mejía-Aranguré, J M

    2009-01-01

    Background: For a child to develop acute leukaemia (AL), environmental exposure may not be sufficient: interaction with a susceptibility factor to the disease, such as Down syndrome (DS), may also be necessary. We assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS. Methods: Children with DS in Mexico City, and either with or without AL, were the cases (N=57) and controls (N=218), respectively. Population was divided in children with AL and with acute lymphoblastic leukaemia (ALL) and also in children ⩽6 and >6 years old. Results: Breastfeeding and early infections showed moderate (but not significant) association for AL, whereas hospitalisation by infection during the first year of life increased the risk: odds ratios (confidence interval 95%) were 0.84 (0.43–1.61), 1.70 (0.82–3.52); and 3.57 (1.59–8.05), respectively. A similar result was obtained when only ALL was analysed. Conclusion: We found that breastfeeding was a protective factor for developing AL and ALL, and during the first year of life, infections requiring hospitalisation were related to a risk for developing the disease in those children with DS >6 years of age. These data do not support the Greaves's hypothesis of early infection being protective for developing ALL. PMID:19707206

  1. The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia.

    PubMed

    Suresh, Sukanya; McCallum, Lynn; Crawford, Lisa J; Lu, Wan Hua; Sharpe, Daniel J; Irvine, Alexandra E

    2013-11-01

    Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3(rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05).Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML.

  2. Applications of imaging flow cytometry in the diagnostic assessment of acute leukaemia.

    PubMed

    Grimwade, Lizz F; Fuller, Kathryn A; Erber, Wendy N

    2017-01-01

    Automated imaging flow cytometry integrates flow cytometry with digital microscopy to produce high-resolution digital imaging with quantitative analysis. This enables cell identification based on morphology (cell size, shape), antigen expression, quantification of fluorescence signal intensity and localisation of detected signals (i.e. surface, cytoplasm, nuclear). We describe applications of imaging flow cytometry for the diagnostic assessment of acute leukaemia. These bone marrow malignancies are traditionally diagnosed and classified by cell morphology, phenotype and cytogenetic abnormalities. Traditionally morphology is assessed by light microscopy, phenotyping by conventional flow cytometry and genetics by karyotype and fluorescence in situ hybridisation (FISH) on interphase nuclei/metaphase spreads of cells on slides. Imaging flow cytometry adds a new dimension to the diagnostic assessment of these neoplasms. We describe three specific applications: From this we conclude that imaging flow cytometry offers benefits over conventional diagnostic methods. Specifically the ability to visualise the cells of interest, the pattern and localisation of expressed antigens and assess cytogenetic abnormalities in one integrated automated high-throughput test. Imaging flow cytometry presents a new paradigm for the diagnostic assessment of leukaemia.

  3. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

    SciTech Connect

    Cowan-Jacob, Sandra W. Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    2007-01-01

    A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia. Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.

  4. Pulmonary mucormycosis with cervical lymph node involvement in a patient with acute myeloid leukaemia: a case report.

    PubMed

    Fanci, Rosa; Pecile, Patrizia; Di Lollo, Simonetta; Dini, Catia; Bosi, Alberto

    2008-07-01

    Here we describe a rare case of pulmonary mucormycosis and simultaneous cervical lymphadenitis in a patient with acute myeloid leukaemia. The patient was successfully treated with liposomal amphotericin B. The diagnosis of Mucor is very difficult, especially in severely immunocompromised patients. This report seems to be the first case about documented lymph node involvement by mucormycosis in humans.

  5. The proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionizing radiation.

    PubMed

    Wakeford, R; Kendall, G M; Little, M P

    2009-04-01

    The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionizing radiation, such as those experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily on studies of the Japanese atomic bomb survivors imply that low-level exposure to ionizing radiation, including ubiquitous natural background radiation, also raises the risk of childhood leukaemia. Using two sets of recently published leukaemia risk models and estimates of natural background radiation red-bone-marrow doses received by children, about 20% of the cases of childhood leukaemia in Great Britain are predicted to be attributable to this source. However, for one of these sets of risk models this attributable fraction is materially dependent on how the radiation-induced risk is assumed to be transferred between the Japanese atomic bomb survivors and Western children. Over a range of annual doses representing the range (0.5-2.5 mSv/year) experienced by most populations, the attributable proportion for the preferred risk-transfer model varies between 8 and 30%, with small deviations from a linear relationship that are largely due to the saturation of the model, although again this range of attributable fractions depends on the assumed transfer of risk between populations.

  6. Multiple adaptive mechanisms affect asparagine synthetase substrate availability in asparaginase-resistant MOLT-4 human leukaemia cells.

    PubMed Central

    Aslanian, A M; Kilberg, M S

    2001-01-01

    Childhood acute lymphoblastic leukaemia is treated by combination chemotherapy with a number of drugs, almost always including the enzyme L-asparaginase (ASNase). Although the initial remission rate is quite high, relapse and associated drug resistance remain a problem. In vitro studies have demonstrated an adaptive increase in asparagine synthetase (AS) expression in ASNase-resistant cells, which is believed to permit ASNase-resistant human leukaemia cells to survive in vivo. The present results, obtained with ASNase-sensitive and -resistant human MOLT-4 leukaemia cell lines, illustrate that several other adaptive processes occur to provide sufficient amounts of the AS substrates, aspartate and glutamine, required to support this increased enzymic activity. In both cell populations, aspartate is derived almost exclusively from intracellular sources, whereas the necessary glutamine arises from both intracellular and extracellular sources. Transport of glutamine into ASNase-resistant cells is significantly enhanced compared with the parental cells, whereas amino acid efflux (e.g. asparagine) is reduced. Most of the adaptive change for the amino acid transporters, Systems A, ASC and L, is rapidly (12 h) reversed following ASNase removal. The enzymic activity of glutamine synthetase is also enhanced in ASNase-resistant cells by a post-transcriptional mechanism. The results demonstrate that there are several sites of metabolic adaptation in ASNase-treated leukaemia cells that serve to promote the replenishment of both glutamine and asparagine. PMID:11485552

  7. Bloodstream infection caused by Acinetobacter junii in a patient with acute lymphoblastic leukaemia after allogenic haematopoietic cell transplantation.

    PubMed

    Cayô, Rodrigo; Yañez San Segundo, Lucrecia; Pérez del Molino Bernal, Inmaculada Concepción; García de la Fuente, Celia; Bermúdez Rodríguez, Maria Aranzazu; Calvo, Jorge; Martínez-Martínez, Luis

    2011-03-01

    Acinetobacter junii is a rare human pathogen associated with bacteraemia in neonates and paediatric oncology patients. We present a case of A. junii causing bacteraemia in an adult transplant patient with leukaemia. The correct identification of Acinetobacter species can highlight the clinical significance of the different species of this genus.

  8. Invasive aspergillosis caused by cryptic Aspergillus species: a report of two consecutive episodes in a patient with leukaemia.

    PubMed

    Peláez, Teresa; Alvarez-Pérez, Sergio; Mellado, Emilia; Serrano, David; Valerio, Maricela; Blanco, José L; Garcia, Marta E; Muñoz, Patricia; Cuenca-Estrella, Manuel; Bouza, Emilio

    2013-03-01

    We report a case of two consecutive episodes of invasive aspergillosis caused by cryptic Aspergillus species in a patient with leukaemia. A first episode of pulmonary infection was caused by Aspergillus calidoustus and Aspergillus novofumigatus, and the second episode by A. novofumigatus and Aspergillus viridinutans. Fungal isolates were identified to species level using traditional and sequencing-based molecular methods.

  9. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia | Office of Cancer Genomics

    Cancer.gov

    There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden.

  10. New cellular markers at diagnosis are associated with isolated central nervous system relapse in paediatric B-cell precursor acute lymphoblastic leukaemia.

    PubMed

    van der Velden, Vincent H J; de Launaij, Daphne; de Vries, Jeltje F; de Haas, Valerie; Sonneveld, Edwin; Voerman, Jane S A; de Bie, Maaike; Revesz, Tamas; Avigad, Smadar; Yeoh, Allen E J; Swagemakers, Sigrid M A; Eckert, Cornelia; Pieters, Rob; van Dongen, Jacques J M

    2016-03-01

    In childhood acute lymphoblastic leukaemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Using microarray-analysis, we discovered multiple differentially expressed genes between B-cell precursor (BCP) ALL cells in bone marrow (BM) and BCP-ALL cells in cerebrospinal fluid (CSF) at the time of isolated CNS relapse. After confirmation by real-time quantitative polymerase chain reaction, selected genes (including SCD and SPP1) were validated at the protein level by flowcytometric analysis of BCP-ALL cells in CSF. Further flowcytometric validation showed that a subpopulation of BCP-ALL cells (>1%) with a 'CNS protein profile' (SCD positivity and increased SPP1 expression) was present in the BM at diagnosis in patients who later developed an isolated CNS relapse, whereas this subpopulation was <1% or absent in all other patients. These data indicate that the presence of a (small) subpopulation of BCP-ALL cells with a 'CNS protein profile' at diagnosis (particularly SCD-positivity) is associated with isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity.

  11. Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation, Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

    PubMed Central

    Maura, Francesco; Mosca, Laura; Fabris, Sonia; Cutrona, Giovanna; Matis, Serena; Lionetti, Marta; Agnelli, Luca; Barbieri, Marzia; D’Anca, Marianna; Manzoni, Martina; Colombo, Monica; Massucco, Carlotta; Reverberi, Daniele; Gentile, Massimo; Recchia, Anna Grazia; Bossio, Sabrina; Ilariucci, Fiorella; Musolino, Caterina; Di Raimondo, Francesco; Cortelezzi, Agostino; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2015-01-01

    IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation. PMID:25786252

  12. CpG oligodeoxynucleotide 5mer-induced apoptosis in MOLT-4 leukaemia cells does not require caspase 3 or new protein synthesis.

    PubMed

    Tidd, David M; Broughton, Caroline M; Clark, Richard E

    2003-05-01

    We have established that CpG oligodeoxynucleotide 5mers, of sequence type CGNNN (N = A, G, C or T), rapidly induce apoptosis/cell cycle arrest in human leukaemia lines. The 5'-CpG is obligatory for these effects. Induction of apoptosis in MOLT-4 cells did not require new protein synthesis and was insensitive to the caspase 3 inhibitor, Ac-DEVD-CHO, although the latter abrogated DNA laddering, phosphatidylserine externalization and collapse of the mitochondrial transmembrane potential. A subline of MOLT-4 cells, MOLT-4CpGR, was selected for acquired resistance to CpG 5mers. Differences in gene expression between MOLT-4 and MOLT-4CpGR cells were identified following three independent reciprocal cDNA subtractions, consensus selection and virtual cloning through targeted display. Several known genes were implicated in the action of or resistance to CpG oligodeoxynucleotide 5mers. Their protein products listed below immediately suggest cell signalling pathways/processes worthy of further investigation in elucidating the mechanism of CpG 5mer activity: caspase 2, the transcription factors Atf4, Hic, HoxB3 and Rqcd1, the splicing factors Rbmx, Sfrs5 and Sfrs7, the DNA replication factors Mcm5 and Brd4, phosphoinositide-3-kinase, annexin A1, mucosa-associated lymphoid tissue lymphoma translocation 1 and three enzymes involved in protein ubiquitylation, Siah1, Gsa7 and Nin283.

  13. Effects of bioactive compounds from carrots (Daucus carota L.), polyacetylenes, beta-carotene and lutein on human lymphoid leukaemia cells.

    PubMed

    Zaini, Rana G; Brandt, Kirsten; Clench, Malcolm R; Le Maitre, Christine L

    2012-07-01

    New therapies for leukaemia are urgently needed. Carrots have been suggested as a potential treatment for leukaemia in traditional medicine and have previously been studied in other contexts as potential sources of anticancer agents. Indicating that carrots may contain bioactive compounds, which may show potential in leukaemia therapies. This study investigated the effects of five fractions from carrot juice extract (CJE) on human lymphoid leukaemia cell lines, together with five purified bioactive compounds found in Daucus carota L, including: three polyacetylenes (falcarinol, falcarindiol and falcarindiol-3-acetate) and two carotenoids (beta-carotene and lutein). Their effects on induction of apoptosis using Annexin V/PI and Caspase 3 activity assays analysed via flow cytometry and inhibition of cellular proliferation using Cell Titer Glo assay and cell cycle analysis were investigated. Treatment of all three lymphoid leukaemia cell lines with the fraction from carrot extracts which contained polyacetylenes and carotenoids was significantly more cytotoxic than the 4 other fractions. Treatments with purified polyacetylenes also induced apoptosis in a dose and time responsive manner. Moreover, falcarinol and falcarindiol-3-acetate isolated from Daucus carota L were more cytotoxic than falcarindiol. In contrast, the carotenoids showed no significant effect on either apoptosis or cell proliferation in any of the cells investigated. This suggests that polyacetylenes rather than beta-carotene or lutein are the bioactive components found in Daucus carota L and could be useful in the development of new leukemic therapies. Here, for the first time, the cytotoxic effects of polyacetylenes have been shown to be exerted via induction of apoptosis and arrest of cell cycle.

  14. Adult myeloid leukaemia, geology, and domestic exposure to radon and gamma radiation: a case control study in central Italy

    PubMed Central

    Forastiere, F.; Sperati, A.; Cherubini, G.; Miceli, M.; Biggeri, A.; Axelson, O.

    1998-01-01

    OBJECTIVES: To investigate whether indoor randon or gamma radiation might play a part in myeloid leukaemia as suggested by studies based on crude geographical or geological data for exposure assessment. METHODS: For six months randon and gamma radiation was measured with solid state nuclear track detectors and thermoluminescent dosimeters in dwellings of 44 adult male cases of acute myeloid leukaemia and 211 controls (all subjects deceased). Conditional logistic regression ORs (ORs) and 95% confidence intervals (95% CIs) were estimated for quartiles of radon and gamma radiation and for municipality and dwelling characteristics. RESULTS: The risk of leukaemia was associated with an increasing urbanisation index (p value for trend = 0.008). An increased OR was found among those living in more modern houses (OR 3.0, 95% CI 1.4 to 6.6). Confirming the findings of a previous study in the same area, geological features bore a positive association with myeloid leukemia, even by adjusting for level of urbanisation. Contrary to expectations from the previous study, however, no association appeared between myeloid leukaemia and radon and gamma radiation; for the highest quartiles of exposure, ORs were 0.56 (95% CI 0.2 to 1.4) and 0.52 (95% CI 0.2 to 1.4), respectively. Considering only subjects who had lived > or = 20 years in the monitored home and adjusting for urbanisation, there was still no effect of exposure to radiation. CONCLUSIONS: In view of the limited numbers, the results do not in general refute a possible risk of myeloid leukaemia from exposure to indoor radon or gamma radiation, but decrease the credibility of such a relation in the area studied and also of other studies suggesting an effect without monitoring indoor radiation. Some other fairly strong determinants have appeared--that is, level of urbanisation and living in modern houses-- that might need further consideration.   PMID:9614394

  15. ‘Shouting from the roof tops’: a qualitative study of how children with leukaemia are diagnosed in primary care

    PubMed Central

    Clarke, Rachel T; Jones, Caroline HD; Mitchell, Christopher D; Thompson, Matthew J

    2014-01-01

    Objectives To investigate the prehospital presentation of paediatric leukaemia and identify the disease and non-disease related factors which facilitate or impede diagnosis. Design Thematic analysis of qualitative semistructured interviews. Setting One tertiary referral centre in Southern England. Participants 21 parents and 9 general practitioners (GPs) of 18 children (<18-year-old) with a new diagnosis of acute leukaemia. Results The majority of children were first seen by GPs before the characteristic signs and symptoms of leukaemia had developed. In their absence, behavioural cues such as the child becoming apathetic or ‘not themselves’ often triggered parents to seek medical help. Most GPs were unclear about the nature and severity of the child's presentation: then, safety netting, thorough history-taking and examination, and reliance on contextual information about the parents or from prior hospital paediatrics experience were used to manage diagnostic uncertainty. The nature of the doctor–parent relationship helped and hindered the diagnostic pathway. GPs’ prior perceptions of parents as being ‘sensible’ or ‘worriers’ influenced how gravely they treated parental concerns, with ‘worriers’ being taken less seriously. Some parents believed GPs failed to listen to their anxieties and discounted their expert knowledge of their child. Specific delay factors included lack of continuity of GP; some GPs’ reluctance to take blood from children; and some parents feeling unable to voice effectively their concerns. Conclusions The presentation of paediatric leukaemia in primary care differs from that described in many hospital studies, with greater diversity and intermittency of symptoms, and the frequent absence of ‘red flags’ of serious illness. A wide range of non-disease related factors potentially delay the diagnosis of paediatric leukaemia, including tensions in the doctor–patient relationship and the doctors’ cognitive biases. The

  16. The spatial and temporal behavior of brightness temperature in Tel-Aviv and its application to air temperature monitoring

    PubMed Central

    Pelta, Ran; Chudnovsky, A. Alexandra; Schwarts, Joel

    2016-01-01

    This study applies remote sensing technology to assess and examine the spatial and temporal Brightness Temperature (BT) profile in the city of Tel-Aviv, Israel over the last 30 years using Landsat imagery. The location of warmest and coldest zones are constant over the studied period. Distinct diurnal and temporal BT behavior divide the city into four different segments. As an example of future application, we applied mixed regression models with daily random slopes to correlate Landsat BT data with monitored air temperature (Tair) measurements using 14 images for 1989–2014. Our preliminary results show a good model performance with R2 = 0.81. Furthermore, based on the model’s results, we analyzed the spatial profile of Tair within the study domain for representative days. PMID:26499933

  17. [The daily life of patients at the Hôtel-Dieu in Lyon in the nineteenth century].

    PubMed

    Bel, Jean-Christophe; Feireisen, Marie; Fessy, Michel-Henri; Broussolle, Christiane; Neidhardt, Jean-Pierre Hano; Ferrandis, Jean-Jacques

    2015-01-01

    In 1802 the Hôtel-Dieu in Lyons was incorporated in the so-called Hospices Civils de Lyon. This allowed the expansion and renovation of buildings, as well as the improvement of the conditions of hygiene and comfort of the patients. This hospital was devoted only to the most severely ill or injured adults. 1100 patients were treated by seven doctors, a main surgeon and his deputy, residents and sisters. Broadly speaking the evolution of surgery can be divided into two periods: that of before anesthesia and septic surgery and that of antiseptic and aseptic surgery. We have to mention Gensoul and the resection of the maxillary before anesthesia, Bonnet and Ollier who were devoted to osteo-articular surgery (Ollier's disease), Poncet who built the first aseptic theater, Jaboulay and the resident Carrel who were transplantation's pioneers, Bouveret (paroxysmal tachycardia and Bouveret syndrome), Destot who did the first medical use of X-rays in 1895.

  18. [The Levinsky Walk-in Clinic in Tel Aviv: holistic services to control sexually transmitted diseases in the community].

    PubMed

    Mor, Zohar; Goor, Yael; de Musquita, Sarah Bueno; Shohat, Tamy

    2010-08-01

    The Israeli Ministry of Health inaugurated two walk-in community sexually transmitted disease (STD) clinics in 2002. This review focuses on the Levinsky Clinic in Tel Aviv. The clinics were established as a response to the increase in N. gonorrhea morbidity during the late 1990's, especially in the Tel Aviv district and following the rise in trafficking of women into Israel. The target populations were later extended to include other individuals at risk of developing STD, such as prostitutes, drug addicts, men who have sex with men, persons who have multiple sex partners or individuals considering themselves to be at high-risk. The clinic is operated by a multi-professional team, including physicians, nurses, social and community workers, and volunteers. Each patient is interviewed by a nurse or social-worker to stratify her/his risk of acquiring STD. Laboratory tests and physical examinations are performed as indicated. The services are free of charge and the clients have the option to remain anonymous in order to hamper possible barriers in accessing the clinic. The medical and psycho-social services of the Levinsky Clinic are tailored for the target populations. Therefore, some of the services are provided by a mobile unit outreaching the streets, brothels, shelters for trafficked women and refugees, correctional facilities, gay venues and drug trade locations. The staff employs the harm reduction strategy, is sensitive to the status of the individual in the community, and attentive to the influence of the environment over the clients' ability to control their risks of acquiring STD. The staff encourages an open and direct conversation with the clients about sex and sexuality, in a non-judgmental and respectful fashion. Many of those interventions are provided by community workers, who are familiar with the unique social behaviors, language, values and life style of the vulnerable populations, and aware of the limitations in adopting safe sex practices.

  19. A case-control study to investigate the risk of leukaemia associated with exposure to benzene in petroleum marketing and distribution workers in the United Kingdom.

    PubMed Central

    Rushton, L; Romaniuk, H

    1997-01-01

    OBJECTIVES: To investigate the risk of leukaemia in workers in the petroleum distribution industry who were exposed to low levels of benzene. METHODS: From the cohort of distribution workers, 91 cases were identified as having leukaemia on either a death certificate or on cancer registration. These cases were compared with controls (four per case) randomly selected from the cohort, who were from the same company as the respective case, matched for age, and alive and under follow up at the time of case occurrence. Work histories were collected for the cases and controls, together with information about the terminals at which they had worked, fuel compositions, and occupational hygiene measurements of benzene. These data were used to derive quantitative estimates of personal exposure to benzene. Odds ratios (OR) were calculated conditional on the matching, to identify those variables in the study which were associated with risk of leukaemia. Examination of the potential effects of confounding and other variables was carried out with conditional logistic regression. Analyses were carried out for all leukaemia and separately for acute lymphoblastic, chronic lymphocytic, acute myeloid and monocytic, and chronic myeloid leukaemias. RESULTS: There was no significant increase in the overall risk of all leukaemias with higher cumulative exposure to benzene or with intensity of exposure, but risk was consistently doubled in subjects employed in the industry for > 10 years. Acute lymphoblastic leukaemia tended to occur in workers employed after 1950, who started work after the age of 30, worked for a short duration, and experienced low cumulative exposure with few peaks. The ORs did not increase with increasing cumulative exposure. The risk of chronic lymphocytic leukaemia seemed to be related most closely to duration of employment and the highest risk occurred in white collar workers with long service. These workers had only background levels of benzene exposure. There was

  20. Role of Ras-related C3 botulinum toxin substrate 2 (Rac2), NADPH oxidase and reactive oxygen species in diallyl disulphide-induced apoptosis of human leukaemia HL-60 cells.

    PubMed

    Yi, Lan; Ji, Xiao-Xia; Tan, Hui; Lin, Min; Tang, Yi; Wen, Ling; Ma, Yan-Hua; Su, Qi

    2010-12-01

    1. Diallyl disulphide (DADS) has potential as a chemopreventive and therapeutic agent. Previous studies have reported that Ras-related C3 botulinum toxin substrate 2 (Rac2), a regulatory subunit of the NADPH oxidase complex, is upregulated in DADS-induced apoptosis in human leukaemia HL-60 cells. The aim of the present study was to investigate the role of Rac2, NADPH oxidase and reactive oxygen species (ROS) in DADS-induced apoptosis. 2. Expression of the Rac2 gene along with that of five other genes of NADPH oxidase subunits were in HL-60 cells measured by Sybergreen quantitative real-time polymerase chain reaction. RNA interference was used to test the effect of Rac2. Protein expression was evaluated using western blot analysis and ROS levels were measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence. DNA fragmentation and flow cytometry analysis were used to detect apoptotic cells. 3. Levels of Rac2 gene and protein were significantly upregulated and NADPH oxidase was activated in DADS-induced apoptosis. Pretreatment of HL-60 cells with small interfering (si) RNAs to inhibit Rac2 blocked DADS-induced apoptosis. Diallyl disulphide-induced intracellular ROS production was increased in phorbol myristate acetate-stimulated cells, but decreased in Rac2 siRNA-treated cells. In Rac2 siRNA-treated cells, activator protein-1 and caspase 3 levels decreased, c-myc protein levels were increased and p38 protein levels were unchanged compared with Rac2-competent, DADS-treated cells. 4. These results demonstrate that NADPH oxidase is the main source of DADS-induced ROS. In addition, Rac2 selectively activates the c-Jun N-terminal kinase pathway, but not the p38 pathway, in DADS-induced apoptosis. So, Rac2, NADPH oxidase and ROS have a critical role in DADS-induced apoptosis in human leukaemia HL-60 cells.

  1. The Dialectics of Assimilation and Multiculturalism: The Case of Children of Refugees and Migrant Workers in the Bialik-Rogozin School, Tel Aviv

    ERIC Educational Resources Information Center

    Dvir, Nurit; Aloni, Nimrod; Harari, Dor

    2015-01-01

    This paper focuses on children of refugees and migrant workers from 48 countries who study together in one multicultural school in the city of Tel Aviv, Israel. The context of our study is the current ethos of globalisation and within it the phenomenon of vast migrations and creation of intercultural social realities. The aims of the study were to…

  2. Glocalized New Age Spirituality: A Mental Map of the New Central Bus Station in Tel Aviv, Deciphered through Its Visual Codes and Based on Ethno-Visual Research

    ERIC Educational Resources Information Center

    Ben-Peshat, Malka; Sitton, Shoshana

    2011-01-01

    We present here the findings of an ethno-visual research study involving the creation of a mental map of images, artifacts and practices in Tel Aviv's New Central Bus Station. This huge and complex building, part bus station, part shopping mall, has become a stage for multicultural encounters and interactions among diverse communities of users.…

  3. Expanding the Scope of Anatomical Sciences: The Case of "Human Evolution--The Fossil Evidence" Course at the Sackler School of Medicine, Tel-Aviv University

    ERIC Educational Resources Information Center

    Notzer, Netta; Abramovitz, Ruth

    2012-01-01

    The Anatomy Department at Tel-Aviv University Medical School offers its students an elective course of 26 didactic hours on human evolution. The course is open to students from all faculties, who must fulfill all academic requirements, without a prerequisite of a background in anatomy. Approximately 120 students attend annually, a third of them…

  4. Mec1/Tel1–dependent phosphorylation of Slx4 stimulates Rad1–Rad10 dependent cleavage of non–homologous DNA tails

    PubMed Central

    Toh, Geraldine W.-L.; Sugawara, Neal; Dong, Junchao; Toth, Rachel; Lee, Sang Eun; Haber, James E.; Rouse, John

    2015-01-01

    Budding yeast Slx4 interacts with the Rad1–Rad10 endonuclease that is involved in nucleotide excision repair (NER), homologous recombination (HR) and single–strand annealing (SSA). We previously showed that Slx4 is dispensable for NER but is essential for SSA. Slx4 is phosphorylated by the Mec1 and Tel1 kinases after DNA damage on at least six Ser/Thr residues, and mutation of all six residues to Ala reduces the efficiency of SSA. In this study, we further investigated the role of Slx4 phosphorylation in SSA, specifically in regulating cleavage of 3′ non–homologous (NH) DNA tails by Rad1-Rad10 during SSA and HR. Slx4 became phosphorylated after induction of a single double–strand break (DSB) during SSA and dephosphorylation coincided approximately with completion of repair. Slx4 is recruited to 3′ NH tails during DSB repair, but this does not require phosphorylation of Slx4. However, we identified specific damage-dependent Mec1/Tel1 site of Slx4 phosphorylation, Thr 113, that is required for efficient cleavage of NH tails by Rad1–Rad10. Consistent with these data, deletion of both Mec1 and Tel1 severely reduces the efficiency of NH DNA tail cleavage during HR. These data show that phosphorylation of Slx4 by Mec1 and Tel1 plays an important role in facilitating NH DNA tail cleavage during HR. PMID:20382573

  5. B-cell receptor configuration and mutational analysis of patients with chronic lymphocytic leukaemia and trisomy 12 reveal recurrent molecular abnormalities.

    PubMed

    Falisi, Erika; Novella, Elisabetta; Visco, Carlo; Guercini, Nicola; Maura, Francesco; Giaretta, Ilaria; Pomponi, Fabrizio; Nichele, Ilaria; Finotto, Silvia; Montaldi, Annamaria; Neri, Antonino; Rodeghiero, Francesco

    2014-03-01

    Trisomy 12 (+12) is the third most frequent cytogenetic aberration in chronic lymphocytic leukaemia (CLL) retrievable both as the sole chromosomal abnormality or in association with additional alterations. NOTCH1 mutations are known to be more prevalent among +12 patients, whereas mutations of FBXW7, a gene involved in NOTCH1 degradation, that lead to the constitutional activation of NOTCH1 have not been investigated in this setting. We analyzed a unicentric cohort of 44 +12 patients with CLL for mutations of TP53, NOTCH1 and FBXW7 genes, and we correlated them with B-cell receptor (BCR) configurations. FBXW7, TP53 and NOTCH1 mutations were identified in 4.5%, 6.8% and 18.2% of patients, respectively. FBXW7 and NOTCH1 mutations appeared in a mutually exclusive fashion, suggesting that both aberrations might affect the same biological pathway. We found that 44.1% of +12 CLL patients had stereotyped B-cell receptors, which is significantly higher than that observed in patients with CLL and no +12 (27%, p = 0.01). Subsets #1, #8, #10, #28 and #59 were the most represented stereotyped patterns, and IGHV4-39*01 was the gene configuration most commonly used. There was a significantly higher risk for Richter's syndrome (RS) transformation in patients with NOTCH1 or FBXW7 mutations, with four of the seven (57%) patients developing RS and characterized at least by one of the two abnormalities. These observations suggest that, similarly to the aberrations of NOTCH1, FBXW7 gene mutations may also result in cell proliferation and evasion from apoptosis in patients with +12 CLL. Together with the extremely high frequency of stereotyped BCRs and RS transformation, these abnormalities appear to cluster in these CLL patients with additional chromosome 12, suggesting a connection with the prognosis of the disease.

  6. Single base discrimination for ribonuclease H-dependent antisense effects within intact human leukaemia cells.

    PubMed Central

    Giles, R V; Ruddell, C J; Spiller, D G; Green, J A; Tidd, D M

    1995-01-01

    We have previously demonstrated, in vitro, that phosphodiester and phosphorothioate antisense oligodeoxynucleotides could direct ribonuclease H to cleave non-target RNA sites and that chimeric methylphosphonodiester/phosphodiester analogue structures were substantially more specific. In this report we show that such chimeric molecules can promote point mutation-specific scission of target mRNA by both Escherichia coli and human RNases H in vitro. Intact human leukaemia cells 'biochemically microinjected' with antisense effectors demonstrated efficient suppression of target mRNA expression. It was noted that the chimeric methylphosphonodiester/phosphodiester structures showed single base discrimination, whereas neither the phosphodiester nor phosphorothioate compounds were as stringent. Finally, we show that the antisense effects obtained in intact cells were due to endogenous RNase H activity. Images PMID:7731809

  7. Acetylome and phosphoproteome modifications in imatinib resistant chronic myeloid leukaemia cells treated with valproic acid.

    PubMed

    Buchi, Francesca; Pastorelli, Roberta; Ferrari, Germano; Spinelli, Elena; Gozzini, Antonella; Sassolini, Francesca; Bosi, Alberto; Tombaccini, Donatella; Santini, Valeria

    2011-07-01

    Chronic myeloid leukaemia has a specific therapy: BCR/ABL inhibitor imatinib. Resistance due to BCR/ABL dependent and independent mechanisms is partially reversible by histone deacetylase inhibitors. We analysed by 2D-electrophoresis and anti-pan-acetylated and anti-phosphotyrosine immunoblots, followed by spot-matching and MALDI-TOF mass spectrometry, which proteome modifications would parallel restoration of sensitivity to imatinib by valproic acid (VPA). VPA plus imatinib significantly increased acetylation of HSP90 and hnRNP L and decreased phosphorylation of HSPs and hnRNPs in imatinib resistant cells. VPA was able to modify profoundly acetylome and phosphoproteome of CML cells, while reverting resistance to imatinib.

  8. Detection of Bovine Leukaemia Virus Antibodies and Proviral DNA in Colostrum Replacers.

    PubMed

    Choudhury, B; Finnegan, C; Phillips, A; Horigan, M; Pollard, T; Steinbach, F

    2015-10-01

    Great Britain has been bovine leukaemia virus (BLV) disease free since 1999. We recently reported three separate incidents of BLV seropositivity on farms with home-reared cattle due to the use of colostrum replacer rather than infection with BLV (Emerg. Infect. Dis., 19, 2013, 1027). These cases were all linked via the use of the same brand of colostrum replacer. Here, we investigate further by examining multiple brands of colostrum replacer for proviral DNA and BLV antibodies. BLV antibodies were detected in 7 of the colostrum replacers tested, with PCR concurring in two cases. Thus, the use of these BLV antibody-positive colostrum replacers may also lead to false-positive serological diagnostics.

  9. A case of mandibular osteomyelitis in a patient with chronic myelomonocytic leukaemia

    PubMed Central

    Kojima, Yuki; Ishigami, Takashi; Akiba, Masakazu

    2016-01-01

    We report a case of chronic myelomonocytic leukaemia (CMMoL) in a 68-year-old man who developed osteomyelitis of the mandible. At the initial visit, he reported uncontrolled gingival bleeding, despite self-administered haemostasis. He complained of severe pain in the socket, despite potent opioid analgesia. After consultation with the internal medicine specialists, we undertook a surgical anti-inflammatory approach that included sequestrectomy with massive blood transfusion. His physical condition was ameliorated after the surgical procedure, and he was discharged from the hospital. However, 3 months later, he died because of cardiac arrest after haemorrhagic shock and cardiovascular failure because his CMMoL had developed to an acute blastic crisis. This experience demonstrates that the most important goal in such cases is to alleviate a patient's discomfort by applying minimally invasive actions to eliminate infection and improve the quality of life without causing deterioration in the CMMoL status. PMID:27572681

  10. Experimental quantification of the feline leukaemia virus in the cat flea (Ctenocephalides felis) and its faeces.

    PubMed

    Vobis, M; D'Haese, J; Mehlhorn, H; Mencke, N

    2005-10-01

    Cat fleas (Ctenocephalides felis) were fed via artificial membranes and infected with the feline leukaemia virus (FeLV) from cell cultures. After removing the fleas from the blood source, the quantity of virus in the flea and its faeces was measured over a defined period of time. The virus was detectable in the fleas for up to 30 h at room temperature and up to 115 h at 4 degrees C. In the faeces, the amount of virus decreased much more slowly--after 2 weeks half of the initial amount of virus could still be detected. Thus the faeces might be a source of further infections, e.g. for the flea larvae or the cat itself.

  11. An atypical, pigment-producing Metschnikowia strain from a leukaemia patient.

    PubMed

    Savini, Vincenzo; Hendrickx, Marijke; Sisti, Maurizio; Masciarelli, Gioviana; Favaro, Marco; Fontana, Carla; Pitzurra, Lucia; Arzeni, Daniela; Astolfi, Daniela; Catavitello, Chiara; Polilli, Ennio; Farina, Claudio; Fazii, Paolo; D'Antonio, Domenico; Stubbe, Dirk

    2013-05-01

    A yeast strain was isolated from the sputum sample of a leukaemia patient in the Spirito Santo Hospital of Pescara, Italy. The fungus produced a pigment that formed a reddish halo around colonies, and was identified and deposited as a Metschnikowia spp. (accession number IHEM 25107-GenBank accession number JQ921016) in the BCCM/IHEM collection of biomedical fungi and yeasts (Bruxelles, Belgium). Although the physiology of the strain was close to that of Metschnikowia sinensis, the D1/D2 sequence did not correspond to any previously described Metschnikowia species. Phylogeny of the genus Metschnikowia is complex and requires far more analysis. We present the first non-M. pulcherrima Metschnikowia spp. isolate recovered from a human, and emphasize the role of man as a transient carrier of environmental yeasts, the pathogenicity of which still needs to be defined.

  12. Non‐tumour bone marrow lymphocytes correlate with improved overall survival in childhood acute lymphoblastic leukaemia

    PubMed Central

    Edwin, Claire; Dean, Joanne; Bonnett, Laura; Phillips, Kate

    2016-01-01

    Abstract Composition of tumour immune cell infiltrates correlates with response to treatment and overall survival (OS) in several cancer settings. We retrospectively examined immune cells present in diagnostic bone marrow aspirates from paediatric patients with B‐cell acute lymphoblastic leukaemia. Our analysis identified a sub‐group (∼30% of patients) with >2.37% CD20 and >6.05% CD7 expression, which had 100% OS, and a sub‐group (∼30% of patients) with ≤2.37% CD20 and ≤6.05% CD7 expression at increased risk of treatment failure (66.7% OS, P < 0.05). Immune cell infiltrate at diagnosis may predict treatment response and could provide a means to enhance immediate treatment risk stratification. PMID:27348401

  13. Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

    PubMed

    Sanchez-Correa, Beatriz; Campos, Carmen; Pera, Alejandra; Bergua, Juan M; Arcos, Maria Jose; Bañas, Helena; Casado, Javier G; Morgado, Sara; Duran, Esther; Solana, Rafael; Tarazona, Raquel

    2016-04-01

    Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56(bright) cells and an accumulation of highly differentiated CD56(dim) NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients.

  14. Survival after acute lymphocytic leukaemia: effects of socioeconomic status and geographic region

    PubMed Central

    Schillinger, J.; Grosclaude, P.; Honjo, S.; Quinn, M.; Sloggett, A.; Coleman, M.

    1999-01-01

    National cancer registry data, linked to an areal measure of material deprivation, were used to explore possible socioeconomic and regional variation in the survival of children (0-14 years) diagnosed with acute lymphocytic leukaemia (ALL) in England and Wales from 1971 to 1990. Survival analysis and Poisson regression were used to estimate observed (crude) survival probabilities and the adjusted hazard of death. There was little evidence of a socioeconomic gradient in survival. Regional differences in survival were observed over time. These differences were most pronounced in the first six months after diagnosis, and may be attributable to differential access to centralised paediatric oncology services or treatment protocols, or to the artefact of variations in regional cancer registry practice. Similar analyses should be repeated for other, less treatable childhood cancers. The results of this study can be used to help identify ways of reducing regional variation in survival.

 PMID:10086933

  15. Isolated testicular relapse in boys with acute lymphoblastic leukaemia: treatment and outcome.

    PubMed Central

    Tiedemann, J; Chessells, J M; Sandland, R M

    1982-01-01

    In 22 boys among a group of 169 with acute lymphoblastic leukaemia the first relapse occurred in the testis. In 14 of these late isolated testicular relapse was detected on routine biopsy or became apparent after treatment was electively stopped. Eleven of these boys were treated with reinduction, irradiation of 2400 rads to both testicles, intrathecal methotrexate, and two years of chemotherapy; 10 remained well and were in second complete remission from two and a half to five and a half years later. It is concluded that boys with late isolated testicular relapse fare better than those with late marrow relapse and may have a change of long-term disease-free survival. Images p1616-a PMID:6814673

  16. Incidence of the 15q+;17q- chromosome translocation in acute promyelocytic leukaemia (APL).

    PubMed Central

    Sheer, D.; Lister, T. A.; Amess, J.; Solomon, E.

    1985-01-01

    Cytogenetic analysis was carried out on peripheral blood cultures from seven patients with acute promyelocytic leukaemia (APL-M3). A reciprocal 15;17 chromosome translocation, t(15q+;17q-), was found in all cases, and the breakpoints estimated to be 15q22 and 17q12-21. In addition to the t(15q+;17q-), trisomy 10 was found in 50% of cells analysed in one case. These results suggest that the 15;17 chromosome translocation may be observed in most cases of APL where the leukaemic cells are cultured before cytogenetic analysis is performed. The use of conditioned media in the culture of leukaemic cells is also described. Images Figure 1 PMID:3860247

  17. Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia

    PubMed Central

    Yeh, Paul; Hunter, Tane; Sinha, Devbarna; Ftouni, Sarah; Wallach, Elise; Jiang, Damian; Chan, Yih-Chih; Wong, Stephen Q.; Silva, Maria Joao; Vedururu, Ravikiran; Doig, Kenneth; Lam, Enid; Arnau, Gisela Mir; Semple, Timothy; Wall, Meaghan; Zivanovic, Andjelija; Agarwal, Rishu; Petrone, Pasquale; Jones, Kate; Westerman, David; Blombery, Piers; Seymour, John F.; Papenfuss, Anthony T.; Dawson, Mark A.; Tam, Constantine S.; Dawson, Sarah-Jane

    2017-01-01

    Several novel therapeutics are poised to change the natural history of chronic lymphocytic leukaemia (CLL) and the increasing use of these therapies has highlighted limitations of traditional disease monitoring methods. Here we demonstrate that circulating tumour DNA (ctDNA) is readily detectable in patients with CLL. Importantly, ctDNA does not simply mirror the genomic information contained within circulating malignant lymphocytes but instead parallels changes across different disease compartments following treatment with novel therapies. Serial ctDNA analysis allows clonal dynamics to be monitored over time and identifies the emergence of genomic changes associated with Richter's syndrome (RS). In addition to conventional disease monitoring, ctDNA provides a unique opportunity for non-invasive serial analysis of CLL for molecular disease monitoring. PMID:28303898

  18. Successful treatment of disseminated mucormycosis in a neutropenic patient with T-cell acute lymphoblastic leukaemia

    PubMed Central

    Guymer, Chelsea; Khurana, Sanjeev; Suppiah, Ram; Hennessey, Iain; Cooper, Celia

    2013-01-01

    Mucormycosis is a rare angioinvasive fungal infection, more commonly seen in immunosuppressed patients, with reported mortality rates of 95% in disseminated disease. We present a case report of a patient with T-cell acute lymphoblastic leukaemia who developed disseminated infection with mucormycosis (involving the pancreas, left occipital lobe, right lower lobe of lung, appendix and right kidney) after having completed induction and consolidation chemotherapy. Growth of Lichtheimia corymbifera was initially isolated following a right pleural tap with fungal elements identified repeatedly on subsequent pathology specimens. Following radical surgical debridement and concurrent treatment with combination antifungal therapy, the patient survived. This case demonstrates that aggressive multisite surgical de-bulking of disseminated fungal foci, in conjunction with combination antifungal therapy and reversal of immunosuppression, can result in survival despite the grave prognosis associated with disseminated mucormycosis. PMID:23904418

  19. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia.

    PubMed

    Sinisalo, Marjatta; Vilpo, Juhani; Itälä, Maija; Väkeväinen, Merja; Taurio, Jyrki; Aittoniemi, Janne

    2007-12-21

    Chronic lymphocytic leukaemia (CLL) is a common adulthood mature B-cell neoplasm. Infections are the most important cause of mortality in this condition, and Streptococcus pneumoniae has been considered the most important single pathogen. We investigated the immunogenicity of 7-valent pneumococcal conjugate vaccine in patients with CLL. The study material comprised 52 patients with CLL and 25 age- and sex-matched controls. The subjects were vaccinated with Prevenar pneumococcal conjugate vaccine. Serum samples were taken for antibody determinations before and four weeks after vaccination. Antibody response rates to vaccine antigens were lower in patients with CLL compared to controls. However, if the vaccine had been administered at an early stage of the disease, i.e. before commencement of chemotherapy and the development of hypogammaglobulinaemia, a significant vaccination response to at least six antigens was obtained in almost 40% of the CLL patients. Our results indicate that early administration of conjugate vaccine may be beneficial in CLL.

  20. Correlations between nuclear morphology and bundles of cytoplasmic fibrils in 50 cases of acute myeloid leukaemia.

    PubMed Central

    Pearson, E C

    1986-01-01

    An electron microscopic examination was carried out of peripheral blood or bone marrow samples, or both, from 50 patients entered into the Medical Research Council 9th Acute Myeloid Leukaemia Trial. The results showed a striking correlation between the presence of conspicuous bundles of fibrils within the cytoplasm of the leukaemic cells and the degree of convolution or lobulation of the nuclei. In none of the samples were predominantly convoluted or lobed nuclei observed in the absence of prominent fibrillar bundles and in only two cases were nuclei of a more regular outline seen in association with many conspicuous bundles of cytoplasmic fibrils. No correlation was found between the apparent degree of maturity of the nuclei, as assessed by the degree of chromatin condensation, and the absence or abundance of fibrillar bundles. Images PMID:3456357

  1. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    PubMed Central

    Blunt, Matthew D.; Steele, Andrew J.

    2015-01-01

    PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID:26500849

  2. The Gemini NICI Planet-finding Campaign: Discovery of a Close Substellar Companion to the Young Debris Disk Star PZ Tel

    NASA Astrophysics Data System (ADS)

    Biller, Beth A.; Liu, Michael C.; Wahhaj, Zahed; Nielsen, Eric L.; Close, Laird M.; Dupuy, Trent J.; Hayward, Thomas L.; Burrows, Adam; Chun, Mark; Ftaclas, Christ; Clarke, Fraser; Hartung, Markus; Males, Jared; Reid, I. Neill; Shkolnik, Evgenya L.; Skemer, Andrew; Tecza, Matthias; Thatte, Niranjan; Alencar, Silvia H. P.; Artymowicz, Pawel; Boss, Alan; de Gouveia Dal Pino, Elisabete; Gregorio-Hetem, Jane; Ida, Shigeru; Kuchner, Marc J.; Lin, Douglas; Toomey, Douglas

    2010-09-01

    We report the discovery of a tight substellar companion to the young solar analog PZ Tel, a member of the β Pic moving group observed with high-contrast adaptive optics imaging as part of the Gemini Near-Infrared Coronagraphic Imager Planet-Finding Campaign. The companion was detected at a projected separation of 16.4 ± 1.0 AU (0farcs33 ± 0farcs01) in 2009 April. Second-epoch observations in 2010 May demonstrate that the companion is physically associated and shows significant orbital motion. Monte Carlo modeling constrains the orbit of PZ Tel B to eccentricities >0.6. The near-IR colors of PZ Tel B indicate a spectral type of M7 ± 2 and thus this object will be a new benchmark companion for studies of ultracool, low-gravity photospheres. Adopting an age of 12+8 -4 Myr for the system, we estimate a mass of 36 ± 6 M Jup based on the Lyon/DUSTY evolutionary models. PZ Tel B is one of the few young substellar companions directly imaged at orbital separations similar to those of giant planets in our own solar system. Additionally, the primary star PZ Tel A shows a 70 μm emission excess, evidence for a significant quantity of circumstellar dust that has not been disrupted by the orbital motion of the companion. Based on observations obtained at the Gemini Observatory, which is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), the Science and Technology Facilities Council (United Kingdom), the National Research Council (Canada), CONICYT (Chile), the Australian Research Council (Australia), Ministério da Ciência e Tecnologia (Brazil), and Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina).

  3. Organ irradiation and combination chemotherapy in treatment of acute lymphocytic leukaemia in children.

    PubMed Central

    Lanzkowsky, P; Shende, A; Aral, I; Saluja, G

    1975-01-01

    Lanzkowsky, P., Shende, A., Aral, I., Saluja, G. (1975). Archives of Disease in Childhood, 50, 685. Organ irradiation and combination chemotherapy in treatment of acute lymphocytic leukaemia in children. A total of 30 consecutive children with acute lymphocytic leukaemia (ALL) were treated from June 1971 until December 1974. Remission was induced with the use of vincristine and prednisone. After induction of remission, cranial irradiation and intrathecal methotrexate were given. Then the liver, spleen, and kidney were irradiated and 6-mercaptopurine, cyclophosphamide, and methotrexate were administered during the maintenance phase. Pulsed doses of vincristine and prednisone were administered at 10- to 12-week intervals. The patients were subdivided into two groups based on their initial white blood cell (WBC) counts: a standard risk group with an initial WBC count of less than 25 000/mm3 (25 X 10(9)/1) and a high risk group with an initial WBC count greater than 25 000/mm3 (25 X 10(9)/1). Of the 30 children entered in this study one standard risk patient died in the induction phase before attaining remission. Analysis of the results is therefore based on the remaining 29 patients, 22 standard risk and 7 high risk patients, who attained complete remission. Survival rates in continuous remission were found to be 43% of the high risk group, 88% for the standard risk group, and 77% for the combined group. Analysis of the data indicates that this therapy is unsatisfactory in high risk ALL. The results to date of this therapy for standard risk are sufficiently encouraging to continue its use in this subgroup of patients. PMID:1059384

  4. Population mixing and the risk of childhood leukaemia in Switzerland: a census-based cohort study.

    PubMed

    Lupatsch, Judith E; Kuehni, Claudia E; Niggli, Felix; Ammann, Roland A; Egger, Matthias; Spycher, Ben D

    2015-12-01

    Childhood leukaemia (CL) may have an infectious cause and population mixing may therefore increase the risk of CL. We aimed to determine whether CL was associated with population mixing in Switzerland. We followed children aged <16 years in the Swiss National Cohort 1990-2008 and linked CL cases from the Swiss Childhood Cancer Registry to the cohort. We calculated adjusted hazard ratios (HRs) for all CL, CL at age <5 years and acute lymphoblastic leukaemia (ALL) for three measures of population mixing (population growth, in-migration and diversity of origin), stratified by degree of urbanisation. Measures of population mixing were calculated for all municipalities for the 5-year period preceding the 1990 and 2000 censuses. Analyses were based on 2,128,012 children of whom 536 developed CL. HRs comparing highest with lowest quintile of population growth were 1.11 [95 % confidence interval (CI) 0.65-1.89] in rural and 0.59 (95 % CI 0.43-0.81) in urban municipalities (interaction: p = 0.271). Results were similar for ALL and for CL at age <5 years. For level of in-migration there was evidence of a negative association with ALL. HRs comparing highest with lowest quintile were 0.60 (95 % CI 0.41-0.87) in urban and 0.61 (95 % CI 0.30-1.21) in rural settings. There was little evidence of an association with diversity of origin. This nationwide cohort study of the association between CL and population growth, in-migration and diversity of origin provides little support for the population mixing hypothesis.

  5. Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes.

    PubMed

    Schmiegelow, Kjeld

    2016-12-01

    Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3-5% of all childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar syndromes being treated by contemporary protocols. Recent studies clearly indicate that many of these patients stand a good chance of cure, and that they should be offered chemotherapy with the intention to cure. Some of these syndromes are characterized by reduced tolerance to radiotherapy and/or specific anticancer agents, while others are not. This review summarises our current knowledge on the risk of acute toxicities for these ALL patients and provides guidance for treatment adjustments.

  6. Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia.

    PubMed

    Henriksen, Louise T; Nersting, Jacob; Raja, Raheel A; Frandsen, Thomas L; Rosthøj, Steen; Schrøder, Henrik; Albertsen, Birgitte K

    2014-07-01

    L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Cerebrospinal fluid (CSF) asparagine depletion is considered a marker of asparaginase effect in the central nervous system (CNS) and may play a role in CNS-directed anti-leukaemia therapy. The objective of this study was to describe CSF asparagine depletion during 30 weeks of pegylated asparaginase therapy, 1000 iu/m(2) i.m. every second week, and to correlate CSF asparagine concentration with serum L-asparaginase enzyme activity. Danish children (1-17 years) with ALL, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, standard and intermediate risk, were included. CSF samples were obtained throughout L-asparaginase treatment at every scheduled lumbar puncture. A total of 128 samples from 31 patients were available for analysis. Median CSF asparagine concentration decreased from a pre-treatment level of 5·3 μmol/l to median levels ≤1·5 μmol/l. However, only 4/31 patients (five samples) had CSF asparagine concentrations below the limit of detection (0·1 μmol/l). In 11 patients, 24 paired same day serum and CSF samples were obtained. A decrease in CSF asparagine corresponded to serum enzyme activities above 50 iu/l. Higher serum enzyme activities were not followed by more extensive depletion. In conclusion, pegylated asparaginase 1000 iu/m(2) i.m. every second week effectively reduced CSF asparagine levels.

  7. Light scatter characteristics of blast cells in acute myeloid leukaemia: association with morphology and immunophenotype.

    PubMed Central

    Vidriales, M B; Orfao, A; López-Berges, M C; González, M; López-Macedo, A; García, M A; Galende, J; San Miguel, J F

    1995-01-01

    AIMS--To analyse the forward scatter/side scatter (FSC/SSC) distribution of acute myeloblastic leukaemia (AML) blast cells in order to assess whether it correlates with their morphology, immunophenotype, and clinical and biological disease characteristics. METHODS--FSC/SSC patterns were established upon taking into account the localisation of the residual T lymphocytes in the FSC/SSC dot plot as an internal biological standard. One hundred and seventy one newly diagnosed AML patients were analysed and five different FSC/SSC patterns were established. These five patterns could be grouped into two major categories taking into account the FSC/SSC distribution of normal cells in a bone marrow aspirate: immature patterns (1 and 2) and mature patterns (3, 4, and 5). These FSC/SSC patterns were correlated with different clinical and biological characteristics of AML patients. RESULTS--No significant associations were detected in relation to the clinical and haematological disease characteristics and the prognosis of these patients. By contrast there was a significant correlation between the FSC/SSC pattern of the AML blast cells and the FAB classification. An increased reactivity for the antigens associated with myeloid differentiation such as CD13, CD33, CD11b, CD15, CD14, CD4, CD56, and/or CD16 was detected among cases showing a mature FSC/SSC pattern (3, 4, and 5), both in the whole series and even within each of the FAB AML subtypes. By contrast, the reactivity for the CD34 precursor cell associated antigen was higher among those cases displaying an immature FSC/SSC pattern, this being observed even within each FAB subgroup. CONCLUSIONS--The FSC/SSC pattern distribution of AML blast cells not only provides an additional objective and reproductible system for the classification of these leukaemias but it may also represent a connection between the FAB morphological groups and the immunophenotypic classification of AML patients. Images PMID:7629293

  8. Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia.

    PubMed

    Hoy, Sheridan M

    2015-02-01

    Obinutuzumab (Gazyva(®); Gazyvaro(®)) is an intravenously administered, glycoengineered, humanized, type II, anti-CD20 monoclonal antibody of the IgG1 subclass. It is available in the EU and the USA as combination therapy with oral chlorambucil in adults with previously untreated chronic lymphocytic leukaemia (CLL). In a multinational phase III study in this patient population, obinutuzumab plus chlorambucil significantly prolonged progression-free survival compared with oral chlorambucil alone and intravenous rituximab plus oral chlorambucil. Significant advantages with obinutuzumab plus chlorambucil over chlorambucil alone and rituximab plus chlorambucil were also observed in event-free survival, the time to a new anti-leukaemia treatment and overall response. The overall survival benefit with obinutuzumab plus chlorambucil is as yet unclear, although the most recent analysis suggests a benefit over chlorambucil alone. In the phase III study, obinutuzumab plus chlorambucil had a manageable tolerability profile in accordance with what would be expected for an anti-CD20 antibody. Neutropenia and infusion-related reactions were the most frequently reported grade 3 or higher treatment-emergent adverse events. In the majority of patients, infusion-related reactions were mild to moderate in severity and occurred predominantly during the first infusion and were managed by slowing or temporarily halting the infusion. Thus, current evidence suggests that obinutuzumab plus chlorambucil is a welcome addition to the treatment options currently available for adults with previously untreated CLL and is recommended by the National Comprehensive Cancer Network guidelines as the preferred first option for some, including those with comorbidities.

  9. Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia

    PubMed Central

    Núñez-Enríquez, J C; Fajardo-Gutiérrez, A; Buchán-Durán, E P; Bernáldez-Ríos, R; Medina-Sansón, A; Jiménez-Hernández, E; Amador-Sanchez, R; Peñaloza-Gonzalez, J G; Paredes-Aguilera, R; Alvarez-Rodriguez, F J; Bolea-Murga, V; de Diego Flores-Chapa, J; Flores-Lujano, J; Bekker-Mendez, V C; Rivera-Luna, R; del Carmen Rodriguez-Zepeda, M; Rangel-López, A; Dorantes-Acosta, E M; Núñez-Villegas, N; Velazquez-Aviña, M M; Torres-Nava, J R; Reyes-Zepeda, N C; Cárdenas-Cardos, R; Flores-Villegas, L V; Martinez-Avalos, A; Salamanca-Gómez, F; Gorodezky, C; Arellano-Galindo, J; Mejía-Aranguré, J M

    2013-01-01

    Background: Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). Methods: A case–control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. Results: Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47–11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20–0.91). Conclusion: Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS. PMID:23695017

  10. Subjects with chronic lymphocytic leukaemia-like B-cell clones with stereotyped B-cell receptors frequently show MDS-associated phenotypes on myeloid cells.

    PubMed

    Rodríguez-Caballero, Arancha; Henriques, Ana; Criado, Ignacio; Langerak, Anton W; Matarraz, Sergio; López, Antonio; Balanzategui, Ana; González, Marcos; Nieto, Wendy G; Cortesão, Emília; Paiva, Artur; Almeida, Julia; Orfao, Alberto

    2015-01-01

    An increasing body of evidence suggests the potential occurrence of antigen encounter by the cell of origin in chronic lymphocytic leukaemia (CLL) and CLL-like monoclonal B-cell lymphocytosis (MBL). However, the scenario in which this event might occur remains unknown. In order to gain insight into this scenario we investigated the molecular, cytogenetic and haematological features of 223 CLL-like (n = 84) and CLL (n = 139) clones with stereotyped (n = 32) versus non-stereotyped (n = 191) immunoglobulin heavy chain variable region (IGHV) amino acid sequences. Overall, stereotyped CLL-like MBL and CLL clones showed a unique IGHV profile, associated with higher IGHV1 and lower IGHV3 gene family usage (P = 0·03), longer IGHV complementary determining region 3 (HCDR3) sequences (P = 0·007) and unmutated IGHV (P < 0·001) versus non-stereotyped clones. Whilst the overall size of the stereotyped B-cell clones in peripheral blood did not appear to be associated with the CLL-related cytogenetic profile of B-cells (P > 0·05), it did show a significant association with the presence of myelodysplastic syndrome (MDS)-associated immunophenotypes on peripheral blood neutrophils and/or monocytes (P = 0·01). Altogether our results point to the potential involvement of different selection forces in the expansion of stereotyped vs. non-stereotyped CLL and CLL-like MBL clones, the former being potentially favoured by an underlying altered haematopoiesis.

  11. Lymphoma-type adult T-cell leukaemia-lymphoma with a bulky cutaneous tumour showing multiple human T-lymphotropic virus-1 DNA integration.

    PubMed

    Kato, N; Sugawara, H; Aoyagi, S; Mayuzumi, M

    2001-06-01

    Human T-lymphotropic virus-1 (HTLV-1) is considered to be the cause of adult T-cell leukaemia-lymphoma (ATL). Monoclonal integration of HTLV-1 proviral DNA, as is analysed by Southern blotting, has been demonstrated in ATL patients. Unusual integration patterns of HTLV-1 proviral DNA have occasionally been described, and it is suggested that the patterns have clinical implications for ATL pathophysiology. Multiple, complete and defective types of integration patterns, in that order, are apparently associated with prognoses from good to poor. We report a 73-year-old Japanese woman with lymphoma-type ATL and a bulky cutaneous tumour on the left thigh. Four bands of slightly differing intensity were seen after EcoRI digestion of skin and lymph node samples on Southern blot analysis of HTLV-1 proviral DNA. Analysis for T-cell receptor-beta gene revealed five novel bands after restriction enzyme digestion with HindIII, indicating that the patient has four separate tumour cell clones, each of which carries one copy of the provirus. She was treated with chemotherapy and radiation and remains under reasonable control despite some relapsing cutaneous nodules. The indolent course in this present case could be related to the multiple integration pattern of HTLV-1 proviral DNA detected.

  12. An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukaemia cases using multiple polymerases.

    PubMed

    Worrillow, L; Baskaran, P; Care, M A; Varghese, A; Munir, T; Evans, P A; O'Connor, S J; Rawstron, A; Hazelwood, L; Tooze, R M; Hillmen, P; Newton, D J

    2016-10-06

    Chronic lymphocytic leukaemia (CLL) is the most common clonal B-cell disorder characterized by clonal diversity, a relapsing and remitting course, and in its aggressive forms remains largely incurable. Current front-line regimes include agents such as fludarabine, which act primarily via the DNA damage response pathway. Key to this is the transcription factor p53. Mutations in the TP53 gene, altering p53 functionality, are associated with genetic instability, and are present in aggressive CLL. Furthermore, the emergence of clonal TP53 mutations in relapsed CLL, refractory to DNA-damaging therapy, suggests that accurate detection of sub-clonal TP53 mutations prior to and during treatment may be indicative of early relapse. In this study, we describe a novel deep sequencing workflow using multiple polymerases to generate sequencing libraries (MuPol-Seq), facilitating accurate detection of TP53 mutations at a frequency as low as 0.3%, in presentation CLL cases tested. As these mutations were mostly clustered within the regions of TP53 encoding DNA-binding domains, essential for DNA contact and structural architecture, they are likely to be of prognostic relevance in disease progression. The workflow described here has the potential to be implemented routinely to identify rare mutations across a range of diseases.

  13. Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia.

    PubMed Central

    Pandolfi, P P; Alcalay, M; Fagioli, M; Zangrilli, D; Mencarelli, A; Diverio, D; Biondi, A; Lo Coco, F; Rambaldi, A; Grignani, F

    1992-01-01

    The acute promyelocytic leukaemia (APL) 15;17 translocation generates a PML/RAR alpha chimeric gene which is transcribed as a fusion PML/RAR alpha mRNA. Molecular studies on a large series of APLs revealed great heterogeneity of the PML/RAR alpha transcripts due to: (i) variable breaking of chromosome 15 within three PML breakpoint cluster regions (bcr1, bcr2 and bcr3), (ii) alternative splicings of the PML portion and (iii) alternative usage of two RAR alpha polyadenylation sites. Nucleotide sequence analysis predicted two types of proteins: multiple PML/RAR alpha and aberrant PML. The PML/RAR alpha proteins varied among bcr1, 2 and 3 APL cases and within single cases. The fusion proteins contained variable portions of the PML N terminus joined to the B-F RAR alpha domains; the only PML region retained was the putative DNA binding domain. The aberrant PML proteins lacked the C terminus, which had been replaced by from two to ten amino acid residues from the RAR alpha sequence. Multiple PML/RAR alpha isoforms and aberrant PML proteins were found to coexist in all APLs. These findings indicate that two potential oncogenic proteins are generated by the t(15;17) and suggest that the PML activation pathway is altered in APLs. Images PMID:1314166

  14. KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia.

    PubMed

    Etchin, Julia; Sanda, Takaomi; Mansour, Marc R; Kentsis, Alex; Montero, Joan; Le, Bonnie T; Christie, Amanda L; McCauley, Dilara; Rodig, Scott J; Kauffman, Michael; Shacham, Sharon; Stone, Richard; Letai, Anthony; Kung, Andrew L; Thomas Look, A

    2013-04-01

    This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia (T-ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T-ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T-ALL and acute myeloid leukaemia (AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T-ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising 'first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T-ALL and AML.

  15. Remission of lymphoblastic leukaemia in an intravascular fluidic environment by pliable drug carrier with a sliding target ligand

    PubMed Central

    Jang, Donghyun; Lee, Yeong Mi; Lee, Jaehyun; Doh, Junsang; Kim, Won Jong

    2017-01-01

    A polyrotaxane-based nanoconstruct with pliable structure carrying a chemotherapeutic drug was developed for targeting circulating lymphoblastic leukaemia cells in a fluidic environment of blood vessels in vivo. By introducing lymphoblast targeting aptamer DNA through cyclodextrin, threaded in poly(ethylene glycol) as polyrotaxane, target aptamer slides along the long polymeric chain and actively search for target ligand, leading to active targeting in dynamic fluidic system which is enhanced by up to 6–fold compared with that of control carriers with non–sliding targeting ligands. Moreover, the drug carrier was made stimuli-responsive by employing i-motif DNA to selective releases of its payload at intracellular acidic condition. These combined features resulted in the effective remission of lymphoblastic leukaemia both in vitro and in dynamic blood vessels in vivo. PMID:28094326

  16. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study

    PubMed Central

    Pearce, Mark S; Salotti, Jane A; Little, Mark P; McHugh, Kieran; Lee, Choonsik; Kim, Kwang Pyo; Howe, Nicola L; Ronckers, Cecile M; Rajaraman, Preetha; Craft, Alan W; Parker, Louise; de González, Amy Berrington

    2012-01-01

    Summary Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. Methods In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. Findings During follow-up, 74 of 178 604 patients were diagnosed with leukaemia and 135 of 176 587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005–0·120; p=0·0097) and brain tumours (0·023, 0·010–0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46–6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose 60·42 mGy) was 2·82 (1·33–6·03). Interpretation Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain

  17. Treatment of adult lymphoblastic leukaemia using cyclical chemotherapy with three combinations of four drugs (COAP, POMP, TRAP schedule).

    PubMed

    Proctor, S J; Finney, R; Walker, W; Thompson, R B

    1981-01-01

    Seventeen adult patients with previously untreated acute lymphoblastic leukaemia (ALL) were entered into a schedule of chemotherapy in which 3 combinations, each of 4 drugs, were administered in a predetermined cyclical rotation in combination with cranial irradiation and intrathecal injections of methotrexate. Of the 17 patients, 16 completed induction therapy and 15 (94%) entered remission. The only patient with T-ALL died before receiving any therapy. The median survival for all patients (17) was 22 months. Meningeal leukaemia did not occur during the haematological remission phase although 3 patients developed this complication following relapse. The authors conclude that the addition of cyclophosphamide and cytosine arabinoside to vincristine/prednisone provides excellent remission induction but the aggressive maintenance schedule employed has not led to significant long-term survival.

  18. Treatment of adult lymphoblastic leukaemia using cyclical chemotherapy with three combinations of four drugs (COAP, POMP, TRAP schedule).

    PubMed Central

    Proctor, S. J.; Finney, R.; Walker, W.; Thompson, R. B.

    1981-01-01

    Seventeen adult patients with previously untreated acute lymphoblastic leukaemia (ALL) were entered into a schedule of chemotherapy in which 3 combinations, each of 4 drugs, were administered in a predetermined cyclical rotation in combination with cranial irradiation and intrathecal injections of methotrexate. Of the 17 patients, 16 completed induction therapy and 15 (94%) entered remission. The only patient with T-ALL died before receiving any therapy. The median survival for all patients (17) was 22 months. Meningeal leukaemia did not occur during the haematological remission phase although 3 patients developed this complication following relapse. The authors conclude that the addition of cyclophosphamide and cytosine arabinoside to vincristine/prednisone provides excellent remission induction but the aggressive maintenance schedule employed has not led to significant long-term survival. PMID:6944694

  19. A Fatal Case of Acute Myeloid Leukaemia-Methotrexate Related or Primary Autoimmune Disease Related: A Rare Case Report.

    PubMed

    Agarwal, Saurabh; Kaeley, Nidhi; Gupta, Priyanka; Gupta, Vibha; Bhatia, Rohan

    2016-03-01

    Methotrexate is being used for many years in the treatment of chronic medical disorders e.g. rheumatoid arthritis since 1951. It has been associated with various systemic toxicities and complications including bone marrow suppression and lymphomas. The development of leukaemia in a patient of chronic rheumatoid arthritis is either related with the primary disease or due to the drugs which are used in the treatment like cyclophosphamide. In our present case, a 70-year-old female who was a known case of Rheumatoid Arthritis (RA) and was on methotrexate once a week orally for the past 20 years presented with complaints of loss of appetite, loss of weight and anaemia since 2 months. After thorough examination and investigation, she was diagnosed with acute myeloid leukaemia (AML-M4) with bilateral chest consolidation.

  20. Genes

    MedlinePlus

    ... Search Search MedlinePlus GO GO About MedlinePlus Site Map FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools Español You Are Here: Home → Medical Encyclopedia → Genes URL of this page: //medlineplus.gov/ency/article/ ...

  1. Gene therapy: X-SCID transgene leukaemogenicity.

    PubMed

    Thrasher, Adrian J; Gaspar, H Bobby; Baum, Christopher; Modlich, Ute; Schambach, Axel; Candotti, Fabio; Otsu, Makoto; Sorrentino, Brian; Scobie, Linda; Cameron, Ewan; Blyth, Karen; Neil, Jim; Abina, Salima Hacein-Bey; Cavazzana-Calvo, Marina; Fischer, Alain

    2006-09-21

    Gene therapy has been remarkably effective for the immunological reconstitution of patients with severe combined immune deficiency, but the occurrence of leukaemia in a few patients has stimulated debate about the safety of the procedure and the mechanisms of leukaemogenesis. Woods et al. forced high expression of the corrective therapeutic gene IL2RG, which encodes the gamma-chain of the interleukin-2 receptor, in a mouse model of the disease and found that tumours appeared in a proportion of cases. Here we show that transgenic IL2RG does not necessarily have potent intrinsic oncogenic properties, and argue that the interpretation of this observation with respect to human trials is overstated.

  2. Studies in chronic lymphocytic leukaemia II. Lymphocyte markers, cellular and humoral immunity and the effect of treatment.

    PubMed Central

    Bazerbashi, M. B.; Chanarin, I.; Denman, A. M.

    1980-01-01

    Observations were made on 15 patients with chronic lymphocytic leukaemia, 3 with non-Hodgkin's lymphoma, and 18 healthy controls. These include characterization of lymphocytes, assessment of humoral and cell-mediated immunity and the effect of treatment. Those responding to therapy showed a disappearance of 'null' lymphocytes from the blood with improvement in clinical and haematological parameters. Their immune capacity, however, remained unchanged or continued to deteriorate. PMID:7393803

  3. Relationship between paediatric CT scans and subsequent risk of leukaemia and brain tumours: assessment of the impact of underlying conditions

    PubMed Central

    de Gonzalez, Amy Berrington; Salotti, Jane A; McHugh, Kieran; Little, Mark P; Harbron, Richard W; Lee, Choonsik; Ntowe, Estelle; Braganza, Melissa Z; Parker, Louise; Rajaraman, Preetha; Stiller, Charles; Stewart, Douglas R; Craft, Alan W; Pearce, Mark S

    2016-01-01

    Background: We previously reported evidence of a dose–response relationship between ionising-radiation exposure from paediatric computed tomography (CT) scans and the risk of leukaemia and brain tumours in a large UK cohort. Underlying unreported conditions could have introduced bias into these findings. Methods: We collected and reviewed additional clinical information from radiology information systems (RIS) databases, underlying cause of death and pathology reports. We conducted sensitivity analyses excluding participants with cancer-predisposing conditions or previous unreported cancers and compared the dose–response analyses with our original results. Results: We obtained information from the RIS and death certificates for about 40% of the cohort (n∼180 000) and found cancer-predisposing conditions in 4 out of 74 leukaemia/myelodysplastic syndrome (MDS) cases and 13 out of 135 brain tumour cases. As these conditions were unrelated to CT exposure, exclusion of these participants did not alter the dose–response relationships. We found evidence of previous unreported cancers in 2 leukaemia/MDS cases, 7 brain tumour cases and 232 in non-cases. These previous cancers were related to increased number of CTs. Exclusion of these cancers reduced the excess relative risk per mGy by 15% from 0.036 to 0.033 for leukaemia/MDS (P-trend=0.02) and by 30% from 0.023 to 0.016 (P-trend<0.0001) for brain tumours. When we included pathology reports we had additional clinical information for 90% of the cases. Additional exclusions from these reports further reduced the risk estimates, but this sensitivity analysis may have underestimated risks as reports were only available for cases. Conclusions: Although there was evidence of some bias in our original risk estimates, re-analysis of the cohort with additional clinical data still showed an increased cancer risk after low-dose radiation exposure from CT scans in young patients. PMID:26882064

  4. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013

    PubMed Central

    Yeoh, Allen EJ; Tan, Daryl; Li, Chi-Kong; Hori, Hiroki; Tse, Eric; Pui, Ching-Hon

    2014-01-01

    The survival rates for both adult and children with acute lymphoblastic leukaemia have improved substantially in recent years with wider use of improved risk-directed therapy and supportive care. In nearly all developed countries, clinical practice guidelines have been formulated by multidisciplinary panels of leukaemia experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, there are huge disparities in economy and infrastructure among the countries, and even among different regions in some large countries. This review summarizes the recommendations developed for Asian countries by a panel of adult and paediatric leukaemia therapists, based on the availability of financial, skill and logistical resources, at a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand. The management strategies described here are stratified by a four-tier system (basic, limited, enhanced and maximum) based on the resources available to a particular country or region. PMID:24176570

  5. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013.

    PubMed

    Yeoh, Allen E J; Tan, Daryl; Li, Chi-Kong; Hori, Hiroki; Tse, Eric; Pui, Ching-Hon

    2013-11-01

    Survival for adults and children with acute lymphoblastic leukaemia has risen substantially in recent years because use of improved risk-directed treatments and supportive care has widened. In nearly all developed countries, multidisciplinary panels of leukaemia experts have formulated clinical practice guidelines in which standard treatment approaches are recommended on the basis of current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, huge disparities in economy and infrastructure exist between countries, and even among different regions in some large countries. At a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand, a panel of experts summarised recommendations for management of adult and paediatric acute lymphoblastic leukaemia. Strategies were developed for Asian countries on the basis of available financial, skill, and logistical resources and were stratified in a four-tier system according to the resources available in a particular country or region (basic, limited, enhanced, and maximum).

  6. High cost factors for leukaemia and lymphoma patients: a new analysis of costs within these diagnosis related groups

    PubMed Central

    Quantin, C.; Entezam, F.; Brunet-Lecomte, P.; Lepage, E.; Guy, H.; Dusserre, L.

    1999-01-01

    STUDY OBJECTIVE: To determine high cost factors to help managers and clinicians to analyse the reasons of adverse costs and provide indications for financial negotiation. DESIGN: To locate high cost or long stay patients, the analysis was designed on the basis of a mixture of Weibull distributions. In this new model, the proportion of high cost patients was expressed according to the multinomial logistic regression, permitting the determination of high cost factors. SETTING: The 1993 French reference database, constituted in the framework of the national study of DRG costs, conducted by the French Ministry of Health. The database of discharge abstracts recorded in 1993 in the Dijon public teaching hospital. PARTICIPANTS: The analyses were based on 1352 abstracts from the French reference database and 368 from the Dijon database concerning patients, aged 18 and over, suffering from leukaemia and lymphoma. MAIN RESULTS: High cost and long stay factors were the same: number of stays, death, transfer, acute leukaemia, neutropenia, septicaemia, high dose aplastic chemotherapy, central venous catheterisation, parenteral nutrition, protected or laminar airflow room, blood transfusion, and intravenous antibiotherapy. CONCLUSIONS: Taking into account high cost predictive factors, as shown in the case of leukaemia and lymphoma patients, would help to reduce the adverse effects of a prospective payment system.   PMID:10326049

  7. The effect of dietary intake changes on nutritional status in acute leukaemia patients after first induction chemotherapy.

    PubMed

    Malihi, Z; Kandiah, M; Chan, Y M; Esfandbod, M; Vakili, M; Hosseinzadeh, M; Zarif Yeganeh, M

    2015-07-01

    This study aimed to evaluate how changes in dietary intake among acute lymphoblastic and acute myeloid leukaemia (ALL and AML) patients affect nutritional status after the first induction chemotherapy. Dietary intake was assessed using 24-h recall and a 136-item food frequency questionnaire. Nutritional status was assessed by Patients Subjective Global Assessment questionnaire before starting induction therapy and again after 1 month. All newly diagnosed acute leukaemia patients aged 15 years old and older who attended three referral hospitals for initiation of their induction chemotherapy were included in the sample selection provided that they gave informed consent. A total of 30 AML and 33 ALL patients participated in the study. Dietary intake and nutritional status worsened after the chemotherapy treatment. Dietary intake in terms of macronutrients, micronutrients, food variety and diet diversity score changed significantly after the induction chemotherapy. No significant relationship was found between the changes in dietary indices and nutritional status. Chemotherapy-related side effects as an additional factor to cancer itself could affect dietary intake of leukaemia patients. The effectiveness of an early assessment of nutritional status and dietary intake should be further investigated in order to deter further deterioration.

  8. The development of a three-dimensional scaffold for ex vivo biomimicry of human acute myeloid leukaemia.

    PubMed

    Blanco, Teresa Mortera; Mantalaris, Athanasios; Bismarck, Alexander; Panoskaltsis, Nicki

    2010-03-01

    Acute myeloid leukaemia (AML) is a cancer of haematopoietic cells that develops in three-dimensional (3-D) bone marrow niches in vivo. The study of AML has been hampered by lack of appropriate ex vivo models that mimic this microenvironment. We hypothesised that fabrication and optimisation of suitable biomimetic scaffolds for culturing leukaemic cells ex vivo might facilitate the study of AML in its native 3-D niche. We evaluated the growth of three leukaemia subtype-specific cell lines, K-562, HL60 and Kasumi-6, on highly porous scaffolds fabricated from biodegradable and non-biodegradable polymeric materials, such as poly (L-lactic-co-glycolic acid) (PLGA), polyurethane (PU), poly (methyl-methacrylate), poly (D, L-lactade), poly (caprolactone), and polystyrene. Our results show that PLGA and PU supported the best seeding efficiency and leukaemic growth. Furthermore, the PLGA and PU scaffolds were coated with extracellular matrix (ECM) proteins, collagen type I (62.5 or 125 microg/ml) and fibronectin (25 or 50 microg/ml) to provide biorecognition signals. The 3 leukaemia subtype-specific lines grew best on PU scaffolds coated with 62.5 microg/ml collagen type I over 6 weeks in the absence of exogenous growth factors. In conclusion, PU-collagen scaffolds may provide a practical model to study the biology and treatment of primary AML in an ex vivo mimicry.

  9. Strong association of the HLA-DP6 supertype with childhood leukaemia is due to a single allele, DPB1*0601.

    PubMed

    Taylor, G M; Hussain, A; Verhage, V; Thompson, P D; Fergusson, W D; Watkins, G; Lightfoot, T; Harrison, C J; Birch, J M

    2009-05-01

    We previously reported that susceptibility to childhood B cell precursor ALL (BCP ALL) is associated with HLA-DPB1 alleles having glutamic acid (E) rather than lysine (K) in the P4 antigenic peptide-binding pocket. Clustering approximately 90% of DPB1 alleles into DPB69E (DP2, 6, 8) and DPB69K (DP1, 3, 4) supertypes revealed that DP2 and DP8 are associated with BCP ALL, but DP6 is also associated with non-BCP leukaemia. Here, we report that only one of seven alleles with the DP6 supertype (DPB1(*)0601) is associated with childhood leukaemia (leukaemia vs controls: odds ratio, 95% confidence interval [OR, CI]: 4.6, 2.0-10.4; corrected P=0.019), but not with childhood solid tumours or lymphomas. DPB1(*)0601 is also significantly associated with leukaemia subtypes, including BCP ALL, Pro-B ALL, T-ALL and AML. DPB1(*)0601 is significantly over-transmitted (76.9%) from parents to children with BCP ALL (OR; CI: 4.7; 1.01-22.2). Sequencing the coding region of DPB1(*)0601 revealed an exon 1-4 haplotype [T-DEAV-KIL-RVI] shared with DPB1(*)0301 and 0901, but no evidence of germline mutations in childhood leukaemia. These results suggest that the DPbeta0601 molecule may be functionally involved in childhood leukaemia. Analysis of peptide binding and T-cell activation by DPbeta0601-peptide complexes should help determine its role in childhood leukaemia causation.

  10. Progress and problems with the use of viral vectors for gene therapy.

    PubMed

    Thomas, Clare E; Ehrhardt, Anja; Kay, Mark A

    2003-05-01

    Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.

  11. Climatic behavior of various urban parks during hot and humid summer in the mediterranean city of Tel Aviv, Israel

    NASA Astrophysics Data System (ADS)

    Potchter, Oded; Cohen, Pninit; Bitan, Arieh

    2006-10-01

    This study examines the climatic behavior of different designs of urban parks during hot and humid summer conditions, and their influence on human comfort in Tel Aviv, Israel. The research was conducted in three different types of urban parks: a park with grass and a few low trees, a park with medium sized trees and a park with high and wide-canopied trees. The results showed that an urban park that contains high trees with a wide canopy has the maximum cooling effect during daytime, reduces temperatures by up to 3.5 °C and lowers heat stress values despite increasing relative humidity values. An urban park that contains dense, medium sized trees can also reduce temperatures during daytime by up to 2.5 °C as well as slightly lower heat stress. However, during nighttime it can create uncomfortable climatic conditions owing to the reduction of wind velocity and increase in relative humidity. An urban park covered with grass can be warmer and sometimes even more humid than the built-up area during the day, which increases heat stress values.

  12. Auto-inhibition of ETV6 (TEL) DNA-binding: appended helices sterically block the ETS domain

    PubMed Central

    Coyne, H. Jerome; De, Soumya; Okon, Mark; Green, Sean M.; Bhachech, Niraja; Graves, Barbara J.; McIntosh, Lawrence P.

    2012-01-01

    ETV6 (or TEL), a transcriptional repressor belonging to the ETS family, is frequently involved in chromosomal translocations linked with human cancers. It displays a DNA-binding mode distinct from other ETS proteins due to the presence of a self-associating PNT domain. In this study, we used NMR spectroscopy to dissect the structural and dynamic bases for the auto-inhibition of ETV6 DNA-binding by sequences C-terminal to its ETS domain. The CID (C-terminal inhibitory domain) contains two helices, H4 and H5, which sterically block the DNA-binding interface of the ETS domain. Importantly, these appended helices are only marginally stable as revealed by amide hydrogen exchange and 15N relaxation measurements. The CID is thus poised to undergo a facile conformational change as required for DNA-binding. The CID also dampens millisecond timescale motions of the ETS domain hypothesized to be critical for the recognition of specific ETS target sequences. This work illustrates the use of appended sequences on conserved structural domains to generate biological diversity, and complements previous studies of the allosteric mechanism of ETS1 auto-inhibition to reveal both common and divergent features underlying the regulation of DNA-binding by ETS transcription factors. PMID:22584210

  13. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

    PubMed Central

    Seymour, John F; Ma, Shuo; Brander, Danielle M; Choi, Michael Y; Barrientos, Jacqueline; Davids, Matthew S; Anderson, Mary Ann; Beaven, Anne W; Rosen, Steven T; Tam, Constantine S; Prine, Betty; Agarwal, Suresh K; Munasinghe, Wijith; Zhu, Ming; Lash, L Leanne; Desai, Monali; Cerri, Elisa; Verdugo, Maria; Kim, Su Young; Humerickhouse, Rod A; Gordon, Gary B; Kipps, Thomas J; Roberts, Andrew W

    2017-01-01

    Summary Background Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Methods Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200–600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2–6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. Findings Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1–2 toxicities

  14. WNT5A expression is regulated by the status of its promoter methylation in leukaemia and can inhibit leukemic cell malignant proliferation.

    PubMed

    Deng, Gang; Li, Zhao Quan; Zhao, Chen; Yuan, Yuan; Niu, Chang Chun; Zhao, Chen; Pan, Jing; Si, Wei Ke

    2011-02-01

    Although down-regulation of WNT5A expression has been reported in some types of leukaemias, the level of WNT5A expression has not been assessed in leukaemia complete remission (CR) cases, the relationship among WNT5A expression level, the status of its promoter methylation, and the curative effect of leukaemia has not been reported, and the effect of WNT5A on cell proliferation has not been assessed. In this study, we analyzed WNT5A expression in various kinds of leukaemia cases, leukaemia CR cases, non-malignant hematopoietic (NMH) cases, as well as in leukemic cell lines and CD34+ cells. The methylation status of the WNT5A promoter and the levels of the Wnt5a protein were also studied. We also investigated the effect of Wnt5a on leukemic cell proliferation. WNT5A expression level was higher in NMH but lower in leukaemia cases compared to that in CR-cases (P<0.01), and was expressed at low level in leukemic cell lines K562, U937 and Jurkat. Wnt5a protein was positive in NMH, CR cases and CD34+, but negative in leukaemia cases. WNT5A promoter was methylated in leukaemia cases and all leukemic cell lines, but not in NMH and CR cases. WNT5A expression was up-regulated after exposure to the demethylating agent 5-Aza-2'-deoxycytidine (Aza) in the K562, U937, Jurkat leukemic cell lines and in 83.3% (10/12) of CR patients after cure, respectively. The increased Wnt5a protein can inhibit K562 malignant proliferation and arrest cell cycle at the G2/M phase after exposure to Aza. These results indicate that WNT5A expression was restored in complete remission cases due to demethylation, and Wnt5a can inhibit leukaemic cell proliferation. We propose that WNT5A can act as a suppressor factor in leukemogenesis and can be used as a potential marker for curative effect assessment in leukaemia.

  15. Case report: hydroquinone and/or glutaraldehyde induced acute myeloid leukaemia?

    PubMed Central

    Makropoulos , Vassilios; Alexopoulos, Evangelos C

    2006-01-01

    Background Exposures to high doses of irradiation, to chemotherapy, benzene, petroleum products, paints, embalming fluids, ethylene oxide, herbicides, pesticides, and smoking have been associated with an increased risk of acute myelogenous leukemia (AML). Although there in no epidemiological evidence of relation between X-ray developer, fixer and replenisher liquids and AML, these included glutaraldehyde which has weakly associated with lymphocytic leukemia in rats and hydroquinone has been increasingly implicated in producing leukemia, causing DNA and chromosomal damage, inhibits topo-isomerase II, alter hematopoiesis and inhibit apoptosis of neoplastic cells. Case presentation Two white females (A and B) hired in 1985 as medical radiation technologists in a primary care center, in Greece. In July 2001, woman A, 38-years-old, was diagnosed as having acute monocytic leukaemia (FAB M5). The patient did not respond to therapy and died threeweeks later. In August 2001, woman B, 35-year-old, was diagnosed with acute promyelocytic leukaemia (FAB M3). Since discharge, she is in continuous complete remission. Both women were non smokers without any medical history. Shortly after these incidents official inspectors and experts inspected workplace, examined equipment, archives of repairs, notes, interviewed and monitored employees. They concluded that shielding was inadequate for balcony's door but personal monitoring did not show any exceeding of TLV of 20 mSv yearly and cytogenetics analysis did not reveal findings considered to be characteristics of ionizing exposure. Equipment for developing photos had a long list of repairs, mainly leakages of liquids and increases of temperature. On several occasions the floor has been flooded especially during 1987–1993 and 1997–2001. Inspection confirmed a complete lack of ventilation and many spoiled medical x-ray films. Employees reported that an "osmic" level was continuously evident and frequently developed symptoms of

  16. Seroprevalence of antibodies against human herpesvirus 8 in a population of renal transplant recipients at Hôtel-Dieu de Québec Hospital.

    PubMed

    Delorme, S; Houde, I; Deschênes, L

    2003-11-01

    We conducted a seroepidemiologic study to determine the prevalence of anti-human herpesvirus 8 antibodies in a renal transplant population at Hôtel-Dieu de Québec Hospital. Testing for immunoglobulin G antibodies against lytic and latent antigens was performed on serum samples from 150 renal transplant patients. Human immunodeficiency virus-positive patients with confirmed Kaposi's sarcoma were used as positive controls. None of the renal transplant patients tested positive.

  17. Increased megakaryocytic proliferation, pro-platelet deposition and expression of fibrosis-associated factors in children with chronic myeloid leukaemia with bone marrow fibrosis.

    PubMed

    Hussein, K; Stucki-Koch, A; Göhring, G; Kreipe, H; Suttorp, M

    2017-03-28

    Paediatric chronic myeloid leukaemia (ped-CML) is rare and ped-CML with fibre accumulation in the bone marrow (MF) is thought to be even rarer. In adults (ad-CML), fibrosis represents an adverse prognostic factor. So far, the pro-fibrotic changes in the bone marrow microenvironment have not been investigated in detail in ped-CML. From a total of 66 ped-CML in chronic phase, biopsies were analysable and 10 had MF1/2 (MF1, n=8/10; MF2, n=2/10). We randomly selected 16 ped-CML and 16 ad-CML cases with and without fibrosis (each n=8) as well as 18 non-neoplastic controls. Bone marrow samples were analysed with a real-time PCR-based assay (including 127 genes for paediatric cases) and by immunohistochemistry. We found increased expression of megakaryocytic genes in ped-CML. The number of megakaryocytes and pro-platelets are increased in CML patients, but the most significant increase was noted for ped-CML-MF1/2. Anti-fibrotic MMP9 expression was lower in children than in adults. Cell mobilisation-related CXCL12 was decreased in young and adult patients with CML but not the corresponding receptor CXCR4. In summary, fibre accumulation in ped-CML-MF1/2 is associated with increased megakaryocytic proliferation and increased interstitial pro-platelet deposition. Deregulated expression of matrix-modulating factors shifts the bone marrow microenvironment towards fibrosis.Leukemia advance online publication, 28 March 2017; doi:10.1038/leu.2017.73.

  18. A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia

    PubMed Central

    Jung, Ji Hoon; Yun, Miyong; Choo, Eun-Jeong; Kim, Sun-Hee; Jeong, Myoung-Seok; Jung, Deok-Beom; Lee, Hyemin; Kim, Eun-Ok; Kato, Nobuo; Kim, Bonglee; Srivastava, Sanjay K; Kaihatsu, Kunihiro; Kim, Sung-Hoon

    2015-01-01

    Background and Purpose Epigallocatechin-3-gallate (EGCG) is a component of green tea known to have chemo-preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent. Experimental Approach Derivatives of EGCG were evaluated for their stability and anti-tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells. Key Results EGCG-mono-palmitate (EGCG-MP) showed most prolonged stability compared with other EGCG derivatives. EGCG-MP exerted greater cytotoxicity and apoptosis in K562 and KBM5 cells than the other EGCG derivatives. EGCG-MP induced Src-homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) leading decreased oncogenic protein BCR-ABL and STAT3 phosphorylation in CML cells, compared with treatment with EGCG. Furthermore, EGCG-MP reduced phosphorylation of STAT3 and survival genes in K562 cells, compared with EGCG. Conversely, depletion of SHP-1 or application of the tyrosine phosphatase inhibitor pervanadate blocked the ability of EGCG-MP to suppress phosphorylation of BCR-ABL and STAT3, and the expression of survival genes downstream of STAT3. In addition, EGCG-MP treatment more effectively suppressed tumour growth in BALB/c athymic nude mice compared with untreated controls or EGCG treatment. Immunohistochemistry revealed increased caspase 3 and SHP-1 activity and decreased phosphorylation of BCR-ABL in the EGCG-MP-treated group relative to that in the EGCG-treated group. Conclusions and Implications EGCG-MP induced SHP-1-mediated inhibition of BCR-ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG. This derivative may be a potent chemotherapeutic agent for CML treatment. PMID:25825203

  19. Simvastatin in combination with bergamottin potentiates TNF-induced apoptosis through modulation of NF-κB signalling pathway in human chronic myelogenous leukaemia.

    PubMed

    Kim, Sung-Moo; Lee, Eun-Jung; Lee, Jong Hyun; Yang, Woong Mo; Nam, Dongwoo; Lee, Jun-Hee; Lee, Seok-Geun; Um, Jae-Young; Shim, Bum Sang; Ahn, Kwang Seok

    2016-10-01

    Context Simvastatin (SV) and bergamottin (BGM) are known to exhibit diverse anti-cancer and anti-inflammatory activities. Objective Very little is known about the potential efficacy of combination of these two agents to potentiate TNF-induced apoptosis in human chronic myelogenous leukaemia (CML). Materials and methods In the present study, we investigated whether SV combined with BGM mediates its effect through suppression of NF-κB-signalling pathway. Results We found that the combination treatment enhanced cytotoxicity and potentiated the apoptosis induced by TNF as indicated by intracellular esterase activity, Annexin V staining and caspase activation. This effect of co-treatment correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1), cell survival (cIAP-1, Bcl-2, Bcl-xL and Survivin), invasion (MMP-9) and angiogenesis (VEGF); all known to be regulated by NF-κB. SV combined with BGM also produced TNF-induced cell-cycle arrest in S-phase and this arrest correlated with a concomitant increase in the levels of cyclin-dependent inhibitor p21 and p27. The combination therapy inhibited TNF-induced NF-κB activation, IκBα degradation and p65 translocation to the nucleus as compared with the treatment with individual agents alone. Besides, SV combined with BGM did not significantly potentiate apoptotic effect induced by TNF in p65(-)(/)(-) cells, as compared with wild-type fibroblasts. Discussion and conclusion Our results provide novel insight into the role of SV and BGM in potentially preventing and treating cancer through modulation of NF-κB signalling pathway and its regulated gene products.

  20. Definition of progression risk based on combinations of cellular and molecular markers in patients with Binet stage A chronic lymphocytic leukaemia.

    PubMed

    Morabito, Fortunato; Cutrona, Giovanna; Gentile, Massimo; Matis, Serena; Todoerti, Katia; Colombo, Monica; Sonaglio, Claudia; Fabris, Sonia; Reverberi, Daniele; Megna, Mauro; Spriano, Mauro; Lucia, Eugenio; Rossi, Edoardo; Callea, Vincenzo; Mazzone, Carla; Festini, Gianluca; Zupo, Simonetta; Molica, Stefano; Neri, Antonino; Ferrarini, Manlio

    2009-06-01

    IGHV mutational status and ZAP-70 or CD38 expression correlate with clinical course in B-cell chronic lymphocytic leukaemia (CLL). The three markers may be discordant in the single case and there is no consensus on their combined use in clinical practise. This multicenter study investigated this issue. Two-hundred and sixty-two Binet stage A patients were studied for the three markers. Sixty patients were profiled with HG-U133A gene expression chips. Disease progression was determined by time from diagnosis to treatment (TTT). The probability of being treatment-free at 3 years was significantly shorter in patients with unmutated IGHV genes (IGHVunmut 66% vs. 93%, chi square of log-rank = 30, P < 0.0001), ZAP-70 positive (ZAP-70pos 73% vs. 96%, chi square of log-rank = 8.2, P = 0.004) or CD38-positive cells (CD38pos 68% vs. 91%, chi square of log-rank = 21, P < 0.0001). Cox multivariate regression analysis showed that the three markers had an independent predictive value for TTT of similar power. A prognostic system based on presence of none (low-risk), one (intermediate-risk) or two or three (high-risk) markers was generated. Based on such criteria, 56%, 23% and 21% of cases were clustered in low (HR = 1), intermediate [HR = 2.8, 95% confidence interval (CI) 2.4-5.8] and high-risk group (HR = 8.0, 95% CI 3.9-16.2). Specific transcriptional patterns were significantly associated with risk groups.

  1. Health-related quality of life assessment and reported outcomes in leukaemia randomised controlled trials - a systematic review to evaluate the added value in supporting clinical decision making.

    PubMed

    Efficace, Fabio; Kemmler, Georg; Vignetti, Marco; Mandelli, Franco; Molica, Stefano; Holzner, Bernhard

    2008-07-01

    Health-related quality of life (HRQOL) is increasingly reported as an important outcome in cancer clinical trials. However, very little evidence exists on the impact of such evaluation in randomised controlled trials (RCTs) of leukaemia patients. A systematic search of the literature from 1980 to 2007 was undertaken and studies were identified and evaluated independently, according to a pre-defined coding scheme, by three reviewers. Both HRQOL outcomes and traditional clinical reported outcomes were systematically analysed to evaluate their consistency and their relevance for supporting clinical decision making. Nine RCTs were identified, involving 3838 patients overall. There were four RCTs involving acute myeloid leukaemia patients (AML), three with chronic myeloid leukaemia (CML) and two with chronic lymphocytic leukaemia (CLL). Six studies were published after 2000 and provided fairly robust methodological quality. Imatinib greatly improved HRQOL compared to interferon based treatments in CML patients and fludarabine plus cyclophosphamide does not seem to have a deleterious impact on patient's HRQOL when compared to fludarabine alone or chlorambucil in CLL patients. This study revealed the paucity of HRQOL research in leukaemia patients. Nonetheless, HRQOL assessment is feasible in RCTs and has the great potential of providing valuable outcomes to further support clinical decision making.

  2. Bio-WiTel: A Low Power Integrated Wireless Telemetry System for Healthcare Applications in 401-406 MHz Band of MedRadio Spectrum.

    PubMed

    Srivastava, Abhishek; Sankar, Nithin; Chatterjee, Baibhab; Das, Devarshi; Ahmad, Meraj; Kukkundoor, Rakesh; Saraf, Vivek; Jayachandran, Ananthpadmanabhan; Sharma, Dinesh; Baghini, Maryam

    2016-12-14

    This paper presents a low power integrated wireless telemetry system (Bio-WiTel) for healthcare applications in 401- 406 MHz frequency band of Medical Device RadioCommunication (MedRadio) spectrum. In this work, necessary design considerations for telemetry system for short range (upto 3 m) communication of bio-signals are presented. These considerations greatly help in taking important design decisions, which eventually lead to a simple, low power, robust and reliable wireless system implementation. Transmitter (TX) and receiver (RX) of Bio-WiTel system have been fabricated in 180 nm mixed mode CMOS technology. While radiating -18 dBm output power to a 50 antenna, the packaged TX IC consumes 250 μW power in 100% on state from 1 V supply whereas the RX IC consumes 990 μW power from 1.8 V supply with a sensitivity of -75 dBm. Measurement results show that TX fulfils the spectral mask requirement at a maximum data rate of 72 kbps. The measured bit error rate of RX is less than 10-4 for a data rate of 200 kbps. The proposed Bio-WiTel system is tested successfully in home and hospital environments for the communication of electrocardiogram (ECG) and photoplethysmogram (PPG) signals at a data rate of 57.6 kbps with a measured BER of < 10-4 for a maximum distance of 3 m.

  3. PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds to Plasmodium falciparum telomeres.

    PubMed

    Sierra-Miranda, Miguel; Vembar, Shruthi S; Delgadillo, Dulce María; Ávila-López, P A; Vargas, Mi