These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

Differential positioning and close spatial proximity of translocation-prone genes in nonmalignant B-cells from multiple myeloma patients.  

PubMed

Accumulating evidence suggests that spatial proximity of potential chromosomal translocation partners influences translocation probability. It is not known, however, whether genome organization differs in nonmalignant cells from patients as compared to their cellular counterparts from healthy donors. This could contribute to translocation potential causing cancer. Multiple myeloma is a hematopoietic cancer of the B-lineage, characterized by karyotypic instability, including chromosomal translocations involving the IGH locus and several translocation partners. Utilizing 3-D FISH and confocal imaging, we investigate whether nuclear spatial positioning of the translocation-prone gene loci, IGH, FGFR3, and CCND1 differs in nonmalignant cell subsets from multiple myeloma patients as compared to positioning in their corresponding healthy donor cell subsets. 3-D analysis software was used to determine the spatial proximity of potential translocation pairs and the radial distribution of each gene. We observed that in all cell subsets, the translocation-prone gene loci are intermediately located in the nucleus, while a control locus occupies a more peripheral position. In nonmalignant B-cells from multiple myeloma patients, however, the translocation-prone gene loci display a more central nuclear position and close spatial proximity. Our results demonstrate that gene positioning in nonmalignant B-cells from multiple myeloma patients differs from that in healthy donors, potentially contributing to translocation probability in patient cells. We speculate that genome reorganization in patient B-cells may closely reflect gene positioning at the time the multiple myeloma-specific translocation initially formed, thus influencing translocation probability between proximal loci in the B-cell population from which the malignancy emerged. PMID:22489023

Martin, Lorri D; Harizanova, Jana; Zhu, George; Righolt, Christiaan H; Belch, Andrew R; Mai, Sabine; Pilarski, Linda M

2012-08-01

2

C-reactive protein induces G2/M phase cell cycle arrest and apoptosis in monocytes through the upregulation of B-cell translocation gene 2 expression.  

PubMed

We hypothesized that C-reactive protein (CRP) may affect the cell cycle and induce apoptotic changes of monocytes. CRP (?25 ?g/ml) significantly increased expressions of B-cell translocation gene 2 (BTG2) mRNA and protein in human monocytes through pathways involving CD32/NADPH oxidase 2/p53, which eventually induced G2/M phase arrest and apoptotic cell death. Such pro-apoptotic effect of CRP was not found in thioglycollate-elicited intraperitoneal monocytes/macrophages harvested from BTG2-knockout male C57BL/6 mice (n=5). Within atheromatous plaques obtained from CRP-transgenic male LDLR(-/-) C57BL/6 mice (n=5) and human coronary arteries, BTG2 co-localized with CRP, p53 and monocytes/macrophages. Therefore the pro-apoptotic pathway of CRP-CD32-Nox2-p53-BTG2 may contribute to the retardation of the atherogenic process. PMID:24440351

Kim, Yuna; Ryu, Jewon; Ryu, Min Sook; Lim, Sunny; Han, Ki Ok; Lim, In Kyoung; Han, Ki Hoon

2014-02-14

3

B-cell translocation gene 2 regulates hepatic glucose homeostasis via induction of orphan nuclear receptor Nur77 in diabetic mouse model.  

PubMed

B-cell translocation gene 2 (BTG2) is a member of an emerging gene family that is involved in cellular functions. In this study, we demonstrate that BTG2 regulates glucose homeostasis via upregulation of Nur77 in diabetic mice. Hepatic BTG2 gene expression was elevated by fasting and forskolin. Overexpression of Btg2 increased the expression of hepatic gluconeogenic genes and blood glucose output and subsequently impaired glucose and insulin tolerance. Upregulation of the transcriptional activity of Nur77, gluconeogenic genes, and glucose production by forskolin was observed by Btg2 transduction, but not in Btg2 knockdown. BTG2-stimulated glucose production and glucose-6-phosphatase promoter activity were attenuated by dominant-negative Nur77. Coimmunoprecipitation and chromatin immunoprecipitation assays showed that BTG2 induced Nur77 occupancy on the glucose-6-phosphatase promoter via a physical interaction. Btg2 gene expression was increased in streptozotocin-treated and db/db mice. Finally, impairment of glucose homeostasis, such as the increase of blood glucose, glucose intolerance, and insulin intolerance, was elevated in diabetic mice, whereas this phenomenon was abolished in knockdown of Btg2. Together, these data suggest that BTG2 participates in the regulation of hepatic glucose homeostasis, which means that BTG2 might serve as a potential therapeutic target for combating metabolic dysfunction. PMID:24647738

Kim, Yong Deuk; Kim, Sun-Gyun; Hwang, Seung-Lark; Choi, Hueng-Sik; Bae, Jae-Hoon; Song, Dae-Kyu; Im, Seung-Soon

2014-06-01

4

Differential nuclear organization of translocation-prone genes in nonmalignant B cells from patients with t(14;16) as compared with t(4;14) or t(11;14) myeloma.  

PubMed

Gene organization in nonmalignant B cells from t(4;14) and t(11;14) multiple myeloma (MM) patients differs from that of healthy donors. Among recurrent IGH translocations in MM, the frequency of t(4;14) (IGH and FGFR3) or t(11;14) (IGH and CCND1) is greater than the frequency of t(14;16) (IGH and MAF). Gene organization in t(14;16) patients may influence translocation potential of MAF with IGH. In patients, three-dimensional FISH revealed the positions of IGH, CCND1, FGFR3, and MAF in nonmalignant B cells that are likely similar to those when MM first arose, compared with B cells from healthy donors. Overall, IGH occupies a more central nuclear position while MAF is more peripherally located. However, for B cells from t(4;14) and t(11;14) patients, IGH and FGFR3, or IGH and CCND1 are found in spatial proximity: IGH and MAF are not. This differs in B cells from t(14;16) patients and healthy donors where IGH is approximately equidistant to FGFR3, CCND1, and MAF, suggesting that gene organization in t(14;16) patients is different from that in t(4;14) or t(11;14) patients. Translocations between IGH and MAF may arise only in the absence of close proximity to the more frequent partners, as appears to be the case for individuals who develop t(14;16) MM. PMID:23460268

Martin, Lorri D; Harizanova, Jana; Righolt, Christiaan H; Zhu, George; Mai, Sabine; Belch, Andrew R; Pilarski, Linda M

2013-06-01

5

Cisplatin modulates B-cell translocation gene 2 to attenuate cell proliferation of prostate carcinoma cells in both p53-dependent and p53-independent pathways  

PubMed Central

Cisplatin is a widely used anti-cancer drug. The B-cell translocation gene 2 (BTG2) is involved in the cell cycle transition regulation. We evaluated the cisplatin effects on prostate cancer cell proliferation and the expressions of BTG2, p53, androgen receptor (AR) and prostate specific antigen (PSA) in prostate carcinoma, p53 wild-type LNCaP or p53-null PC-3, cells. Cisplatin treatments attenuated cell prostate cancer cell growth through inducing Go/G1 cell cycle arrest in lower concentration and apoptosis at higher dosage. Cisplatin treatments enhanced p53 and BTG2 expression, repressed AR and PSA expression, and blocked the activation of androgen on the PSA secretion in LNCaP cells. BTG2 knockdown in LNCaP cells attenuated cisplatin-mediated growth inhibition. Cisplatin enhanced BTG2 gene expression dependent on the DNA fragment located within -173 to -82 upstream of BTG2 translation initiation site in prostate cancer cells. Mutation of the p53 response element from GGGCAGAGCCC to GGGCACC or mutation of the NF?B response element from GGAAAGTCC to GGAAAGGAA by site-directed mutagenesis abolished the stimulation of cisplatin on the BTG2 promoter activity in LNCaP or PC-3 cells, respectively. Our results indicated that cisplatin attenuates prostate cancer cell proliferation partly mediated by upregulation of BTG2 through the p53-dependent pathway or p53-independent NF?B pathway. PMID:24981574

Chiang, Kun-Chun; Tsui, Ke-Hung; Chung, Li-Chuan; Yeh, Chun-Nan; Feng, Tsui-Hsia; Chen, Wen-Tsung; Chang, Phei-Lang; Chiang, Hou-Yu; Juang, Horng-Heng

2014-01-01

6

Evolution of B-cell malignancy; Pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene  

SciTech Connect

The authors have analyzed the molecular genetics of the breakpoints involved in the t(8;14) and t(14;18) translocations of an acute pre-B-cell leukemia from a patient with a history of follicular lymphoma. In this patient's leukemic cells, the breakpoint of the t(14;18) translocation occurred in the major breakpoint-cluster region of the BCL2 gene and became linked to the J{sub H}4 joining-region gene segment of the immunoglobulin heavy-chain locus on the 14q+ chromosome as previously observed in follicular lymphoma. An N region and heptamer and nonamer signal sequences indicated that this translocation occurred as a mistake in V{sub H}-D{sub H}-J{sub H} joining (where V{sub H} and D{sub H} are the variable and diversity segments). In the t(8;14) translocation, the breakpoint was located immediately 5' of the first exon of the MYC protooncogene, which was juxtaposed with the C{gamma}2 constant gene segment of the second 14q+ chromosome. The finding of repeated sequences typical of switch regions suggested that this translocation occurred during heavy-chain isotype switching, resulting in progression to pre-B-cell leukemia with both the 5(8;14) and the t(14;18) translocations. The terminal deoxynucleotidyltransferase-positive phenotype of the patient's leukemic cells further suggests that the pre-B-cell leukemia was derived from a pre-B cell carrying a t(14;18) translocation in the original follicular lymphoma. The polymerase chain reaction method was then used to identify cancer cells in the bone marrow of the patient.

Gauwerky, C.E.; Haluska, F.G.; Tsujimoto, Y.; Nowell, P.C.; Croce, C.M. (Wistar Institute of Anatomy and Biology, Philadelphia, PA (USA))

1988-11-01

7

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.  

PubMed

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB. PMID:17353367

Lenz, Georg; Nagel, Inga; Siebert, Reiner; Roschke, Anna V; Sanger, Warren; Wright, George W; Dave, Sandeep S; Tan, Bruce; Zhao, Hong; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D; Campo, Elias; Jaffe, Elaine S; Smeland, Erlend B; Fisher, Richard I; Kuehl, W Michael; Chan, Wing C; Staudt, Louis M

2007-03-19

8

Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells.  

PubMed

Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought. PMID:23435460

Walker, Brian A; Wardell, Christopher P; Johnson, David C; Kaiser, Martin F; Begum, Dil B; Dahir, Nasrin B; Ross, Fiona M; Davies, Faith E; Gonzalez, David; Morgan, Gareth J

2013-04-25

9

BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma  

PubMed Central

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32;q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14;18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup. PMID:15215171

Iqbal, Javeed; Sanger, Warren G.; Horsman, Douglas E.; Rosenwald, Andreas; Pickering, Diane L.; Dave, Bhavana; Dave, Sandeep; Xiao, Li; Cao, Kajia; Zhu, Quiming; Sherman, Simon; Hans, Christine P.; Weisenburger, Dennis D.; Greiner, Timothy C.; Gascoyne, Randy D.; Ott, German; Muller-Hermelink, H. Konrad; Delabie, Jan; Braziel, Rita M.; Jaffe, Elaine S.; Campo, Elias; Lynch, James C.; Connors, Joseph M.; Vose, Julie M.; Armitage, James O.; Grogan, Thomas M.; Staudt, Louis M.; Chan, Wing C.

2004-01-01

10

Molecular cytogenetic characterization of t(14;19)(q32;p13), a new recurrent translocation in B cell malignancies.  

PubMed

Translocations involving an immunoglobulin (IG) locus are a recurring theme in B cell neoplasia. The rearrangements lead to the joining of an IG gene with a (proto)oncogene, whereby the latter comes under the influence of transcription-stimulating sequences in the constitutively active IG locus resulting in deregulation of the oncogene and neoplastic growth. We present here three cases of B cell neoplasia that showed a t(14;19)(q32;p13) by karyotypic analysis. Detailed molecular cytogenetic characterization of the breakpoints on chromosomes 14 and 19 in the two cases from which extra material was available, demonstrated the involvement of the immunoglobulin heavy-chain (IGH@)-variable region on chromosome 14 in both and, in one case, that the breakpoint was within the BRD4 gene on chromosome 19. Against the background of what one knows about IGH@ involvement in lymphatic malignancies, it is difficult to envisage a fusion gene with qualitatively altered protein product as the crucial pathogenetic outcome of the translocation. In spite of the fact that we found BRD4 split by the t(14;19)(q32;p13) in one of the two informative cases, we cannot be sure that this was the pathogenetically relevant target gene. Other pathogenetic possibilities could be deregulation of the neighboring NOTCH3 and/or ABHD9 genes, located distal to BRD4 in 19p13. PMID:17406891

Micci, Francesca; Panagopoulos, Ioannis; Tjønnfjord, Geir E; Kolstad, Arne; Delabie, Jan; Beiske, Klaus; Heim, Sverre

2007-05-01

11

Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes  

PubMed Central

Mature IgM+ B-cell lymphomas that arise in certain ataxia telangiectasia-mutated (ATM)-deficient compound mutant mice harbor translocations that fuse V(D)J recombination-initiated IgH double-strand breaks (DSBs) on chromosome 12 to sequences downstream of c-myc on chromosome 15, generating dicentric chromosomes and c-myc amplification via a breakage-fusion-bridge mechanism. As V(D)J recombination DSBs occur in developing progenitor B cells in the bone marrow, we sought to elucidate a mechanism by which such DSBs contribute to oncogenic translocations/amplifications in mature B cells. For this purpose, we applied high-throughput genome-wide translocation sequencing to study the fate of introduced c-myc DSBs in splenic IgM+ B cells stimulated for activation-induced cytidine deaminase (AID)-dependent IgH class switch recombination (CSR). We found frequent translocations of c-myc DSBs to AID-initiated DSBs in IgH switch regions in wild-type and ATM-deficient B cells. However, c-myc also translocated frequently to newly generated DSBs within a 35-Mb region downstream of IgH in ATM-deficient, but not wild-type, CSR-activated B cells. Moreover, we found such DSBs and translocations in activated B cells that did not express AID or undergo CSR. Our findings indicate that ATM deficiency leads to formation of chromosome 12 dicentrics via recombination-activating gene-initiated IgH DSBs in progenitor B cells and that these dicentrics can be propagated developmentally into mature B cells where they generate new DSBs downstream of IgH via breakage-fusion-bridge cycles. We propose that dicentrics formed by joining V(D)J recombination–associated IgH DSBs to DSBs downstream of c-myc in ATM-deficient B lineage cells similarly contribute to c-myc amplification and mature B-cell lymphomas. PMID:24982162

Hu, Jiazhi; Tepsuporn, Suprawee; Meyers, Robin M.; Gostissa, Monica; Alt, Frederick W.

2014-01-01

12

Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes.  

PubMed

Mature IgM(+) B-cell lymphomas that arise in certain ataxia telangiectasia-mutated (ATM)-deficient compound mutant mice harbor translocations that fuse V(D)J recombination-initiated IgH double-strand breaks (DSBs) on chromosome 12 to sequences downstream of c-myc on chromosome 15, generating dicentric chromosomes and c-myc amplification via a breakage-fusion-bridge mechanism. As V(D)J recombination DSBs occur in developing progenitor B cells in the bone marrow, we sought to elucidate a mechanism by which such DSBs contribute to oncogenic translocations/amplifications in mature B cells. For this purpose, we applied high-throughput genome-wide translocation sequencing to study the fate of introduced c-myc DSBs in splenic IgM(+) B cells stimulated for activation-induced cytidine deaminase (AID)-dependent IgH class switch recombination (CSR). We found frequent translocations of c-myc DSBs to AID-initiated DSBs in IgH switch regions in wild-type and ATM-deficient B cells. However, c-myc also translocated frequently to newly generated DSBs within a 35-Mb region downstream of IgH in ATM-deficient, but not wild-type, CSR-activated B cells. Moreover, we found such DSBs and translocations in activated B cells that did not express AID or undergo CSR. Our findings indicate that ATM deficiency leads to formation of chromosome 12 dicentrics via recombination-activating gene-initiated IgH DSBs in progenitor B cells and that these dicentrics can be propagated developmentally into mature B cells where they generate new DSBs downstream of IgH via breakage-fusion-bridge cycles. We propose that dicentrics formed by joining V(D)J recombination-associated IgH DSBs to DSBs downstream of c-myc in ATM-deficient B lineage cells similarly contribute to c-myc amplification and mature B-cell lymphomas. PMID:24982162

Hu, Jiazhi; Tepsuporn, Suprawee; Meyers, Robin M; Gostissa, Monica; Alt, Frederick W

2014-07-15

13

Activation of MYC in a masked t(8;17) translocation results in an aggressive B-cell leukemia.  

PubMed Central

We have analyzed the oncogene rearrangements involving BCL2 and MYC in the leukemia cells of a patient with an aggressive prolymphocytic leukemia that had an abnormal karyotype including a t(14;18) translocation and a chromosome 17q+. Molecular analysis showed that BCL2 was rearranged in the major breakpoint cluster region and had joined into the immunoglobulin heavy chain gene as in follicular lymphoma. Cloning and sequence analysis of the rearranged MYC gene revealed that MYC was truncated at the Pvu II site at the end of the first exon of MYC and had joined into the regulatory elements of a gene that we called BCL3 (B-cell leukemia/lymphoma 3). The BCL3 locus was mapped to chromosome 17 band q22. We found BCL3 transcribed as a message of 1.7 kilobases in many hematopoietic cell lines representing all hematopoietic lineages. In the patient's leukemia cells, the truncated MYC gene was highly expressed under the influence of BCL3 regulatory elements, leading to an aggressive B-cell leukemia that presumably had been derived from an indolent lymphoma carrying a rearranged BCL2 gene. Images PMID:2682663

Gauwerky, C E; Huebner, K; Isobe, M; Nowell, P C; Croce, C M

1989-01-01

14

Low-grade B-Cell lymphomas with plasmacytic differentiation lack PAX5 gene rearrangements.  

PubMed

The chromosomal translocation t(9;14)(p13;q32) has been reported in association with lymphoplasmacytic lymphoma (LPL). Although this translocation involving the paired homeobox-5 (PAX5) gene at chromosome band 9p13 and the immunoglobulin heavy chain (IgH) gene at 14q32 has been described in approximately 50% of LPL cases, the actual number of cases studied is quite small. Many of the initial cases associated with t(9;14)(p13;q32) were actually low-grade B-cell lymphomas with plasmacytic differentiation other than LPL. Thus, we analyzed a series of low-grade B-cell lymphomas for PAX5 gene rearrangements. We searched records from the Department of Pathology, Stanford University Medical Center for low-grade B-cell lymphomas, with an emphasis on plasmacytic differentiation, that had available paraffin blocks or frozen tissue. We identified 37 cases, including 13 LPL, 18 marginal zone lymphomas (nodal, extranodal, splenic, and alpha-heavy chain disease), and 6 small lymphocytic lymphomas. A novel dual-color break-apart bacterial artificial chromosome probe was designed to flank the PAX5 gene, spanning previously described PAX5 breakpoints, and samples were analyzed by interphase fluorescence in situ hybridization. All cases failed to demonstrate a PAX5 translocation, indicating that t(9;14)(p13;q32) and other PAX5 translocations are uncommon events in low-grade B-cell lymphomas with plasmacytic differentiation. This study also confirms recent reports that found an absence of PAX5 rearrangements in LPL, suggesting the reassessment of PAX5 rearrangements in LPL. PMID:16049306

George, Tracy I; Wrede, Joanna E; Bangs, Charles D; Cherry, Athena M; Warnke, Roger A; Arber, Daniel A

2005-08-01

15

Induction of plasmacytoid differentiation by phorbol ester in B-cell lymphoma cell lines bearing 8;14 translocations.  

PubMed Central

At nanomolar concentrations, phorbol 12-myristate 13-acetate induced differentiation in a human Epstein-Barr virus-negative B-cell line, JD 38, derived from an undifferentiated lymphoma and containing an 8;14 translocation. The changes induced by phorbol 12-myristate 13-acetate were consistent with differentiation towards plasma cells and included (i) a marked increase (30-fold) in IgM secretion; (ii) a decrease in the nuclear/cytoplasmic ratio associated with the development of a single prominent nucleolus instead of multiple nucleoli; (iii) the development of parallel arrays of rough endoplasmic reticulum, eccentric nuclei, and marginated heterochromatin; (iv) a reduction in the expression of surface markers, including common acute lymphoblastic leukemia antigen, IgM, and C3 receptors. Essentially all cells showed plasmacytoid differentiation, although the degree varied. Rare cells (less than 1%) appeared to be terminally differentiated into plasma cells. The increase in secreted IgM was preceded by a small increase in mu-chain RNA, with an increase in the ratio of secreted to membrane form. A small increase in c-myc RNA was also detected with differentiation. This might reflect coordinate regulation of the transcription of immunoglobulin and the translocated c-myc gene. Thus, the maturational arrest of this lymphoma cell line can be overcome with phorbol 12-myristate 13-acetate, indicating that translocation of the c-myc gene does not permanently block the capacity for differentiation. Further, this gene continues to be expressed to at least the same level during cell maturation. Similar ultrastructural changes were induced by phorbol 12-myristate 13-acetate in four of seven additional lines studied. Images PMID:6203124

Benjamin, D; Magrath, I T; Triche, T J; Schroff, R W; Jensen, J P; Korsmeyer, S J

1984-01-01

16

Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.  

PubMed

The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma. PMID:21487109

Salaverria, Itziar; Philipp, Claudia; Oschlies, Ilske; Kohler, Christian W; Kreuz, Markus; Szczepanowski, Monika; Burkhardt, Birgit; Trautmann, Heiko; Gesk, Stefan; Andrusiewicz, Miroslaw; Berger, Hilmar; Fey, Miriam; Harder, Lana; Hasenclever, Dirk; Hummel, Michael; Loeffler, Markus; Mahn, Friederike; Martin-Guerrero, Idoia; Pellissery, Shoji; Pott, Christiane; Pfreundschuh, Michael; Reiter, Alfred; Richter, Julia; Rosolowski, Maciej; Schwaenen, Carsten; Stein, Harald; Trümper, Lorenz; Wessendorf, Swen; Spang, Rainer; Küppers, Ralf; Klapper, Wolfram; Siebert, Reiner

2011-07-01

17

Translocations among Antibody Genes in Human Cancer  

Microsoft Academic Search

The characteristic chromosomal translocations that occur in certain human malignancies offer opportunities to understand how two gene systems can affect one another when they are accidentally juxtaposed. In the case of Burkitt lymphoma, such a translocation joins the cellular oncogene, c-myc, to a region encoding one of the immunoglobulin genes. In at least one example, the coding sequence of the

Philip Leder; Jim Battey; Gilbert Lenoir; Christopher Moulding; William Murphy; Huntington Potter; Timothy Stewart; Rebecca Taub

1983-01-01

18

DNA repair genes are selectively mutated in diffuse large B cell lymphomas  

PubMed Central

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis. PMID:23960188

de Miranda, Noel FCC; Peng, Roujun; Georgiou, Konstantinos; Wu, Chenglin; Sorqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R.; Rosenquist, Richard; Sundstrom, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David

2013-01-01

19

A novel nested-PCR strategy for the detection of rearranged immunoglobulin heavy-chain genes in B cell tumors  

Microsoft Academic Search

Several methods have been developed for the detection of minimal residual disease (MRD) in B cell tumors. Chromosomal translocations or the rearrangement of the immunoglobulin heavy chain (IgH) and T cell receptor genes are generally employed. We report a novel PCR method to detect MRD using IgH genes. IgH rearranged variable region (VDJ) were amplified from tumor specimens using consensus

C Voena; M Ladetto; M Astolfi; D Provan; JG Gribben; M Boccadoro; A Pileri; P Corradini

1997-01-01

20

Gene Translocations in Musculoskeletal Neoplasms  

PubMed Central

Establishing the best diagnosis for musculoskeletal neoplasms requires a multidisciplinary approach using clinical, radiographic, and histologic analyses. Despite this rigorous approach, establishing accurate diagnoses and prognoses remains challenging. Improved diagnostic methods are expected as unique molecular signals for specific bone and soft tissue cancers are identified. We performed a systematic review of the best available evidence to explore three major applications of molecular genetics that will best benefit clinical management of musculoskeletal neoplasms: diagnostic, prognostic, and therapeutic applications. The specific questions addressed in this systematic review are: (1) What sets of histopathologic sarcoma subtypes will benefit from molecular evaluation and diagnosis? (2) What molecular methods are best applied to histopathologic sarcomas to distinguish between major subtypes? (3) How do the molecular patterns discovered on genetic diagnosis affect prognosis of certain sarcomas? (4) Which sarcoma translocations can benefit from an improved response and outcome using existing and forthcoming pharmacogenetic approaches targeting molecular events? This review summarizes recent advances in molecular genetics that are available and will soon be available to clinicians to better predict outcomes and subsequently help make future treatment decisions. Level of Evidence: Level IV, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID:18566876

Krishnan, Balaji; Khanna, Gaurav

2008-01-01

21

AID-Targeting and Hypermutation of Non-Immunoglobulin Genes Does Not Correlate with Proximity to Immunoglobulin Genes in Germinal Center B Cells  

PubMed Central

Upon activation, B cells divide, form a germinal center, and express the activation induced deaminase (AID), an enzyme that triggers somatic hypermutation of the variable regions of immunoglobulin (Ig) loci. Recent evidence indicates that at least 25% of expressed genes in germinal center B cells are mutated or deaminated by AID. One of the most deaminated genes, c-Myc, frequently appears as a translocation partner with the Ig heavy chain gene (Igh) in mouse plasmacytomas and human Burkitt's lymphomas. This indicates that the two genes or their double-strand break ends come into close proximity at a biologically relevant frequency. However, the proximity of c-Myc and Igh has never been measured in germinal center B cells, where many such translocations are thought to occur. We hypothesized that in germinal center B cells, not only is c-Myc near Igh, but other mutating non-Ig genes are deaminated by AID because they are near Ig genes, the primary targets of AID. We tested this “collateral damage” model using 3D-fluorescence in situ hybridization (3D-FISH) to measure the distance from non-Ig genes to Ig genes in germinal center B cells. We also made mice transgenic for human MYC and measured expression and mutation of the transgenes. We found that there is no correlation between proximity to Ig genes and levels of AID targeting or gene mutation, and that c-Myc was not closer to Igh than were other non-Ig genes. In addition, the human MYC transgenes did not accumulate mutations and were not deaminated by AID. We conclude that proximity to Ig loci is unlikely to be a major determinant of AID targeting or mutation of non-Ig genes, and that the MYC transgenes are either missing important regulatory elements that allow mutation or are unable to mutate because their new nuclear position is not conducive to AID deamination. PMID:22768095

Gramlich, Hillary Selle; Reisbig, Tara; Schatz, David G.

2012-01-01

22

Overexpression of the human BCL-2 gene product results in growth enhancement of Epstein-Barr virus-immortalized B cells  

SciTech Connect

The biological activity of the human BCL-2 gene product was analyzed in an Epstein-Barr virus (EBV)-infected human lymphoblastoid B-cell line transfected with BCL-2 sequences driven by the simian virus 40 promoter and enhancer. Overproduction of the BCL-2 protein conferred a selective growth advantage to the EBV-infected B cells as compared with control transfectants in low-serum medium and also after seeding at limiting dilution but did not render the cells tumorigenic in athymic nude mice. This growth enhancement was also seen in cells transfected with the BCL-2 gene with its own promoter juxtaposed to the immunoglobulin heavy chain gene enhancer, which represents the translocated form of the BCL-2 gene observed in follicular lymphomas with the t(14;18) translocation. The growth advantage of EBV-infected B cells overproducing the BCL-2 protein is neither due to the enhanced growth factor production nor due to an enhanced sensitivity of the BCL-2 transfectants to interleukins 1 or 6, although both lymphokines are known to stimulate proliferation of EBV-infected B-cell lines. The growth advantage of EBV-infected B-cell lines. The growth advantage of EBV-infected B cells by overproduction of the BCL-2 protein suggests the direct involvement of the BCL-2 gene product in the pathogenesis of follicular lymphoma.

Tsujimoto, Yoshihide (Wistar Institute of Anatomy and Biology, Philadelphia, PA (USA))

1989-03-01

23

Chromosomal location targets different MYC family gene members for oncogenic translocations  

PubMed Central

The MYC family of cellular oncogenes includes c-Myc, N-myc, and L-myc, which encode transcriptional regulators involved in the control of cell proliferation and death. Accordingly, these genes become aberrantly activated and expressed in specific types of cancers. For example, c-Myc translocations occur frequently in human B lymphoid tumors, while N-myc gene amplification is frequent in human neuroblastomas. The observed association between aberrations in particular MYC family genes and specific subsets of malignancies might reflect, at least in part, tissue-specific differences in expression or function of a given MYC gene. Since c-Myc and N-myc share substantial functional redundancy, another factor that could influence tumor-specific gene activation would be mechanisms that target aberrations (e.g., translocations) in a given MYC gene in a particular tumor progenitor cell type. We have previously shown that mice deficient for the DNA Ligase4 (Lig4) nonhomologous DNA end-joining factor and the p53 tumor suppressor routinely develop progenitor (pro)-B cell lymphomas that harbor translocations leading to c-Myc amplification. Here, we report that a modified allele in which the c-Myc coding sequence is replaced by N-myc coding sequence (NCR allele) competes well with the wild-type c-Myc allele as a target for oncogenic translocations and amplifications in the Lig4/p53-deficient pro-B cell lymphoma model. Tumor onset, type, and cytological aberrations are similar in tumors harboring either the wild-type c-Myc gene or the NCR allele. Our results support the notion that particular features of the c-Myc locus select it as a preferential translocation/amplification target, compared to the endogenous N-myc locus, in Lig4/p53-deficient pro-B cell lymphomas. PMID:19174520

Gostissa, Monica; Ranganath, Sheila; Bianco, Julia M.; Alt, Frederick W.

2009-01-01

24

DNA microarray gene expression profile of marginal zone versus follicular B cells and idiotype positive marginal zone B cells before and after immunization with Streptococcus pneumoniae.  

PubMed

Marginal zone (MZ) B cells play an important role in the clearance of blood-borne bacterial infections via rapid T-independent IgM responses. We have previously demonstrated that MZ B cells respond rapidly and robustly to bacterial particulates. To determine the MZ-specific genes that are expressed to allow for this response, MZ and follicular (FO) B cells were sort purified and analyzed via DNA microarray analysis. We identified 181 genes that were significantly different between the two B cell populations. Ninety-nine genes were more highly expressed in MZ B cells while 82 genes were more highly expressed in FO B cells. To further understand the molecular mechanisms by which MZ B cells respond so rapidly to bacterial challenge, Id-positive and -negative MZ B cells were sort purified before (0 h) or after (1 h) i.v. immunization with heat-killed Streptococcus pneumoniae, R36A, and analyzed via DNA microarray analysis. We identified genes specifically up-regulated or down-regulated at 1 h following immunization in the Id-positive MZ B cells. These results give insight into the gene expression pattern in resting MZ vs FO B cells and the specific regulation of gene expression in Ag-specific MZ B cells following interaction with Ag. PMID:18453586

Kin, Nicholas W; Crawford, Dianna M; Liu, Jiabin; Behrens, Timothy W; Kearney, John F

2008-05-15

25

Translocation of the B cell receptor to lipid rafts is inhibited in B cells from BLV-infected, persistent lymphocytosis cattle  

Microsoft Academic Search

Bovine leukemia virus (BLV) infection causes a significant polyclonal expansion of CD5+, IgM+ B lymphocytes known as persistent lymphocytosis (PL) in approximately 30% of infected cattle. There is evidence that this expanded B cell population has altered signaling, and resistance to apoptosis has been proposed as one mechanism of B cell expansion. In human and murine B cells, antigen binding

Valerie T Hamilton; Diana M Stone; Glenn H Cantor

2003-01-01

26

Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine  

Microsoft Academic Search

Chromosomal translocations represent an important prognostic indicator in B-cell chronic lymphocytic leukemia (B-CLL). However, their value had been neither determined in homogeneously treated patients nor compared to that of IgVH mutational status. Sixty-five B-CLL patients were investigated using cytogenetics, interphase fluorescence in situ hybridization (FISH), analysis of IgVH and of TP53 mutational status before treatment with 2-chloro-2?-deoxyadenosine (CdA). Translocations (n=45)

E Van Den Neste; V Robin; J Francart; A Hagemeijer; M Stul; P Vandenberghe; A Delannoy; A Sonet; V Deneys; S Costantini; A Ferrant; A Robert; L Michaux

2007-01-01

27

Blimp1 Orchestrates Plasma Cell Differentiation by Extinguishing the Mature B Cell Gene Expression Program  

Microsoft Academic Search

Blimp-1, a transcriptional repressor, drives the terminal differentiation of B cells to plasma cells. Using DNA microarrays, we found that introduction of Blimp-1 into B cells blocked expression of a remarkably large set of genes, while a much smaller number was induced. Blimp-1 initiated this cascade of gene expression changes by directly repressing genes encoding several transcription factors, including Spi-B

A. L. Shaffer; Kuo-I Lin; Tracy C. Kuo; Xin Yu; Elaine M. Hurt; Andreas Rosenwald; Jena M. Giltnane; Liming Yang; Hong Zhao; Kathryn Calame; Louis M. Staudt

2002-01-01

28

A strong promoter activity of pre-B cell stage-specific Crlz1 gene is caused by one distal LEF-1 and multiple proximal Ets sites  

Microsoft Academic Search

The promoter of pre-B cell stage-specific Crlz1 gene, whose protein translocates the cytoplasmic core binding factor ? (CBF?)\\u000a into the nucleus and thereby allows its heterodimerization with Runx, has a very strong activity, which is about 25% of cytomegalovirus\\u000a (CMV) promoter activity and comparable to the EF-1? promoter activity. Its transcription start site was mapped at 155 nt upstream\\u000a of

Sung-Kyun Park; Youngsook Son; Chang-Joong Kang

29

Expression of Essential B Cell Development Genes in Horses with Common Variable Immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is a heterogeneous disorder of B cell differentiation or function with inadequate antibody production. Our laboratory studies a natural form of CVID in horses characterized by late-onset B cell lymphopenia due to impaired B cell production in the bone marrow. This study was undertaken to assess the status of B cell differentiation in the bone marrow of CVID-affected horses by measuring the expression of genes essential for early B cell commitment and development. Standard RT-PCR revealed that most of the transcription factors and key signaling molecules that directly regulate B cell differentiation in the bone marrow and precede PAX5 are expressed in the affected horses. Yet, the expression of PAX5 and relevant target genes was variable. Quantitative RT-PCR analysis confirmed that the mRNA expression of E2A, PAX5, CD19, and IGHD was significantly reduced in equine CVID patients when compared to healthy horses (p < 0.05). In addition, the PAX5/EBF1 and PAX5/B220 ratios were significantly reduced in CVID patients (p < 0.01). Immunohistochemical analysis confirmed the absence of PAX5-BSAP expression in the bone marrow of affected horses. Our data suggest that B cell development seems to be impaired at the transition between pre-pro-B cells and pro-B cells in equine CVID patients. PMID:22464097

Tallmadge, R.L.; Such, K.A.; Miller, K.C.; Matychak, M.B.; Felippe, M.J.B.

2012-01-01

30

Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia  

PubMed Central

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease. PMID:11733578

Rosenwald, Andreas; Alizadeh, Ash A.; Widhopf, George; Simon, Richard; Davis, R. Eric; Yu, Xin; Yang, Liming; Pickeral, Oxana K.; Rassenti, Laura Z.; Powell, John; Botstein, David; Byrd, John C.; Grever, Michael R.; Cheson, Bruce D.; Chiorazzi, Nicholas; Wilson, Wyndham H.; Kipps, Thomas J.; Brown, Patrick O.; Staudt, Louis M.

2001-01-01

31

Novel BLIMP1\\/PRDM1 gene mutations in B-cell lymphoma  

Microsoft Academic Search

B lymphocyte–induced maturation protein 1 (BLIMP1)\\/PR domain containing 1 with zinc finger domain (PRDM1) is a transcriptional repressor with a SET domain and Kruppel-type zinc fingers. BLIMP1\\/PRDM1 is expressed in a subset of germinal center B cells and in all plasma cells, and it is required for terminal B-cell differentiation. Mutations of the BLIMP1 gene have been reported in patients

Genshu Tate; Yoshiko Hirayama-Ohashi; Koji Kishimoto; Toshiyuki Mitsuya

2007-01-01

32

Regulation of RasGRP1 by B Cell Antigen Receptor Requires Cooperativity between Three Domains Controlling Translocation to the Plasma Membrane  

PubMed Central

RasGRP1 is a Ras-activating exchange factor that is positively regulated by translocation to membranes. RasGRP1 contains a diacylglycerol-binding C1 domain, and it has been assumed that this domain is entirely responsible for RasGRP1 translocation. We found that the C1 domain can contribute to plasma membrane-targeted translocation of RasGRP1 induced by ligation of the B cell antigen receptor (BCR). However, this reflects cooperativity of the C1 domain with the previously unrecognized Plasma membrane Targeter (PT) domain, which is sufficient and essential for plasma membrane targeting of RasGRP1. The adjacent suppressor of PT (SuPT) domain attenuates the plasma membrane-targeting activity of the PT domain, thus preventing constitutive plasma membrane localization of RasGRP1. By binding to diacylglycerol generated by BCR-coupled phospholipase C?2, the C1 domain counteracts the SuPT domain and enables efficient RasGRP1 translocation to the plasma membrane. In fibroblasts, the PT domain is inactive as a plasma membrane targeter, and the C1 domain specifies constitutive targeting of RasGRP1 to internal membranes where it can be activated and trigger oncogenic transformation. Selective use of the C1, PT, and SuPT domains may contribute to the differential targeting of RasGRP1 to the plasma membrane versus internal membranes, which has been observed in lymphocytes and other cell types. PMID:17567957

Beaulieu, Nadine; Zahedi, Bari; Goulding, Rebecca E.; Tazmini, Ghazaleh; Anthony, Kira V.; Omeis, Stephanie L.; de Jong, Danielle R.

2007-01-01

33

Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas  

Microsoft Academic Search

Diffuse large B-cell lymphoma (DLBCL) is a common type of non-Hodgkin's lym- phoma (NHL) that is highly heteroge- neous from both clinical and histopatho- logic viewpoints. The immunoglobulin (Ig) heavy (H) chain variable region genes were examined in 71 patients with un- treated primary DLBCL. Fifty-eight poten- tially functional VH genes were detected in 53 DLBCL cases; VH genes were

I. S. Lossos; C. Y. Okada; R. Tibshirani; R. Warnke; J. M. Vose; T. C. Greiner; R. Levy

2000-01-01

34

Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation  

SciTech Connect

The MLL gene, on human chromosome 11q23, undergoes chromosomal translocation in acute leukemias, resulting in gene fusion with AF4 (chromosome 4) and ENL (chromosome 19). The authors report here translocation of MLL with nine different chromosomes and two paracentric chromosome 11 deletions in early B cell, B- or T-cell lineage, or nonlymphocytic acute leukemias. The mRNA translocation junction from 22t(4;11) patients, including six adult leukemias, and nine t(11;19) tumors reveals a remarkable conservation of breakpoints within MLL, AF4, or ENL genes, irrespective of tumor phenotype. Typically, the breakpoints are upstream of the zinc-finger region of MLL, and deletion of this region can accompany translocation, supporting the der(11) chromosome as the important component in leukemogenesis. Partial sequence of a fusion between MLL and the AFX1 gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA. These data suggest that the heterogeneous 11q23 abnormalities might cause attachment of Ser/Pro-rich segments to the NH[sub 2] terminus of MLL, lacking the zinc-finger region, and that translocation occurs in early hematopoietic cells, before commitment to distinct lineages. 36 refs., 2 figs.

Corral, J.; Forster, A.; Thompson, S.; Rabbitts, T.H. (Medical Research Council Laboratory of Molecular Biology, Cambridge (United Kingdom)); Lampert, F. (Kinderklinik-Universitaet Giessen (Germany)); Kaneko, Y. (Saitama Cancer Centre, Saitama (Japan)); Slater, R.; Kroes, W.G. (Univ. of Amsterdam (Netherlands)); Van Der Schoot, C.E. (Central Laboratory of the Netherlands Red Cross, Amsterdam (Netherlands)); Ludwig, W.D. (Institut fur Humangenetik und Antrhopologie, Heidelberg (Germany)); Karpas, A. (Univ. of Cambridge (United Kingdom)); Pocock, C.; Cotter, F. (Institute of Child Health, London (United Kingdom))

1993-09-15

35

Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas  

PubMed Central

Background Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL). Methodology The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-?B, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL). Results ?IgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by ?IgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The ?IgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses or negative feedback loops. Using chemical inhibitors for selected kinases we show that mitogen activated protein kinase- and phosphoinositide 3 kinase-signalling are dominantly involved in regulating genes included in the ?IgM gene module. Conclusion We provide an in vitro model system to investigate pathway activation in lymphomas. We defined the extent to which different immune response associated pathways are responsible for differences in gene expression which distinguish individual DLBCL cases. Our results support the view that tonic or constitutively active MAPK/ERK pathways are an important part of oncogenic signalling in NHL. The experimental model can now be applied to study the therapeutic potential of deregulated oncogenic pathways and to develop individual treatment strategies for lymphoma patients. PMID:23253402

2012-01-01

36

Analysis of the immunoglobulin heavy chain gene variable region of intravascular large B-cell lymphoma  

Microsoft Academic Search

Intravascular large B-cell lymphoma (IVLBL) is a rare neoplasm characterized by proliferation of lymphoma cells within the blood vessels. The cell origin of IVLBL has not yet been determined. We examined cell lineage, with immunohistochemical staining and molecular analysis, using polymerase chain reaction (PCR) of the variable region of the immunoglobulin heavy chain (Ig-VH) gene. We also investigated the cell

M. Kanda; J. Suzumiya; K. Ohshima; S. Haraoka; N. Nakamura; M. Abe; K. Tamura; M. Kikuchi

2001-01-01

37

Differential usage of an Ig heavy chain variable region gene by human B-cell tumors.  

PubMed

A monoclonal anti-idiotypic antibody has been raised that recognizes Igs with heavy chains encoded by a member of the VH4 family, the VH4-21 gene segment. The idiotope (Id) is detectable on a high percentage of early B cells in fetal spleen, and is expressed by certain autoantibodies, particularly cold-reactive anti-red blood cell antibodies. Therefore, it was of interest to investigate usage of this VH gene by neoplastic B cells; 81 chronic lymphocytic leukemias (CLLs) involving CD5+ B cells and 62 B-cell lymphomas of varying histologic type have been analyzed. The Id was expressed by only 3 of 81 (3.7%) of the CLLs, indicating a relatively low usage by these tumors. In contrast, the Id was expressed by 9 of 62 (14.5%) of the lymphomas across a range of histologic types, indicating a differential use of the VH4-21 gene among B-cell neoplasms. For three of the Id-positive lymphomas, each of a different histologic class, the nucleotide sequence of the tumor-derived VH gene was determined; the VH4-21 gene was identified, as expected. The sequence from the CLL was identical to the germline sequence, and the marginal zone lymphoma showed only 3 nucleotide changes, 2 of which gave rise to amino acid substitutions. In contrast, the sequence from the follicular lymphoma showed 29 nucleotide changes giving rise to 14 amino acid substitutions, which were scattered among the CDR and FW regions. PMID:8324224

Stevenson, F K; Spellerberg, M B; Treasure, J; Chapman, C J; Silberstein, L E; Hamblin, T J; Jones, D B

1993-07-01

38

Expression profiling of starch metabolism-related plastidic translocator genes in rice  

Microsoft Academic Search

The genes encoding the major putative rice plastidic translocators involved in the carbon flow related to starch metabolism\\u000a were identified by exhaustive database searches. The genes identified were two for the triose phosphate\\/phosphate translocator\\u000a (TPT), five for the glucose 6-phosphate\\/phosphate translocator (GPT) including putatively non-functional ones, four for the phosphoenolpyruvate\\/phosphate translocator (PPT), three for the putative ADP-glucose translocator (or Brittle-1

Kentaro Toyota; Masahiro Tamura; Takashi Ohdan; Yasunori Nakamura

2006-01-01

39

Harnessing Gene Conversion in Chicken B Cells to Create a Human Antibody Sequence Repertoire  

PubMed Central

Transgenic chickens expressing human sequence antibodies would be a powerful tool to access human targets and epitopes that have been intractable in mammalian hosts because of tolerance to conserved proteins. To foster the development of the chicken platform, it is beneficial to validate transgene constructs using a rapid, cell culture-based method prior to generating fully transgenic birds. We describe a method for the expression of human immunoglobulin variable regions in the chicken DT40 B cell line and the further diversification of these genes by gene conversion. Chicken VL and VH loci were knocked out in DT40 cells and replaced with human VK and VH genes. To achieve gene conversion of human genes in chicken B cells, synthetic human pseudogene arrays were inserted upstream of the functional human VK and VH regions. Proper expression of chimeric IgM comprised of human variable regions and chicken constant regions is shown. Most importantly, sequencing of DT40 genetic variants confirmed that the human pseudogene arrays contributed to the generation of diversity through gene conversion at both the Igl and Igh loci. These data show that engineered pseudogene arrays produce a diverse pool of human antibody sequences in chicken B cells, and suggest that these constructs will express a functional repertoire of chimeric antibodies in transgenic chickens. PMID:24278246

Schusser, Benjamin; Yi, Henry; Collarini, Ellen J.; Izquierdo, Shelley Mettler; Harriman, William D.; Etches, Robert J.; Leighton, Philip A.

2013-01-01

40

Comparison of Gene Expression Profiles in Chromate Transformed BEAS-2B Cells  

PubMed Central

Background Hexavalent chromium [Cr(VI)] is a potent human carcinogen. Occupational exposure has been associated with increased risk of respiratory cancer. Multiple mechanisms have been shown to contribute to Cr(VI) induced carcinogenesis, including DNA damage, genomic instability, and epigenetic modulation, however, the molecular mechanism and downstream genes mediating chromium's carcinogenicity remain to be elucidated. Methods/Results We established chromate transformed cell lines by chronic exposure of normal human bronchial epithelial BEAS-2B cells to low doses of Cr(VI) followed by anchorage-independent growth. These transformed cell lines not only exhibited consistent morphological changes but also acquired altered and distinct gene expression patterns compared with normal BEAS-2B cells and control cell lines (untreated) that arose spontaneously in soft agar. Interestingly, the gene expression profiles of six Cr(VI) transformed cell lines were remarkably similar to each other yet differed significantly from that of either control cell lines or normal BEAS-2B cells. A total of 409 differentially expressed genes were identified in Cr(VI) transformed cells compared to control cells. Genes related to cell-to-cell junction were upregulated in all Cr(VI) transformed cells, while genes associated with the interaction between cells and their extracellular matrices were down-regulated. Additionally, expression of genes involved in cell proliferation and apoptosis were also changed. Conclusion This study is the first to report gene expression profiling of Cr(VI) transformed cells. The gene expression changes across individual chromate exposed clones were remarkably similar to each other but differed significantly from the gene expression found in anchorage-independent clones that arose spontaneously. Our analysis identified many novel gene expression changes that may contribute to chromate induced cell transformation, and collectively this type of information will provide a better understanding of the mechanism underlying chromate carcinogenicity. PMID:21437242

Sun, Hong; Clancy, Harriet A.; Kluz, Thomas; Zavadil, Jiri; Costa, Max

2011-01-01

41

t(8; 14) chromosome translocation of the Burkitt lymphoma cell line Daudi occurred during immunoglobulin gene rearrangement and involved the heavy chain diversity region  

SciTech Connect

Recent molecular analyses of Burkitt lymphomas carrying the t(8;14) chromosome translocation have indicated that a dichotomy exists regarding the molecular mechanisms by which the translocations occur. Most sporadic Burkitt tumors carry translocations that apparently arise due to mistakes in the immunoglobulin isotype-switching process. In contrast, there is evidence that the translocations of most endemic Burkitt lymphomas occur as a consequence of aberrant V-D-J recombination of variable, diversity, and joining gene segments, catalyzed by the recombinase enzymes. This phenomenon was first noted in follicular lymphomas and chronic lymphocytic leukemias of the B-cell lineage and has been described in T-cell malignancies as well. In each of these cases, analysis of the nucleotide sequence at chromosome breakpoints demonstrated the involvement of immunoglobulin heavy chain J/sub H/ or T-cell-receptor ..cap alpha..-chain J..cap alpha.. gene segments in the translocation. The authors now have cloned and sequenced both the 8q- and 14q+ translocation breakpoints deriving from the t(8;14) translocation of the endemic Burkitt lymphoma line Daudi. The data show that the translocation resulted from a reciprocal exchange between the D/sub H/ region on chromosome 14 and sequences far 5' of the MYC protooncogene on chromosome 8. Features of the nucleotide sequences surrounding the breakpoint further implicate the V-D-J joining machinery in the genesis of chromosome translocation in endemic Burkitt lymphomas and, more generally, in other lymphoid malignancies as well.

Haluska, F.G.; Tsujimoto, Y.; Croce, C.M.

1987-10-01

42

An AICDA-independent mechanism of secondary VH gene rearrangement in preimmune human B cells Running title: Secondary rearrangement in human B cells  

PubMed Central

VH replacement is a form of IgH chain receptor editing that is believed to be mediated by recombinase cleavage at cryptic recombination signals (cRSS) embedded in IGHV genes. Whereas there are several reports of IGHV replacement in primary and transformed human B cells and murine models, it remains unclear whether IGHV replacement contributes to the normal human B cell repertoire. We identified VH ? VHDJH compound rearrangements from fetal liver, fetal bone marrow and naive peripheral blood, all of which involved invading and recipient IGHV4 genes that contain a cryptic heptamer, 13 base pair (bp) spacer and nonamer in the 5' portion of framework region (FR) 3. Surprisingly, all pseudohybrid joins lacked molecular processing associated with typical VHDJH recombination or nonhomologous end joining. Although inefficient compared to a canonical RSS, the IGHV4 cRSS was a significantly better substrate for in vitro RAG-mediated cleavage than the IGHV3 cRSS. It has been suggested that activation induced cytidine deamination (AICDA) may contribute to VH replacement. However, we found similar secondary rearrangements utilizing IGHV4 genes in AICDA-deficient human B cells. The data suggest that IGHV4 replacement in preimmune human B cells is mediated by an AICDA-independent mechanism resulting from inefficient but selective RAG activity. PMID:19017972

Longo, Nancy S.; Grundy, Gabrielle J.; Lee, Jisoo; Gellert, Martin; Lipsky, Peter E.

2008-01-01

43

Absence of missense mutations in activated c-myc genes in avian leukosis virus-induced B-cell lymphomas  

SciTech Connect

The authors determined the nucleotide sequences of two independent DNA clones which contained the activated c-myc genes from avian leukosis virus-induced B-cell lymphomas. Neither of these c-myce genes contained missense mutations. This strongly supports the notion that the c-myc photo-oncogene in avian leukosis virus-induced B-cell lymphomas can be oncogenically activated by altered expression of the gene without a change in the primary structure of the gene product.

Hahn, M.; Hayward, W.S.

1988-06-01

44

Human Immunoglobulin (Ig)M+IgD+ Peripheral Blood B Cells Expressing the CD27 Cell Surface Antigen Carry Somatically Mutated Variable Region Genes: CD27 as a General Marker for Somatically Mutated (Memory) B Cells  

PubMed Central

Immunoglobulin (Ig)M+IgD+ B cells are generally assumed to represent antigen-inexperienced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM+IgD+ peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM+IgD+ B cells. IgM+IgD+CD27+ B cells resemble class-switched and IgM-only memory cells in terms of cell phenotype, and comprise ?15% of PB B lymphocytes in healthy adults. Moreover, a very small population (<1% of PB B cells) of highly mutated IgD-only B cells was detected, which likely represent the PB counterpart of IgD-only tonsillar germinal center and plasma cells. Overall, the B cell pool in the PB of adults consists of ?40% mutated memory B cells and 60% unmutated, naive IgD+CD27? B cells (including CD5+ B cells). In the somatically mutated B cells, VH region genes carry a two- to threefold higher load of somatic mutation than rearranged V? genes. This might be due to an intrinsically lower mutation rate in ? light chain genes compared with heavy chain genes and/or result from ? light chain gene rearrangements in GC B cells. A common feature of the somatically mutated B cell subsets is the expression of the CD27 cell surface antigen which therefore may represent a general marker for memory B cells in humans. PMID:9802980

Klein, Ulf; Rajewsky, Klaus; Kuppers, Ralf

1998-01-01

45

ROS-mediated JNK/p38-MAPK activation regulates Bax translocation in Sorafenib-induced apoptosis of EBV-transformed B cells.  

PubMed

Sorafenib (SRF) is a multi-kinase inhibitor that has been shown to have antitumor activity against several types of cancers, but the effect of SRF on EBV-transformed B cells is unknown. We report that SRF can induce the apoptosis of EBV-transformed B cells through JNK/p38-MAPK activation. SRF triggered the generation of reactive oxygen species (ROS), translocation of Bax into the mitochondria, disruption of mitochondrial membrane potential, activation of caspase-9, caspase-3 and PARP, and subsequent apoptosis. Moreover, we found that SRF exposure activated the phosphorylation of JNK and p38-MAPK and suppressed the phosphorylation of PI3K-p85 and Akt. N-acetyl-l-cysteine (NAC) inhibited the activation of JNK and p38-MAPK. SP600125 and SB203580 blocked apoptosis and mitochondrial membrane disruption but did not affect ROS production after SRF treatment. These findings provide novel insights into the molecular mechanisms driving SRF-mediated cell death and suggest that SRF could be a potential therapeutic drug for the treatment of EBV-related malignant diseases. PMID:24402682

Park, Ga Bin; Choi, Yunock; Kim, Yeong Seok; Lee, Hyun-Kyung; Kim, Daejin; Hur, Dae Young

2014-03-01

46

B-cell lymphoma gene regulatory networks: biological consistency among inference methods  

PubMed Central

Despite the development of numerous gene regulatory network (GRN) inference methods in the last years, their application, usage and the biological significance of the resulting GRN remains unclear for our general understanding of large-scale gene expression data in routine practice. In our study, we conduct a structural and a functional analysis of B-cell lymphoma GRNs that were inferred using 3 mutual information-based GRN inference methods: C3Net, BC3Net and Aracne. From a comparative analysis on the global level, we find that the inferred B-cell lymphoma GRNs show major differences. However, on the edge-level and the functional-level—that are more important for our biological understanding—the B-cell lymphoma GRNs were highly similar among each other. Also, the ranks of the degree centrality values and major hub genes in the inferred networks are highly conserved as well. Interestingly, the major hub genes of all GRNs are associated with the G-protein-coupled receptor pathway, cell-cell signaling and cell cycle. This implies that hub genes of the GRNs can be highly consistently inferred with C3Net, BC3Net, and Aracne, representing prominent targets for signaling pathways. Finally, we describe the functional and structural relationship between C3Net, BC3Net and Aracne gene regulatory networks. Our study shows that these GRNs that are inferred from large-scale gene expression data are promising for the identification of novel candidate interactions and pathways that play a key role in the underlying mechanisms driving cancer hallmarks. Overall, our comparative analysis reveals that these GRNs inferred with considerably different inference methods contain large amounts of consistent, method independent, biological information. PMID:24379827

de Matos Simoes, Ricardo; Dehmer, Matthias; Emmert-Streib, Frank

2013-01-01

47

Compositions and methods for detecting gene rearrangements and translocations  

DOEpatents

Disclosed is a series of nucleic acid probes for use in diagnosing and monitoring certain types of leukemia using, e.g., Southern and Northern blot analyses and fluorescence in situ hybridization (FISH). These probes detect rearrangements, such as translocations involving chromosome band 11q23 with other chromosomes bands, including 4q21, 6q27, 9p22, 19p13.3, in both dividing leukemic cells and interphase nuclei. The breakpoints in all such translocations are clustered within an 8.3 kb BamHI genomic region of the MLL gene. A novel 0.7 kb BamH1 cDNA fragment derived from this gene detects rearrangements on Southern blot analysis with a single BamHI restriction digest in all patients with the common 11q23 translocations and in patients with other 11q23 anomalies. Northern blot analyses are presented demonstrating that the MLL gene has multiple transcripts and that transcript size differentiates leukemic cells from normal cells. Also disclosed are MLL fusion proteins, MLL protein domains and anti-MLL antibodies.

Rowley, Janet D. (Chicago, IL); Diaz, Manuel O. (Chicago, IL)

2000-01-01

48

Primary sacral non-germinal center type diffuse large B-cell lymphoma with MYC translocation: a case report and a review of the literature  

PubMed Central

An 85-year-old man presented with pain and numbness in the left buttock, and physical examination revealed an approximately 7 cm mass extending from the first to the third sacral vertebrae; biopsy of the mass led to the diagnosis of CD10-negative, BCL6-weakly positive, MUM1-positive, non-germinal center (non-GC) type diffuse large B-cell lymphoma (DLBCL). Furthermore, serological testing showed negative results for Epstein-Barr virus (EBV) infection, and fluorescence in situ hybridization (FISH) revealed a MYC translocation. Radiographs showed no remarkable osteolytic bone destruction, and the patient was staged with Stage IAE. After 8 cycles of rituximab therapy and 6 cycles of CHOP therapy, complete remission has been maintained until now, approximately 1 year after the treatment. Primary sacral lymphoma is very rare, with only 6 reported cases, including the present one. A review of the reported cases revealed that the disease predominantly affects elderly men, is usually non-GC-type DLBCL and stage IAE, measures approximately 2-7 cm in diameter in general, and does not show early recurrence after chemotherapy or chemoradiotherapy. There is no report in the literature yet of primary sacral DLBCL with MYC translocation, and this is the first case report. On the other hand, 35 cases of CD10-negative DLBCL with MYC translocation, including the present one, have been reported, and a review of the reported cases showed that the disease predominantly affects Asians, middle-aged or elderly men, shows positivity for either BCL6 or MUM1 and negativity for EBV, and has a high international prognostic index and poor prognosis. PMID:24040459

Shimada, Asami; Sugimoto, Kei-Ji; Wakabayashi, Mutsumi; Imai, Hidenori; Sekiguchi, Yasunobu; Nakamura, Noriko; Sawada, Tomohiro; Ota, Yasunori; Komatsu, Norio; Noguchi, Masaaki

2013-01-01

49

Prediction of Survival in Diffuse Large-B-Cell Lymphoma Based on the Expression of Six Genes  

Microsoft Academic Search

background Several gene-expression signatures can be used to predict the prognosis in diffuse large-B-cell lymphoma, but the lack of practical tests for a genome-scale analysis has restricted the use of this method. methods We studied 36 genes whose expression had been reported to predict survival in diffuse large-B-cell lymphoma. We measured the expression of each of these genes in inde-

Izidore S. Lossos; Debra K. Czerwinski; Mark A. Wechser; Rob Tibshirani; David Botstein; Ronald Levy

2004-01-01

50

A Gene Panel, Including LRP12, Is Frequently Hypermethylated in Major Types of B-Cell Lymphoma  

PubMed Central

Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB) and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12), which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL). The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively). BMPER (58%), DUSP4 (32%) and BMP7 (22%), were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils) as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma. PMID:25226156

Bethge, Nicole; Honne, Hilde; Andresen, Kim; Hilden, Vera; Tr?en, Gunhild; Liest?l, Knut; Holte, Harald; Delabie, Jan; Lind, Guro E.; Smeland, Erlend B.

2014-01-01

51

Inhibitor of Kappa B Epsilon (I?B?) Is a Non-Redundant Regulator of c-Rel-Dependent Gene Expression in Murine T and B Cells  

PubMed Central

Inhibitors of kappa B (I?Bs) -?, -? and -? effect selective regulation of specific nuclear factor of kappa B (NF-?B) dimers according to cell lineage, differentiation state or stimulus, in a manner that is not yet precisely defined. Lymphocyte antigen receptor ligation leads to degradation of all three I?Bs but activation only of subsets of NF-?B-dependent genes, including those regulated by c-Rel, such as anti-apoptotic CD40 and BAFF-R on B cells, and interleukin-2 (IL-2) in T cells. We report that pre-culture of a mouse T cell line with tumour necrosis factor-? (TNF) inhibits IL-2 gene expression at the level of transcription through suppressive effects on NF-?B, AP-1 and NFAT transcription factor expression and function. Selective upregulation of I?B? and suppressed nuclear translocation of c-Rel were very marked in TNF-treated, compared to control cells, whether activated via T cell receptor (TCR) pathway or TNF receptor. I?B? associated with newly synthesised c-Rel in activated cells and, in contrast to I?B? and -?, showed enhanced association with p65/c-Rel in TNF-treated cells relative to controls. Studies in I?B?-deficient mice revealed that basal nuclear expression and nuclear translocation of c-Rel at early time-points of receptor ligation were higher in I?B??/? T and B cells, compared to wild-type. I?B??/? mice exhibited increased lymph node cellularity and enhanced basal thymidine incorporation by lymphoid cells ex vivo. I?B??/? T cell blasts were primed for IL-2 expression, relative to wild-type. I?B??/? splenic B cells showed enhanced survival ex vivo, compared to wild-type, and survival correlated with basal expression of CD40 and induced expression of CD40 and BAFF-R. Enhanced basal nuclear translocation of c-Rel, and upregulation of BAFF-R and CD40 occurred despite increased I?B? expression in I?B??/? B cells. The data imply that regulation of these c-Rel-dependent lymphoid responses is a non-redundant function of I?B?. PMID:21915344

Clark, Joanna M.; Aleksiyadis, Karolina; Martin, Alex; McNamee, Kay; Tharmalingam, Tharsana; Williams, Richard O.; Memet, Sylvie; Cope, Andrew P.

2011-01-01

52

Extensive Gene-Specific Translational Reprogramming in a Model of B Cell Differentiation and Abl-Dependent Transformation  

Microsoft Academic Search

To what extent might the regulation of translation contribute to differentiation programs, or to the molecular pathogenesis of cancer? Pre-B cells transformed with the viral oncogene v-Abl are suspended in an immortalized, cycling state that mimics leukemias with a BCR-ABL1 translocation, such as Chronic Myelogenous Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL). Inhibition of the oncogenic Abl kinase with imatinib

Jamie G. Bates; Julia Salzman; Damon May; Patty B. Garcia; Gregory J. Hogan; Martin McIntosh; Mark S. Schlissel; Pat O. Brown

2012-01-01

53

IRF8 Governs Expression of Genes Involved in Innate and Adaptive Immunity in Human and Mouse Germinal Center B Cells  

PubMed Central

IRF8 (Interferon Regulatory Factor 8) is a transcription factor expressed throughout B cell differentiation except for mature plasma cells. Previous studies showed it is part of the transcriptional network governing B cell specification and commitment in the bone marrow, regulates the distribution of mature B cells into the splenic follicular and marginal zone compartments, and is expressed at highest levels in germinal center (GC) B cells. Here, we investigated the transcriptional programs and signaling pathways affected by IRF8 in human and mouse GC B cells as defined by ChIP-chip analyses and transcriptional profiling. We show that IRF8 binds a large number of genes by targeting two distinct motifs, half of which are also targeted by PU.1. Over 70% of the binding sites localized to proximal and distal promoter regions with ?25% being intragenic. There was significant enrichment among targeted genes for those involved in innate and adaptive immunity with over 30% previously defined as interferon stimulated genes. We also showed that IRF8 target genes contributes to multiple aspects of the biology of mature B cells including critical components of the molecular crosstalk among GC B cells, T follicular helper cells, and follicular dendritic cells. PMID:22096565

Morse, Herbert C.

2011-01-01

54

The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene.  

PubMed

The t(9;14)(p13;q32) translocation is associated with approximately 50% of lymphoplasmacytoid lymphoma (LPL), a subtype of B-cell non-Hodgkin's lymphoma (NHL). We cloned the chromosomal breakpoint of der (14) from an LPL case (1052) and showed that it involved a junction between 9p13 and the switch micro region of the Ig heavy chain locus (IgH) on 14q32. Using a YAC contig spanning 1.5 megabase (Mb), we determined that the 9p13 breakpoint in one case (1052) mapped within a 270-kb restriction fragment containing two previously reported 9p breakpoints associated with a alpha-heavy chain disease case (MAL) and KI-1 positive diffuse large cell lymphoma (DLCL) cell line (KIS-1). The same fragment also contained the PAX-5 gene which encodes a B-cell specific transcription factor involved in the control of B-cell proliferation and differentiation. The breakpoints of KIS-1 and 1052 were mapped within the 5' noncoding region of PAX-5, while the 9p13 breakpoint of MAL mapped 230 to 270 kb upstream to PAX-5. In all three cases, the translocation caused the juxtaposition of the PAX-5 gene to the IgH locus in the opposite direction of transcription. When compared with six other DLCL cell lines lacking t(9;14)(p13;q32), the KIS-1 cell line showed an 11-fold overexpression of PAX-5 mRNA and a significantly reduced expression of the p53 gene, which is normally regulated by PAX-5. Moreover, metaphase and interphase fluorescence in situ hybridization (FISH) analysis using a YAC clone spanning 1 Mb including the PAX-5 as a probe identified chromosomal translocations in 5 of 7 cases carrying 9p13 translocations. These findings suggest that the PAX-5 gene is the target of the t(9;14) in LPL whereby its expression may be deregulated by juxtaposition to IgH regulatory elements, thus contributing to lymphomagenesis. PMID:8943844

Iida, S; Rao, P H; Nallasivam, P; Hibshoosh, H; Butler, M; Louie, D C; Dyomin, V; Ohno, H; Chaganti, R S; Dalla-Favera, R

1996-12-01

55

The Regulated Expression of B Lineage Associated Genes during B Cell Differentiation in Bone Marrow and Fetal Liver  

Microsoft Academic Search

Sllmmary The expression of B lineage associated genes during early B cell differentiation stages is not firmly established. Using cell surface markers and multiparameter flow cytometry, bone marrow (BM) cells can be resolved into six fractions, representing sequential stages of development; i.e., pre- Pro-B, early Pro-B, late Pro-B\\/large Pre-B, small Pre-B, immature B, and mature B cells. Here we quantitate

Yue-Sheng Li; Kyoko Hayakawa; Richard R. Hardy

56

Assessing somatic hypermutation in Ramos B cells after overexpression or knockdown of specific genes.  

PubMed

B cells start their life with low affinity antibodies generated by V(D)J recombination. However, upon detecting a pathogen, the variable (V) region of an immunoglobulin (Ig) gene is mutated approximately 100,000-fold more than the rest of the genome through somatic hypermutation (SHM), resulting in high affinity antibodies. In addition, class switch recombination (CSR) produces antibodies with different effector functions depending on the kind of immune response that is needed for a particular pathogen. Both CSR and SHM are initiated by activation-induced cytidine deaminase (AID), which deaminates cytosine residues in DNA to produce uracils. These uracils are processed by error-prone forms of repair pathways, eventually leading to mutations and recombination. Our current understanding of the molecular details of SHM and CSR come from a combination of studies in mice, primary cells, cell lines, and cell-free experiments. Mouse models remain the gold standard with genetic knockouts showing critical roles for many repair factors (e.g. Ung, Msh2, Msh6, Exo1, and polymerase ?). However, not all genes are amenable for knockout studies. For example, knockouts of several double-strand break repair proteins are embryonically lethal or impair B-cell development. Moreover, sometimes the specific function of a protein in SHM or CSR may be masked by more global defects caused by the knockout. In addition, since experiments in mice can be lengthy, altering expression of individual genes in cell lines has become an increasingly popular first step to identifying and characterizing candidate genes. Ramos - a Burkitt lymphoma cell line that constitutively undergoes SHM - has been a popular cell-line model to study SHM. One advantage of Ramos cells is that they have a built-in convenient semi-quantitative measure of SHM. Wild type cells express IgM and, as they pick up mutations, some of the mutations knock out IgM expression. Therefore, assaying IgM loss by fluorescence-activated cell scanning (FACS) provides a quick read-out for the level of SHM. A more quantitative measurement of SHM can be obtained by directly sequencing the antibody genes. Since Ramos cells are difficult to transfect, we produce stable derivatives that have increased or lowered expression of an individual gene by infecting cells with retroviral or lentiviral constructs that contain either an overexpression cassette or a short hairpin RNA (shRNA), respectively. Here, we describe how we infect Ramos cells and then use these cells to investigate the role of specific genes on SHM (Figure 1). PMID:22083360

Upton, Dana C; Unniraman, Shyam

2011-01-01

57

The Capsid Gene of Feline Calicivirus Contains Linear B-Cell Epitopes in both Variable and Conserved Regions  

Microsoft Academic Search

In order to map linear B-cell (LBC) epitopes in the major capsid protein of feline calicivirus (FCV), an expression library containing random, short (100- to 200-bp) fragments of the FCV F9 capsid gene was constructed. Analysis of this library showed it to be representative of the region of the capsid gene that encodes the mature capsid protein. The library was

ALAN D. RADFORD; KIM WILLOUGHBY; SUSAN DAWSON; CHRISTINA MCCRACKEN; ROSALIND M. GASKELL

1999-01-01

58

Gene expression profiling of Epstein-Barr virus-positive and -negative monomorphic B-cell posttransplant lymphoproliferative disorders.  

PubMed

Although most posttransplant lymphoproliferative disorders (PTLD) are related to Epstein-Barr virus (EBV) infection, approximately 20% lack detectable EBV (EBV-). It is uncertain whether the latter cases are truly distinct from EBV+ PTLD or possibly relate to another infectious agent. This study used gene expression profiling to further investigate the relationship between EBV+ and EBV- monomorphic B-cell PTLD, and to search for clues to their pathogenesis. Affymetrix HU133A GeneChips were used to compare 4 EBV+ and 4 EBV- cases of monomorphic B-cell PTLD. Hierarchical clustering successfully distinguished the EBV+ and EBV- groups. Relative to EBV- PTLD, 54 transcripts were over-expressed in EBV+ PTLD. The transcripts identified included IRF7 (a known regulator of EBV LMP1 expression), EBI2 (EBV-induced gene 2), and 3 that are interferon induced (MX1, IFITM1, and IFITM3). In addition, the EBV+ group contained 232 transcripts decreased relative to the EBV- group, including changes concordant with those previously reported after EBV infection of cultured B-cell lines. In summary, in a small group of monomorphic B-cell PTLD, EBV+ cases demonstrated a subset of gene expression changes associated with EBV infection of B cells. By contrast, EBV- PTLD lacked viral-associated changes suggesting that they are biologically distinct. PMID:17721324

Craig, Fiona E; Johnson, Lawrence R; Harvey, Stephen A K; Nalesnik, Michael A; Luo, Jianhua H; Bhattacharya, Soumyaroop D; Swerdlow, Steven H

2007-09-01

59

CD5-positive, cyclinD1-negative mantle cell lymphoma with a translocation involving the CCND2 gene and the IGL locus.  

PubMed

Distinguishing mantle cell lymphoma (MCL), from low-grade B-cell lymphoma is important because MCL is clinically more aggressive and is treated differently. Though most MCL overexpress cyclinD1 (CCND1) and have a t(11;14)(q13;q32), MCL that are negative for CCND1 exist. Some have translocations involving cyclinD2 (CCND2) and either the immunoglobulin heavy chain or kappa light chain locus. We present a CD5-positive, CCND1-negative B-cell lymphoma with a novel translocation involving CCND2 and the immunoglobulin lambda (IGL) gene. A 64-year-old male underwent resection of a polypoid mass of the ileum. Histology showed atypical, medium-sized lymphoid cells positive for CD20, CD5, CD43, and CCND2 by immunohistochemistry, and negative for CCND1, CCND3, and p27. Fluorescence in situ hybridization was negative for CCND1 abnormalities, but demonstrated a CCND2/IGL fusion. Clinical workup revealed stage IV disease. Current diagnostic criteria are insufficient for subclassifying this case, highlighting the need for additional studies on CCND2-translocated B-cell lymphomas to guide therapy appropriately. PMID:21504716

Shiller, Shirley Michelle; Zieske, Arthur; Holmes, Houston; Feldman, Andrew L; Law, Mark E; Saad, Rana

2011-03-01

60

Active suppression of major histocompatibility complex class II gene expression during differentiation from B cells to plasma cells  

SciTech Connect

Constitutive expression of major histocompatibility complex class II genes is acquired very early in B-cell ontogeny and is maintained up to the B-cell blast stage. Terminal differentiation in plasma cells is, however, accompanied by a loss of class II gene expression. In B cells this gene system is under the control of several loci encoding transacting factors with activator function, one of which, the aIr-1 gene product, operates across species barriers. In this report human class II gene expression is shown to be extinguished in somatic cell hybrids between the human class II-positive B-cell line Raji and the mouse class-II negative plasmacytoma cell line P3-U1. Since all murine chromosomes are retained in these hybrids and no preferential segregation of a specific human chromosome is observed, the results are compatible with the presence of suppressor factors of mouse origin, operating across species barriers and inhibiting class II gene expression. Suppression seems to act at the level of transcription or accumulation of class II-specific mRNA, since no human, and very few murine, class II transcripts are detectable in the hybrids.

Latron, F.; Maffei, A.; Scarpellino, L.; Bernard, M.; Accolla, R.S. (Ludwig Institute for Cancer Research, Epalinges (Switzerland)); Jotterand-Bellomo, M. (Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland)); Strominger, J.L. (Harvard Univ., Cambridge, MA (USA))

1988-04-01

61

Molecular cloning and nucleotide sequence of a transforming gene detected by transfection of chicken B-cell lymphoma DNA  

NASA Astrophysics Data System (ADS)

A transforming gene detected by transfection of chicken B-cell lymphoma DNA has been isolated by molecular cloning. It is homologous to a conserved family of sequences present in normal chicken and human DNAs but is not related to transforming genes of acutely transforming retroviruses. The nucleotide sequence of the cloned transforming gene suggests that it encodes a protein that is partially homologous to the amino terminus of transferrin and related proteins although only about one tenth the size of transferrin.

Goubin, Gerard; Goldman, Debra S.; Luce, Judith; Neiman, Paul E.; Cooper, Geoffrey M.

1983-03-01

62

Gene Expression Profiling of the Response to Interferon Beta in Epstein-Barr-Transformed and Primary B Cells of Patients with Multiple Sclerosis  

PubMed Central

The effects of interferon-beta (IFN-?), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-?. To identify gene expression changes and pathways induced by IFN-? in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-? exposure, with over 50 previously unrecognized as IFN-? response genes. Pathways analysis demonstrated that IFN-? affected LCLs in a similar manner to other cell types by activating known IFN-? canonical pathways. Additionally, IFN-? increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-? response genes in primary B cells. In this study new IFN-? response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component. PMID:25025430

Khsheibun, Rana; Paperna, Tamar; Volkowich, Anat; Lejbkowicz, Izabella; Avidan, Nili; Miller, Ariel

2014-01-01

63

Gene expression profiling of the response to interferon beta in Epstein-Barr-transformed and primary B cells of patients with multiple sclerosis.  

PubMed

The effects of interferon-beta (IFN-?), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-?. To identify gene expression changes and pathways induced by IFN-? in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-? exposure, with over 50 previously unrecognized as IFN-? response genes. Pathways analysis demonstrated that IFN-? affected LCLs in a similar manner to other cell types by activating known IFN-? canonical pathways. Additionally, IFN-? increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-? response genes in primary B cells. In this study new IFN-? response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component. PMID:25025430

Khsheibun, Rana; Paperna, Tamar; Volkowich, Anat; Lejbkowicz, Izabella; Avidan, Nili; Miller, Ariel

2014-01-01

64

FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations.  

PubMed

The transcription factor Forkhead box protein P1 (FOXP1) is highly expressed in a proportion of diffuse large B-cell lymphoma (DLBCL). In this report, we provide cytogenetic and fluorescence in situ hybridization (FISH) data showing that FOXP1 (3p13) is recurrently targeted by chromosome translocations. The genomic rearrangement of FOXP1 was identified by FISH in three cases with a t(3;14)(p13;q32) involving the immunoglobulin heavy chain (IGH) locus, and in one case with a variant t(2;3) affecting sequences at 2q36. These aberrations were associated with strong expression of FOXP1 protein in tumor cells, as demonstrated by immunohistochemistry (IHC). The cases with t(3p13) were diagnosed as DLBCL ( x 1), gastric MALT lymphoma ( x 1) and B-cell non-Hodgkin's lymphoma, not otherwise specified ( x 2). Further IHC and FISH studies performed on 98 cases of DLBCL and 93 cases of extranodal marginal zone lymphoma showed a high expression of FOXP1 in approximately 13 and 12% of cases, respectively. None of these cases showed, however, FOXP1 rearrangements by FISH. However, over-representation of the FOXP1 locus found in one additional case of DLBCL may represent another potential mechanism underlying an increased expression of this gene. PMID:15944719

Wlodarska, I; Veyt, E; De Paepe, P; Vandenberghe, P; Nooijen, P; Theate, I; Michaux, L; Sagaert, X; Marynen, P; Hagemeijer, A; De Wolf-Peeters, C

2005-08-01

65

Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays  

Microsoft Academic Search

Follicular lymphomas (FLs) are neoplas- tic counterparts of normal germinal cen- ter (GC) B cells. FLs are characterized by t(14;18) with deregulation of the Bcl-2 (BCL2) gene. The presence of t(14;18) and overexpression of Bcl-2 is necessary, but not sufficient, to cause this disease. An array containing 588 complementary DNAs (cDNAs) was used to compare the gene expression between GC

Elizabeth G. Carideo; Donna Neuberg; Joachim Schultze; Olivier Munoz; Peter W. Marks; John W. Donovan; Antoinette C. Chillemi; Peter O'Connell; Arnold S. Freedman

2002-01-01

66

Gene therapy delivery of myelin oligodendrocyte glycoprotein (MOG) via hematopoietic stem cell transfer induces MOG-specific B cell deletion.  

PubMed

The various mechanisms that have been described for immune tolerance govern our ability to control self-reactivity and minimize autoimmunity. However, the capacity to genetically manipulate the immune system provides a powerful avenue to supplement this natural tolerance in an Ag-specific manner. We have previously shown in the mouse model of experimental autoimmune encephalomyelitis that transfer of bone marrow (BM) transduced with retrovirus encoding myelin oligodendrocyte glycoprotein (MOG) promotes disease resistance and CD4(+) T cell deletion within the thymus. However, the consequence of this strategy on B cell tolerance is not known. Using BM from IgH(MOG) mice that develop MOG-specific B cell receptors, we generated mixed chimeras together with BM-encoding MOG. In these animals, the development of MOG-specific B cells was abrogated, resulting in a lack of MOG-specific B cells in all B cell compartments examined. This finding adds a further dimension to our understanding of the mechanisms of tolerance that are associated with this gene therapy approach to treating autoimmunity and may have important implications for Ab-mediated autoimmune disorders. PMID:24532581

Chung, Jie-Yu; Figgett, William; Fairfax, Kirsten; Bernard, Claude; Chan, James; Toh, Ban-Hock; Mackay, Fabienne; Alderuccio, Frank

2014-03-15

67

A MOUSE B-CELL ALLOANTIGEN DETERMINED BY GENE(S) LINKED TO THE MAJOR HISTOCOMPATIBILITY COMPLEX  

PubMed Central

Antibodies cytotoxic for only a subpopulation of C57Bl/10 lymph node and spleen cells were detected when rat antiserum against B10.D2 was exhaustively absorbed with B10.A lymphocytes. Antibodies of similar specificity were also detected in B10.A anti-B10.D2 and in B10.A anti-C57Bl/10 alloantisera. Reactions with recombinant strains of mice indicate that the cell-surface antigen(s) responsible for this specificity is determined by gene(s) in or to the left of the Ir-1 region of the major histocompatibility complex. A variety of criteria implicate B cells as the subpopulation of lymphocytes bearing this antigen. In view of these data and the recent report by others of a T-cell alloantigen determined by gene(s) in the major histocompatibility complex, it seems possible that there may be a variety of H-2-linked alloantigens expressed preferentially on subclasses of lymphocytes. PMID:4128439

Sachs, David H.; Cone, James L.

1973-01-01

68

Genomic Uracil Homeostasis during Normal B Cell Maturation and Loss of This Balance during B Cell Cancer Development.  

PubMed

Activation-induced deaminase (AID) converts DNA cytosines to uracils in immunoglobulin genes, creating antibody diversification. It also causes mutations and translocations that promote cancer. We examined the interplay between uracil creation by AID and its removal by UNG2 glycosylase in splenocytes undergoing maturation and in B cell cancers. The genomic uracil levels remain unchanged in normal stimulated B cells, demonstrating a balance between uracil generation and removal. In stimulated UNG(-/-) cells, uracil levels increase by 11- to 60-fold during the first 3 days. In wild-type B cells, UNG2 gene expression and enzymatic activity rise and fall with AID levels, suggesting that UNG2 expression is coordinated with uracil creation by AID. Remarkably, a murine lymphoma cell line, several human B cell cancer lines, and human B cell tumors expressing AID at high levels have genomic uracils comparable to those seen with stimulated UNG(-/-)splenocytes. However, cancer cells express UNG2 gene at levels similar to or higher than those seen with peripheral B cells and have nuclear uracil excision activity comparable to that seen with stimulated wild-type B cells. We propose that more uracils are created during B cell cancer development than are removed from the genome but that the uracil creation/excision balance is restored during establishment of cell lines, fixing the genomic uracil load at high levels. PMID:25154417

Shalhout, Sophia; Haddad, Dania; Sosin, Angela; Holland, Thomas C; Al-Katib, Ayad; Martin, Alberto; Bhagwat, Ashok S

2014-11-01

69

Disruption of two novel genes by a translocation co-segregating with schizophrenia  

Microsoft Academic Search

A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypoth- esize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of

J. Kirsty Millar; Julie C. Wilson-Annan; Susan Anderson; Sheila Christie; M artin S. Taylor; Colin A. M. Semple; Rebecca S. Devon; D avid M. St Clair; W alter J. Muir; Douglas H. R. Blackwood; David J. Porteous

2000-01-01

70

Evidence for immunoglobulin heavy chain variable region gene replacement in a patient with B cell chronic lymphocytic leukemia.  

PubMed

Immunoglobulin heavy chain variable (V) gene replacement is an unusual recombinatorial event characterized by rearrangement of a germline V gene to a preformed VDJ gene complex. This phenomenon has occasionally been implicated in the emergence of clonal subpopulations during the course of acute lymphoblastic leukemia; it has also been found in murine precursor B cell lines. V gene replacement has never been described in lymphoproliferative disorders corresponding to more differentiated stages of B cell ontogeny. The present communication provides evidence for the operation of the same mechanism in B cell chronic lymphocytic leukemia (B-CLL). Genomic DNA and total cellular RNA extracted from peripheral blood mononuclear cells of a 48-year-old female patient diagnosed as having typical B-CLL were subjected to polymerase chain reaction (PCR) amplification aiming to detect rearranged clonal heavy and light chain variable genes (VH and VL, respectively). PCR consistently gave two VH amplification products, both at the DNA and the RNA level; similar analysis for the VL region revealed the presence of a single rearranged VK gene. Direct sequence analysis of the PCR products revealed that, except for a number of silent mutations, the single rearranged VK gene was identical to the germline A1-A17 VK gene. The two rearranged VH gene segments belong to the VHl and VHIII gene families and are closely homologous, respectively, to the germline gene segments V1-18 and V3-30, which have been shown to be used by autoantibodies. Both rearranged VH genes showed identical in-frame D-N-JH junctions and JH gene usage (JH5b), whereas the VH-N-D junctions were different. The above findings indicate that, during the course of the disease of our patient, VH gene replacement took place giving rise to two different clonally related subpopulations. This raises the intriguing possibility that the recombinase machinery, which governs Ig recombinatorial processes, might be operative even at more advanced stages in B cell ontogeny. PMID:8751479

Stamatopoulos, K; Kosmas, C; Stavroyianni, N; Loukopoulos, D

1996-09-01

71

Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production  

PubMed Central

Interleukin 5 (IL-5) has been suggested to be involved in the growth and differentiation of B cells and eosinophils. Especially, Ly-1+ B cells, which have been considered to produce autoantibodies, are selectively developed by this lymphokine in long-term bone marrow culture. To envisage the possible engagement of IL-5 in the development of these cells in vivo, transgenic mice carrying the mouse IL-5 gene ligated with a metallothionein promoter were generated. Transgenic mice carrying the IL-5 gene exhibited elevated levels of IL-5 in the serum and an increase in the levels of serum IgM and IgA. A massive eosinophilia in peripheral blood, bone marrow, and spleen, and an infiltration of muscle and liver with eosinophils, were observed. When cadmium-containing saline was injected intraperitoneally into transgenic mice, IL-5 production was augmented about five times within 24 h, and a distinctive Ly-1+ B cell population became apparent in the spleen after 5 d. IL-5 receptors were detected on those cells by monoclonal antibodies against IL-5 receptors. Another interesting finding in these transgenic mice was an increase in polyreactive anti- DNA antibodies of IgM class. It is suggested, therefore, that aberrant expression of the IL-5 gene may induce accumulation of Ly-1+ B cells and eosinophils. Furthermore, this IL-5 transgenic mouse can be a model mouse for eosinophilia, and we can determine the role of IL-5 in the differentiation of Ly-1+ B cells and eosinophils by using this mouse. PMID:1988543

1991-01-01

72

Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis  

Microsoft Academic Search

EPSTEiN-Barr virus (EBV), a human herpesvirus, establishes a persistent asymptomatic infection of the circulating B-lymphocyte pool1-3. The mechanism of virus persistence is not understood but, given the limited lifespan of most B cells in vivo, it seems most likely that EBV-infected cells must gain access to the long-lived memory B-cell pool. Here we show in an in vitro system that

Christopher D. Gregory; Caroline Dive; Sheila Henderson; Christopher A. Smith; Gwyn T. Williams; John Gordon; Alan B. Rickinson

1991-01-01

73

Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma  

Microsoft Academic Search

The early stages of murine B-cell differentiation are characterized by a series of immunoglobulin gene rearrangements which are required for the assembly of heavy(H)- and light(L)-chain variable regions from germline gene segments. Rearrangement at the heavy-chain locus is initiated first and consists of the joining of a diversity (DH) gene segment to a joining (JH) gene segment. This forms a

Robert Kleinfield; Richard R. Hardy; David Tarlinton; Jeffery Dangl; Leonard A. Herzenberg; Martin Weigert

1986-01-01

74

FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-?B to promote survival of human B cells.  

PubMed

The forkhead transcription factor FOXP1 is involved in B-cell development and function and is generally regarded as an oncogene in activated B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue lymphoma, lymphomas relying on constitutive nuclear factor ?B (NF-?B) activity for survival. However, the mechanism underlying its putative oncogenic activity has not been established. By gene expression microarray, upon overexpression or silencing of FOXP1 in primary human B cells and DLBCL cell lines, combined with chromatin immunoprecipitation followed by next-generation sequencing, we established that FOXP1 directly represses a set of 7 proapoptotic genes. Low expression of these genes, encoding the BH3-only proteins BIK and Harakiri, the p53-regulatory proteins TP63, RASSF6, and TP53INP1, and AIM2 and EAF2, is associated with poor survival in DLBCL patients. In line with these findings, we demonstrated that FOXP1 promotes the expansion of primary mature human B cells by inhibiting caspase-dependent apoptosis, without affecting B-cell proliferation. Furthermore, FOXP1 is dependent upon, and cooperates with, NF-?B signaling to promote B-cell expansion and survival. Taken together, our data indicate that, through direct repression of proapoptotic genes, (aberrant) expression of FOXP1 complements (constitutive) NF-?B activity to promote B-cell survival and can thereby contribute to B-cell homeostasis and lymphomagenesis. PMID:25267198

van Keimpema, Martine; Grüneberg, Leonie J; Mokry, Michal; van Boxtel, Ruben; Koster, Jan; Coffer, Paul J; Pals, Steven T; Spaargaren, Marcel

2014-11-27

75

HBL-3 Cell Line, Derived from Precursor B-cell lymphoblastic Leukemia, Lacks Somatic Hypermutation of Immunoglobulin Heavy Chain Variable Region Genes  

Microsoft Academic Search

Somatic mutation (SM) analysis provides a useful tool for understanding the stages at which neoplastic differentiate from normal B-cells. B-cell precursor neoplasms are considered to be somatically premutational. However, the variable frequency of SM of the variable region (VH) genes has been described in cases of precursor B-cell acute lymphoblastic leukemia (PB-ALL). To better characterize PB-ALL based on the differentiation

Hiroshi Hojo; Yoshikazu Sasaki; Naoya Nakamura; Michiko Sato; Masafumi Abe

2004-01-01

76

High Frequency of Monoallelic Retinoblastoma Gene Deletion in B-Cell Chronic Lymphoid Leukemia Shown by Interphase Cytogenetics  

Microsoft Academic Search

Inactivation of the retinoblastoma tumor-suppressor gene (RB-I ) has been associated with tumorigenicity in various human malignancies. In chronic lymphoid leukemias of B- cell origin (B-CLL) an involvement of RB-1 has been sug- gested based on cytogenetic data. We examined RB-1 and its chromosomal locus 13ql4 in 35 cases of B-CLL by dual- color in situ hybridization to interphase nuclei

Stephan Stilgenbauer; Hartmut Dohner; Mehtap Bulgay-Morschel; Sandra Weitz; Martin Bentz; Peter Lichter

1993-01-01

77

Expression of a single gene, BCL6, strongly predicts survival in patients with diffuse large B-cell lymphoma  

Microsoft Academic Search

Diffuse large B-cell lymphoma (DLBCL) is characterized by a marked degree of mor- phologic and clinical heterogeneity. Es- tablishment of parameters that can pre- dict outcome could help to identify patients who may benefit from risk-ad- justed therapies. BCL-6 is a proto-onco- gene commonly implicated in DLBCL pathogenesis. A real-time reverse tran- scription-polymerase chain reaction as- say was established for

Izidore S. Lossos; Carol D. Jones; Roger Warnke; Yasodha Natkunam; Herbert Kaizer; James L. Zehnder; Rob Tibshirani; Ronald Levy

2001-01-01

78

AID-induced remodeling of immunoglobulin genes and B cell fate.  

PubMed

Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells. PMID:24851241

Laffleur, Brice; Denis-Lagache, Nicolas; Péron, Sophie; Sirac, Christophe; Moreau, Jeanne; Cogné, Michel

2014-03-15

79

AID-induced remodeling of immunoglobulin genes and B cell fate  

PubMed Central

Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells. PMID:24851241

Laffleur, Brice; Denis-Lagache, Nicolas; Peron, Sophie; Sirac, Christophe; Moreau, Jeanne; Cogne, Michel

2014-01-01

80

Chromosomal localization of the gene for human B-cell antigen CD40  

SciTech Connect

CD40 is a surface glycoprotein expressed on all human B lymphocytes and plays an important role in B-cell development, growth, and differentiation. Anti-CD40 monoclonal antibodies cause isotype switching in B cells treated with IL-4. CD40 is a member of a family of proteins that include low-affinity nerve growth factor receptor, TNF receptor, and the antigen Fas. The ligand for CD40 had been recently identified and had been assigned to the X chromosome. Using a panel of human-rodent somatic cell hybrids, the authors now show that CD40 maps to human chromosome 20.

Ramesh, N.; Geha, R. (Harvard Medical School, Boston, MA (United States)); Ramesh, V.; Gusella, J.F. (Massachusetts General Hospital, Boston (United States))

1993-05-01

81

Somatic Diversification and Selection of Immunoglobulin Heavy and Light Chain Variable Region Genes in IgG+CD5 + Chronic Lymphocytic Leukemia B Cells  

Microsoft Academic Search

Summary Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5-expressing B lymphocytes. Most studies have found that these leukemic CD5 + B cells, like their normal counterparts, use immunoglobulin (Ig) variable (V) region genes that exhibit minimal, if any, somatic diversity. These and other observations have suggested that CD5 § B cells may be incapable of generating

Shiori Hashimoto; Mariella Dono; Mariko Wakai; Steven L. Allen; Stuart M. Lichtman; Philip Schulman; Vincent P. Vinciguerra; Manlio Ferrarini; Jack Silver; Nicholas Chiorazzi

82

VH1-44 gene usage defines a subset of canine B-cell lymphomas associated with better patient survival.  

PubMed

The use of specific immunoglobulin heavy chain variable region (VH) genes has been associated with increased patient survival in human B-cell lymphomas (hBCL). Given the similarity of human and canine BCL (cBCL) in morphology and clinical treatment, we examined the choice of VH in cBCL and determined whether VH gene selection was a distinct feature associated with survival time in dogs. VH gene selection and mutational status in 52 cBCL, including 29 diffuse large B-cell lymphomas (cDLBCL, the most common subtype of cBCL), were analyzed by comparison with the 80 published canine germline VH gene sequences. We further examined the prognostic impact of the subgroups defined by these features on canine survival. We found that VH1-44 was preferentially expressed in the majority of the 52 cBCLs (60%) as well as in the majority of the cDLBCL subset (59%). VH1-44 gene expression was associated with a statistically better overall survival (p=0.039) in cBCL patients, as well as in the cDLBCL subset of patients (p=0.038). These findings suggest that VH gene selection in cBCL is not random and may therefore have functional implications for cBCL lymphomagenesis, in addition to being a useful prognostic biomarker. PMID:24332568

Chen, Hsiao-Wei; Small, George W; Motsinger-Reif, Alison; Suter, Steven E; Richards, Kristy L

2014-02-15

83

Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling  

Microsoft Academic Search

12 Pathology and Microbiology, and 13 Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have

Ash A. Alizadeh; Michael B. Eisen; R. Eric Davis; Izidore S. Lossos; Andreas Rosenwald; Jennifer C. Boldrick; Hajeer Sabet; Truc Tran; Xin Yu; John I. Powell; Liming Yang; Gerald E. Marti; Troy Moore; James Hudson Jr; Lisheng Lu; David B. Lewis; Robert Tibshirani; Gavin Sherlock; Wing C. Chan; Timothy C. Greiner; Dennis D. Weisenburger; James O. Armitage; Roger Warnke; Ronald Levy; Wyndham Wilson; Michael R. Grever; John C. Byrd; David Botstein; Patrick O. Brown; Louis M. Staudt

2000-01-01

84

Diffuse large B-cell lymphoma outcome prediction by gene- expression profiling and supervised machine learning  

Microsoft Academic Search

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the

MARGARET A. SHIPP; KEN N. ROSS; PABLO TAMAYO; ANDREW P. WENG; JEFFERY L. KUTOK; RICARDO C. T. AGUIAR; MICHELLE GAASENBEEK; MICHAEL ANGELO; MICHAEL REICH; GERALDINE S. PINKUS; TANE S. RAY; MARGARET A. KOVAL; KIM W. LAST; T. ANDREW LISTER; JILL MESIROV; DONNA S. NEUBERG; ERIC S. LANDER; JON C. ASTER; TODD R. GOLUB

2002-01-01

85

Distinct gene expression signature in Btk-defective T1 B-cells  

Microsoft Academic Search

Bruton’s tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase important for B-lymphocyte maturation. Mutations in Btk give rise to the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in man and X-linked immunodeficiency (Xid) in mice. Recent studies have subdivided the mouse immature, or transitional, B-cells into two distinct subsets according to their respective surface markers. Transitional type 1 (T1) and transitional

Jessica M. Lindvall; K. Emelie M. Blomberg; Anna Berglöf; C. I. Edvard Smith

2006-01-01

86

A novel five-way translocation, t(3;9;13;8;14)(q27;p13;q32;q24;q32), with concurrent MYC and BCL6 rearrangements in a primary bone marrow B-cell lymphoma.  

PubMed

Chromosomal translocations involving MYC at 8q24 are found in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU). Here, we describe a novel five-way translocation, t(3;9;13;8;14)(q27;p13;q32;q24;q32), involving MYC, BCL6, and the immunoglobulin heavy locus (IGH@) in a 73-year-old man with BCLU. The bone marrow was massively infiltrated with 95.6% abnormal medium- to large-sized lymphoid cells without vacuoles. Flow cytometric analyses indicated that the infiltrating cells were positive for CD10, CD19, CD20, CD25, HLA-DR, and ? chain. Immunohistochemistry revealed that they were also positive for BCL2 and CD10, and weakly positive for BCL6. The MIB1 index was approximately 99%. G-banding and spectral karyotyping demonstrated the presence of a t(3;9;13;8;14)(q27;p13;q32;q24;q32). Fluorescence in situ hybridization detected an IGH/MYC fusion signal on the der(14)t(8;14)(q24;q32). In addition, 5' and 3'BCL6 signals were separated onto the der(9)t(3;9)(q27;p13) and the der(3)t(3;14)(q27;q32), respectively. Unexpectedly, no BCL6 signal was found on the non-translocated chromosome 3. Finally, the revised karyotype was as follows: 49,XY,del(3)(q27q27),t(3;9;13;8;14)(q27;p13;q32;q24;q32), +der(6)t(6;13)(q13;q32)t(9;13)(p13;q32),+7,+12,i(18)(q10)[2]/50,sl,+7[2]/50,sl,+2[1]. These results suggest that this five-way translocation could bring about the deregulated expression of MYC on the der(14)t(8;14) and BCL6 on the der(3)t(3;14) by the IGH@ enhancer/promoter in a single event and may have contributed to the development of this BCLU. PMID:22018272

Yamamoto, Katsuya; Matsuoka, Hiroshi; Yakushijin, Kimikazu; Funakoshi, Yohei; Okamura, Atsuo; Hayashi, Yoshitake; Minami, Hironobu

2011-09-01

87

Transcription factor B cell lineage-specific activator protein regulates the gene for human X-box binding protein 1  

PubMed Central

The transcription factor human X-box binding protein 1 (hXBP-1) is a basic region-leucine zipper protein implicated in the regulation of major histocompatibility complex class II gene expression as well as in exocrine gland and skeletal development. Multiple regulatory elements in the hXBP-1 promoter lie 3' to the transcription start site, including the hX2 site, whose core sequence is an AP-1-like element identical to the hXBP-1 target sequence in the HLA-DRA promoter. One complex identified by electrophoretic mobility shift assay (EMSA), complex 3, was previously shown to protect the hX2 site and more 3' bases. Sequence analysis now shows that this region contains a consensus binding site for transcription factor BSAP (B cell lineage- specific activator protein). Complex 3 and BSAP have identical cell- type specificities, as they are found only in pre-B and mature B cell lines. In EMSAs, BSAP antibody specifically recognized complex 3, and in vitro translated BSAP could bind to an hXBP promoter fragment. Cotransfections using an hXBP-1 reporter construct indicated that BSAP downregulates the hXBP-1 promoter. The highest levels of hXBP-1 mRNA were found when BSAP was not expressed, in pre-Pro-B cells and in plasma cell lines. In addition, hXBP-1 and BSAP levels were inversely correlated along the early stages of B cell development. In the regulation of the hXBP-1 promoter, a strong positive transcriptional influence at the hX2 site is opposed by the downregulatory actions of BSAP. PMID:8627152

1996-01-01

88

Nucleotide variations amongst V(H)Genes of AMA-producing B cell clones in primary biliary cirrhosis.  

PubMed

Primary biliary cirrhosis, a chronic liver disease characterized by progressive inflammatory destruction of intrahepatic bile ducts, is also characterized by the presence of antimitochondrial antibodies (AMA). The predominant autoantibody is directed at the E2 component of pyruvate dehydrogenase (PDC-E2). Recent studies of this autoantibody response have analysed immunoglobulin-variable regions of human monoclonal antibodies and provided evidence for antigen-driven clonal selection. However, the number of clones analysed has been very limited and the presence of somatic mutations not formally proven. In this study, we took advantage of three stable B cell lines producing human IgG anti-PDC-E2 mAbs from a patient with PBC. We analysed the V(H)and V(L)gene structure of these reagents and, in addition, analysed 10 V(H)-D and D-J(H)sequences over a period of nearly 3 years. The expressed Ig V regions of the heavy chain (V(H)) and the light chain (V(L)) genes of mAb18, mAb37, and mAb82 utilized the V(H)III-VlambdaI, V(H)IV-VlambdaIII, and V(H)IV-V(k)IV gene families, respectively. The utilized gene elements were Ig gene elements that were found frequently in other antibodies with different specificity and affinity. Presence of somatic point-mutations was confirmed in mAb82 by comparison of the expressed V(H)gene sequence with that of corresponding germline V(H)gene obtained from the granulocyte genomic DNA of the same patient. Interestingly, clonally related B cells were consistently found throughout the observation period and nucleotide variations among the V(H)genes were very few, ranging from 0.19 to 0.72% per base. These findings suggest that long-lived B cell clones can exist and may contribute, at least in part, to maintenance of autoantibodies in humans. PMID:10756087

Fukushima, N; Ikematsu, H; Nakamura, M; Matsui, M; Shimoda, S; Hayashida, K; Niho, Y; Koike, K; Gershwin, M E; Ishibashi, H

2000-05-01

89

T and B cells that recognize the same antigen do not transcribe similar heavy chain variable region gene segments  

PubMed Central

We have attempted to determine whether T cells and B cells that have the same antigenic specificity and whose receptors share idiotypic determinants in fact express similar VH gene segments. To do this, we have obtained and characterized a cDNA clone containing the entire coding sequence for the VH gene from a glutamic acid60/alanine30/tyrosine10 (GAT)-binding immunoglobulin that carries the CGAT idiotype. The GAT-VH clone was hybridized to Northern blots of GAT-specific T cell RNAs; there was no evidence of a T cell transcript that hybridized to the GAT-VH probe. The T cells analyzed included: (a) 10 GAT-binding suppressor T cell hybridomas, 6 of which secreted factors with CGAT idiotypic determinants, (b) one GAT-specific helper T cell hybridoma, and (c) two GAT-specific helper T cell lines grown in the absence of feeder cells. The detection limit of the Northern blot analysis was 1-2 copies of a particular mRNA species per cell for the hybridomas and 5-10 copies per cell for the T cell lines. Therefore, we conclude that T and B lymphocytes responding to GAT do not utilize similar VH gene segments. Furthermore, the presence of idiotypic determinants on T lymphocytes does not necessarily imply close structural similarity between T and B cell antigen receptors. PMID:6190977

1983-01-01

90

Epstein - Barr virus transforming protein LMP-1 alters B cells gene expression by promoting accumulation of the oncoprotein ?Np73?.  

PubMed

Many studies have proved that oncogenic viruses develop redundant mechanisms to alter the functions of the tumor suppressor p53. Here we show that Epstein-Barr virus (EBV), via the oncoprotein LMP-1, induces the expression of ?Np73?, a strong antagonist of p53. This phenomenon is mediated by the LMP-1 dependent activation of c-Jun NH2-terminal kinase 1 (JNK-1) which in turn favours the recruitment of p73 to ?Np73? promoter. A specific chemical inhibitor of JNK-1 or silencing JNK-1 expression strongly down-regulated ?Np73? mRNA levels in LMP-1-containing cells. Accordingly, LMP-1 mutants deficient to activate JNK-1 did not induce ?Np73? accumulation. The recruitment of p73 to the ?Np73? promoter correlated with the displacement of the histone-lysine N-methyltransferase EZH2 which is part of the transcriptional repressive polycomb 2 complex. Inhibition of ?Np73? expression in lymphoblastoid cells (LCLs) led to the stimulation of apoptosis and up-regulation of a large number of cellular genes as determined by whole transcriptome shotgun sequencing (RNA-seq). In particular, the expression of genes encoding products known to play anti-proliferative/pro-apoptotic functions, as well as genes known to be deregulated in different B cells malignancy, was altered by ?Np73? down-regulation. Together, these findings reveal a novel EBV mechanism that appears to play an important role in the transformation of primary B cells. PMID:23516355

Accardi, Rosita; Fathallah, Ikbal; Gruffat, Henri; Mariggiò, Giuseppe; Le Calvez-Kelm, Florence; Voegele, Catherine; Bartosch, Birke; Hernandez-Vargas, Hector; McKay, James; Sylla, Bakary S; Manet, Evelyne; Tommasino, Massimo

2013-03-01

91

Epstein - Barr Virus Transforming Protein LMP-1 Alters B Cells Gene Expression by Promoting Accumulation of the Oncoprotein ?Np73?  

PubMed Central

Many studies have proved that oncogenic viruses develop redundant mechanisms to alter the functions of the tumor suppressor p53. Here we show that Epstein-Barr virus (EBV), via the oncoprotein LMP-1, induces the expression of ?Np73?, a strong antagonist of p53. This phenomenon is mediated by the LMP-1 dependent activation of c-Jun NH2-terminal kinase 1 (JNK-1) which in turn favours the recruitment of p73 to ?Np73? promoter. A specific chemical inhibitor of JNK-1 or silencing JNK-1 expression strongly down-regulated ?Np73? mRNA levels in LMP-1-containing cells. Accordingly, LMP-1 mutants deficient to activate JNK-1 did not induce ?Np73? accumulation. The recruitment of p73 to the ?Np73? promoter correlated with the displacement of the histone-lysine N-methyltransferase EZH2 which is part of the transcriptional repressive polycomb 2 complex. Inhibition of ?Np73? expression in lymphoblastoid cells (LCLs) led to the stimulation of apoptosis and up-regulation of a large number of cellular genes as determined by whole transcriptome shotgun sequencing (RNA-seq). In particular, the expression of genes encoding products known to play anti-proliferative/pro-apoptotic functions, as well as genes known to be deregulated in different B cells malignancy, was altered by ?Np73? down-regulation. Together, these findings reveal a novel EBV mechanism that appears to play an important role in the transformation of primary B cells. PMID:23516355

Accardi, Rosita; Fathallah, Ikbal; Gruffat, Henri; Mariggio, Giuseppe; Le Calvez-Kelm, Florence; Voegele, Catherine; Bartosch, Birke; Hernandez-Vargas, Hector; McKay, James; Sylla, Bakary S.; Manet, Evelyne; Tommasino, Massimo

2013-01-01

92

Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect  

PubMed Central

Here, we investigated the antitumor effect of adenovirus-mediated gene transfer of LIGHT, the tumor-necrosis factor (TNF) superfamily member also known as TNFSF14, in the murine A20 B-cell lymphoma. LIGHT gene modification resulted in upregulated expression of Fas and the accessory molecule—intercellular adhesion molecule-1 (ICAM-1) on A20 cells and led to enhanced A20 cell apoptosis. LIGHT-modified A20 cells effectively stimulated the proliferation of T lymphocytes and interferon (IFN)-? production in vitro. Immunization of BALB/c mice with a LIGHT-modified A20 cell vaccine efficiently elicited protective immunity against challenge with the parental tumor cell line. Adenovirus-mediated gene transfer of LIGHT by intratumoral injection exerted a very potent antitumor effect against pre-existing A20 cell lymphoma in BALB/c mice. This adenovirus-mediated LIGHT therapy induced substantial splenic natural killer (NK) and cytotoxic T lymphocyte (CTL) activity, enhanced tumor infiltration by inflammatory cells and increased chemokine expression of CC chemokine ligand 21 (CCL21), IFN-inducible protein-10 (IP-10) and monokine induced by IFN-? (Mig) from tumor tissues. Thus, adenovirus-mediated LIGHT therapy might have potential utility for the prevention and treatment of B-cell lymphoma. PMID:20418899

Hu, Guili; Liu, Yang; Li, Hong; Zhao, Dekuang; Yang, Liuqing; Shen, Jiangen; Hong, Xuejun; Cao, Xuetao; Wang, Qingqing

2010-01-01

93

A Cohort of Balanced Reciprocal Translocations Associated with Dyslexia: Identification of Two Putative Candidate Genes at DYX1  

Microsoft Academic Search

Dyslexia is one of the most common neurodevelopmental disorders where likely many genes are involved in the pathogenesis.\\u000a So far six candidate dyslexia genes have been proposed, and two of these were identified by rare chromosomal translocations\\u000a in affected individuals. By systematic re-examination of all translocation carriers in Denmark, we have identified 16 different\\u000a translocations associated with dyslexia. In four

Roberta Buonincontri; Iben Bache; Asli Silahtaroglu; Carsten Elbro; Anne-Mette Veber Nielsen; Reinhard Ullmann; Ger Arkesteijn; Niels Tommerup

2011-01-01

94

Gene selection and cancer type classification of diffuse large-B-cell lymphoma using a bivariate mixture model for two-species data.  

PubMed

: A bivariate mixture model utilizing information across two species was proposed to solve the fundamental problem of identifying differentially expressed genes in microarray experiments. The model utility was illustrated using a dog and human lymphoma data set prepared by a group of scientists in the College of Veterinary Medicine at North Carolina State University. A small number of genes were identified as being differentially expressed in both species and the human genes in this cluster serve as a good predictor for classifying diffuse large-B-cell lymphoma (DLBCL) patients into two subgroups, the germinal center B-cell-like diffuse large B-cell lymphoma and the activated B-cell-like diffuse large B-cell lymphoma. The number of human genes that were observed to be significantly differentially expressed (21) from the two-species analysis was very small compared to the number of human genes (190) identified with only one-species analysis (human data). The genes may be clinically relevant/important, as this small set achieved low misclassification rates of DLBCL subtypes. Additionally, the two subgroups defined by this cluster of human genes had significantly different survival functions, indicating that the stratification based on gene-expression profiling using the proposed mixture model provided improved insight into the clinical differences between the two cancer subtypes. PMID:23289441

Su, Yuhua; Nielsen, Dahlia; Zhu, Lei; Richards, Kristy; Suter, Steven; Breen, Matthew; Motsinger-Reif, Alison; Osborne, Jason

2013-01-01

95

Gene selection and cancer type classification of diffuse large-B-cell lymphoma using a bivariate mixture model for two-species data  

PubMed Central

A bivariate mixture model utilizing information across two species was proposed to solve the fundamental problem of identifying differentially expressed genes in microarray experiments. The model utility was illustrated using a dog and human lymphoma data set prepared by a group of scientists in the College of Veterinary Medicine at North Carolina State University. A small number of genes were identified as being differentially expressed in both species and the human genes in this cluster serve as a good predictor for classifying diffuse large-B-cell lymphoma (DLBCL) patients into two subgroups, the germinal center B-cell-like diffuse large B-cell lymphoma and the activated B-cell-like diffuse large B-cell lymphoma. The number of human genes that were observed to be significantly differentially expressed (21) from the two-species analysis was very small compared to the number of human genes (190) identified with only one-species analysis (human data). The genes may be clinically relevant/important, as this small set achieved low misclassification rates of DLBCL subtypes. Additionally, the two subgroups defined by this cluster of human genes had significantly different survival functions, indicating that the stratification based on gene-expression profiling using the proposed mixture model provided improved insight into the clinical differences between the two cancer subtypes. PMID:23289441

2013-01-01

96

Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients  

PubMed Central

Secondary MYC translocations in myeloma have been shown to be important in the pathogenesis and progression of disease. Here, we have used a DNA capture and massively parallel sequencing approach to identify the partner chromosomes in 104 presentation myeloma samples. 8q24 breakpoints were identified in 21 (20%) samples with partner loci including IGH, IGK and IGL, which juxtapose the immunoglobulin (Ig) enhancers next to MYC in 8/23 samples. The remaining samples had partner loci including XBP1, FAM46C, CCND1 and KRAS, which are important in B-cell maturation or myeloma pathogenesis. Analysis of the region surrounding the breakpoints indicated the presence of superenhancers on the partner chromosomes and gene expression analysis showed increased expression of MYC in these samples. Patients with MYC translocations had a decreased progression-free and overall survival. We postulate that translocation breakpoints near MYC result in colocalization of the gene with superenhancers from loci, which are important in the development of the cell type in which they occur. In the case of myeloma these are the Ig loci and those important for plasma cell development and myeloma pathogenesis, resulting in increased expression of MYC and an aggressive disease phenotype. PMID:24632883

Walker, B A; Wardell, C P; Brioli, A; Boyle, E; Kaiser, M F; Begum, D B; Dahir, N B; Johnson, D C; Ross, F M; Davies, F E; Morgan, G J

2014-01-01

97

Genomic Hallmarks of Genes Involved in Chromosomal Translocations in Hematological Cancer  

PubMed Central

Reciprocal chromosomal translocations (RCTs) leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available high-throughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs). Our results show that fusion genes are generally overexpressed due to increased promoter activity of 5? TPGs and to more stable 3?-UTR regions of 3? TPGs. Furthermore, expression profiling of 5? TPGs and of interaction partners of 3? TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 5? and 3? TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 5? and 3? TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C) we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in hematological tissues, with functional constraints being responsible for specific gene combinations. PMID:23236267

Shugay, Mikhail; Ortiz de Mendibil, Inigo; Vizmanos, Jose L.; Novo, Francisco J.

2012-01-01

98

IKAROS Deletions Dictate a Unique Gene Expression Signature in Patients with Adult B-Cell Acute Lymphoblastic Leukemia  

PubMed Central

Background Deletions of IKAROS (IKZF1) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106 BCR-ABL1-positive and 38 B-ALL negative for known molecular rearrangements) was screened for IKZF1 deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling. Principal Findings Total or partial deletions of IKZF1 were more frequent in BCR-ABL1-positive than in BCR-ABL1-negative B-ALL cases (75% vs 58%, respectively, p?=?0.04). Comparison of the gene expression signatures of patients carrying IKZF1 deletion vs those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle, JAK-STAT signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both in vivo and in vitro, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as IGLL1, BLK, EBF1, MSH2, BUB3, ETV6, YES1, CDKN1A (p21), CDKN2C (p18) and MCL1. Conclusions Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis. PMID:22848414

Messina, Monica; Lonetti, Annalisa; Chiaretti, Sabina; Valli, Emanuele; Ferrari, Anna; Papayannidis, Cristina; Paoloni, Francesca; Vitale, Antonella; Storlazzi, Clelia Tiziana; Ottaviani, Emanuela; Guadagnuolo, Viviana; Durante, Sandra; Vignetti, Marco; Soverini, Simona; Pane, Fabrizio; Foa, Robin; Baccarani, Michele; Muschen, Markus; Perini, Giovanni; Martinelli, Giovanni

2012-01-01

99

Regulation of translocated c-myc genes transfected into plasmacytoma cells  

SciTech Connect

The authors have transfected two translocated c-myc oncogene clones, derived from two human lymphomas carrying the t(8;14) chromosome translocation, into mouse plasmacytoma cells to study the regulation of their expression. In one case, the transfected clone contained the two coding exons of the c-myc oncogene translocated to an immunoglobulin heavy-chain switch region; in the other case, the two coding exons were translocated 5' of the enhancer element located between the heavy-chain joining region (J/sub H/) and the switch region S/sub ..mu../. Nuclease S1 protection experiments indicate that only the c-myc translocated 5' of the enhancer element is transcribed in the plasmacytoma cells. Thus, 5'-truncation of the c-myc gene per se does not lead to c-myc deregulation. Further, since the level of c-myc transcripts in the parental human lymphoma cells was 3- to 4-fold higher than in the transfectants, it seems likely that additional elements within the heavy-chain locus may play a role in the enhancement of c-myc gene transcription in lymphoma cells.

Feo, S.; Harvey, R.; Showe, L.; Croce, C.M.

1986-02-01

100

NK and B cell deficiency in a MPS type II family with novel mutation in the IDS gene.  

PubMed

The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. Whereas the lysosome is essential to the functioning of the immune system, some authors suggest that the MPS patients have abnormalities in the immune system similar to the patients with primary immunodeficiency. In this study, we evaluated 8 male MPS type II patients of the same family with novel mutation in the IDS gene. We found in this MPS family a quantitative deficiency of NK and B cells with normal values of IgG, IgM and IgA serum antibodies and normal response to polysaccharide antigens. Interestingly, abnormalities found in these patients were not observed in other MPS patients, suggesting that the type of mutation found in the IDS gene can be implicated in the immunodeficiency. PMID:25038527

Torres, Leuridan Cavalcante; Soares, Diogo Cordeiro de Queiroz; Kulikowski, Leslie Domenici; Franco, Jose Francisco; Kim, Chong Ae

2014-10-01

101

Stimulation of corticotropin-releasing factor gene expression by FosB in rat hypothalamic 4B cells.  

PubMed

The Fos- and Jun family proteins are immediate-early gene products, and the Fos/Jun heterodimer, activator protein-1 (AP-1), may be involved in the regulation of corticotropin-releasing factor (CRF) gene expression. FosB is a member of the Fos family proteins that is expressed in the paraventricular nucleus of the hypothalamus upon stress exposure, but it has not been clear whether FosB participates in the regulation of CRF gene expression. This study aimed to explore the effect of the FosB and cJun proteins on CRF gene expression in rat hypothalamic 4B cells. The levels of FosB mRNA and cJun mRNA increased following treatment with forskolin, phorbol-12-myristate-13-acetate (PMA), or A23187 in the hypothalamic cells. Overexpression of FosB or cJun potently increased CRF mRNA levels. Furthermore, downregulation of FosB or cJun suppressed the CRF gene expression induced by forskolin, PMA, or A23187. In addition, the basal CRF mRNA levels were partially reduced by cJun downregulation. These findings suggest that FosB, together with cJun, may mediate CRF gene expression in the hypothalamic cells. PMID:24246425

Kageyama, Kazunori; Itoi, Keiichi; Iwasaki, Yasumasa; Niioka, Kanako; Watanuki, Yutaka; Yamagata, Satoshi; Nakada, Yuki; Das, Gopal; Suda, Toshihiro; Daimon, Makoto

2014-01-01

102

Type II mixed cryoglobulinaemia as an oligo rather than a mono B-cell disorder: evidence from GeneScan and MALDI-TOF analyses  

Microsoft Academic Search

Objective. To identify and characterize rheumatoid factor (RF)-producing B-cells and cryoprecipitate immunoglobulin (Ig) M in hepatitis C virus (HCV)-positive patients. Methods. We purified and characterized, by peptide mass fingerprinting integrated with an NCBI IgBlast data bank search, the IgM component of cryoprecipitate and analysed the VDJ pattern of bone marrow B-cells by gene scan analysis of 17 HCV-positive patients with

V. De Re; S. De Vita; D. Sansonno; D. Gasparotto; M. P. Simula; F. A. Tucci; A. Marzotto; M. Fabris; A. Gloghini; A. Carbone; F. Dammacco; M. Boiocchi

2006-01-01

103

Detection of immunoglobulin heavy chain genes rearrangements in B-cell leukemias, lymphomas, multiple myelomas, monoclonal and polyclonal gammopathies.  

PubMed

Polymerase chain reaction (PCR) based assays were found to be a realistic alternative to Southern blot hybridization for the assessment of clonal immunoglobulin heavy chain gene rearrangements. However, a comparison of the different PCR based studies reveals considerable variation in experimental design and marked differences in the reported results. This study compared different single- and double-step PCR assays relying on various FR3, FR2, FR1 and JH based primers for the detection of B cell clonality in acute lymphoblastic leukemias (ALL), non-Hodgkin's-lymphoma (NHL), multiple myeloma (MM), monoclonal gammopathies of unknown significance (MGUS) and three polyclonal gammopathies (PG). The highest monoclonality rate was observed using seminested CDR-III region amplification. This method achieved a monoclonal product in 6 of 13 pro-B ALL 21 of 29 c-ALL, 7 of 8 pre-B-ALL, 18 of 21 B-ALL, 14 of 17 B-NHL (intermediate or high grade) with bone marrow involvement, 0 of 9 B-NHL without bone marrow involvement, 9 of 9 low grade B-NHL (immunocytoma and including chronic lymphocytic leucemia), 13 of 19 MM, 2 of 9 MGUS, and 0 of 3 PG. Additional monoclonality was detected with nested CDR I PCR in 1 pro-B-ALL, 1 c-ALL, and 2 MM. CDR III IgH PCR has been confirmed as an efficient method for determining clonality in B-cell neoplasias. Some additional monoclonal products can be seen with CDR I-based PCR. Detection of monoclonality depends on the maturation grade of the neoplastic B-cell population. PMID:10975394

Gleissner, B; Maurer, J; Thiel, E

2000-09-01

104

BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma.  

PubMed

Follicular lymphoma (FL) is characterized by a relatively indolent clinical course, but the disease often transforms into a more aggressive large cell lymphoma with a rapidly progressive clinical course. In the present study, we analyzed 41 cases of FL known to have subsequently transformed to aggressive lymphoma and an additional 64 FL samples from patients not subsequently transformed. We studied BCL6 gene rearrangement by the methodology of long-distance inverse polymerase chain reaction (LDI-PCR). Of the 41 cases known to transform, 16 (39.0%) harbored BCL6 translocation or deletion at the time of FL diagnosis. Among 64 cases not known to transform, BCL6 translocation was detected in 9 (14.1%). The prevalence of BCL6 translocation in the group known to transform was significantly higher (P =.0048). Among the transformation cases, the partners of the BCL6 translocation were identified in 13 cases and included IGH, CIITA, U50HG, MBNL, GRHPR, LRMP, EIF4A2, RhoH/TTF, and LOC92656 (similar to NAPA), whereas in the control group the BCL6 partners were IGH, CIITA, SIAT1, and MBNL. In 13 cases paired specimens before and after transformation were available. Among these paired specimens, a loss (3 cases) or a gain (1 case) of BCL6 translocation was observed after the transformation. Analysis of clonality showed that all of these cases represented the evolution of a subclone of the original tumor population. Our study demonstrated that BCL6 translocation is not necessary for transformation but that BCL6 translocation in FL may constitute a subgroup with a higher risk to transform into aggressive lymphoma. PMID:12738680

Akasaka, Takashi; Lossos, Izidore S; Levy, Ronald

2003-08-15

105

In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes.  

PubMed

In studies of patients with multiple myeloma (MM), gene expression profiling (GEP) of myeloma cells demonstrates substantially higher expression of MMSET, FGFR3, CCND3, CCND1, MAF, and MAFB--the partner genes of 14q32 translocations--than GEP of plasma cells from healthy individuals. Interphase fluorescent in situ hybridization (FISH) was used to discriminate between chromosomal translocations involving different regions of the immunoglobulin heavy chain (IGH) genes at 14q32. With special probes designed for the constant region (IGHC) and the variable region (IGHV), IGH translocations were shown to be definite, nonrandom chromosomal fusions of IGHC with the loci of FGFR3, CCND1, CCND3, MAF, and MAFB genes; and IGHV with the locus of MMSET gene. When correlated with GEP results, the IGH translocations were found to drive expression levels of the partner genes to significantly higher levels (spikes) than copy-number variations. Hence, 42% of IGH translocations were identified among newly diagnosed MM patients (448/1,060). As GEP has become essential for assessing cancer risk, this novel approach is highly consistent with the cytogenetic features of the chromosomal translocations to effectively stratify molecular subgroups of MM on the basis of gene expression profiles of the IGH translocation partner genes in myeloma cells. © 2014 Wiley Periodicals, Inc. PMID:24638926

Tian, Erming; Sawyer, Jeffrey R; Heuck, Christoph J; Zhang, Qing; van Rhee, Frits; Barlogie, Bart; Epstein, Joshua

2014-07-01

106

PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.  

PubMed

Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC's effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation. PMID:24709691

Fabbri, C; Marsano, A; Albani, D; Chierchia, A; Calati, R; Drago, A; Crisafulli, C; Calabrò, M; Kasper, S; Lanzenberger, R; Zohar, J; Juven-Wetzler, A; Souery, D; Montgomery, S; Mendlewicz, J; Serretti, A

2014-10-01

107

Variant B cell receptor isotype functions differ in hairy cell leukemia with mutated BRAF and IGHV genes.  

PubMed

A functional B-cell receptor (BCR) is critical for survival of normal B-cells, but whether it plays a comparable role in B-cell malignancy is as yet not fully delineated. Typical Hairy Cell Leukemia (HCL) is a rare B-cell tumor, and unique in expressing multiple surface immunoglobulin (sIg) isotypes on individual tumor cells (mult-HCL), to raise questions as to their functional relevance. Typical mult-HCL also displays a mutated BRAF V(600)E lesion. Since wild type BRAF is a primary conduit for transducing normal BCR signals, as revealed by deletion modelling studies, it is as yet not apparent if mutated BRAF alters BCR signal transduction in mult-HCL. To address these questions, we examined BCR signalling in mult-HCL cases uniformly displaying mutated BRAF and IGHV genes. Two apparent functional sets were delineated by IgD co-expression. In sIgD(+ve) mult-HCL, IgD mediated persistent Ca(2+) flux, also evident via >1 sIgH isotype, linked to increased ERK activation and BCR endocytosis. In sIgD(-ve) mult-HCL however, BCR-mediated signals and downstream effects were restricted to a single sIgH isotype, with sIgM notably dysfunctional and remaining immobilised on the cell surface. These observations reveal discordance between expression and function of individual isotypes in mult-HCL. In dual sIgL expressing cases, only a single sIgL was fully functional. We examined effects of anti-BCR stimuli on mult-HCL survival ex-vivo. Significantly, all functional non-IgD isotypes increased ERK1/2 phosphorylation but triggered apoptosis of tumor cells, in both subsets. IgD stimuli, in marked contrast retained tumor viability. Despite mutant BRAF, BCR signals augment ERK1/2 phosphorylation, but isotype dictates functional downstream outcomes. In mult-HCL, sIgD retains a potential to transduce BCR signals for tumor survival in-vivo. The BCR in mult-HCL emerges as subject to complex regulation, with apparent conflicting signalling by individual isotypes when co-expressed with sIgD. This suggests the possibility that mutant BRAF by-passes BCR constraints in mult-HCL. PMID:24497953

Weston-Bell, Nicola J; Forconi, Francesco; Kluin-Nelemans, Hanneke C; Sahota, Surinder S

2014-01-01

108

BMI1, the polycomb-group gene, is recurrently targeted by genomic rearrangements in progressive B-cell leukemia/lymphoma.  

PubMed

BMI1, a Polycomb-group gene located at 10p12.2, is implicated in the pathogenesis of a variety of tumors. However, the genetic molecular mechanisms underlying its aberrant expression in cancer cells remain largely unknown. In this study, we show that BMI1 is recurrently targeted by chromosomal aberrations in B-cell leukemia/lymphoma. We identified a novel t(10;14)(p12;q32)/IGH-BMI1 rearrangement and its IGL variant in six cases of chronic lymphocytic leukemia (CLL) and found that these aberrations were consistently acquired at time of disease progression and high grade transformation of leukemia (Richter syndrome). The IG-BMI1 translocations were not associated with any particular molecular subtype of CLL and the leukemias were negative for common mutations of NOTCH1 and TP53, known to increase a risk of progression and transformation in CLL. In addition, using FISH and SNP array analysis, we identified a wide range of BMI1-involving 10p12 lesions in 17 cases of mantle cell lymphoma (MCL). These aberrations included various balanced and unbalanced structural abnormalities and very frequently but not exclusively, were associated with gain of the BMI1 locus and loss of the 10p terminal sequences. These findings point to genomic instability at the 10p region in MCL which likely promotes rearrangements and deregulation of BMI1. Our findings are in line with previously published observations correlating overexpression of BMI1 with tumor progression and chemoresistance. In summary, our study provides new insights into genetic molecular mechanisms underlying aberrant expression of BMI1 in lymphoma and documents its contribution in the pathogenesis of Richter syndrome and MCL. PMID:23873701

Rouhigharabaei, Leila; Ferreiro, Julio Finalet; Put, Natalie; Michaux, Lucienne; Tousseyn, Thomas; Lefebvre, Christine; Gardiner, Anne; De Kelver, Wim; Demuynck, Hilde; Verschuere, Johan; Théate, Ivan; Vicente, Carmen; Vandenberghe, Peter; Cools, Jan; Wlodarska, Iwona

2013-10-01

109

A Mouse Variable Gene Fragment Binds to DNA Independently of the BCR Context: A Possible Role for Immature B-Cell Repertoire Establishment  

PubMed Central

B-cell maturation occurs in several steps and requires constant stimulus for its continuing development. From the emergence of the pre-B-cell receptor, signal transduction stimulates and supports B-cell development. Current viewpoints indicate that both positive selection pressure for autoantigens and tonic signaling constitutively stimulate B-cell maturation. In this work, we tested for the presence of a putative DNA binding site in a variable gene segment in a germline configuration, independently of VDJ recombination. After a survey of the public antibody databases, we chose a single mouse heavy variable gene segment that is highly represented in anti-nucleic acid antibodies and tested it for ssDNA binding. A phage display approach was used to search for intrinsic binding to oligo deoxythymidine. The results revealed that binding to an antigen can be influenced by the use of a specific DNA binding V gene segment. Our data support the idea that some variable genes have intrinsic reactivity towards specific types of endogenous autoantigens, and this property may contribute to the establishment of the immature B-cell repertoire. PMID:24023756

Maranhao, Andrea Queiroz; Costa, Maria Beatriz Walter; Guedes, Leonardo; Moraes-Vieira, Pedro Manoel; Raiol, Taina; Brigido, Marcelo Macedo

2013-01-01

110

The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion  

PubMed Central

Background Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth. Results We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-?B p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation. Conclusions Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts. PMID:23320978

2013-01-01

111

Anti-B cell autoantibodies encoded by VH 4-21 genes in human fetal spleen do not require in vivo somatic selection.  

PubMed

We isolated immunoglobulin (Ig) VH4 genes that were rearranged in the genomic DNA of 160 day human fetal spleen. Productively rearranged VH 4-21 genes were cloned into pRTM1, a human IgM expression vector. This allowed us to generate IgM kappa-expressing transfectomas by co-transfecting each of these constructs with pSVG-V kappa 3, an Ig kappa light-chain expression vector that has a variable region encoded Humkv325, a conserved V kappa gene that is frequently expressed early B cell ontogeny. We find that all transfectomas expressing IgM kappa encoded by VH 4-21 make IgM autoantibodies reactive with i, a linear poly-N-acetyllactosamine determinant present on neonatal red blood cells and a B cell-restricted isoform of the CD45 surface molecule. In contrast, a transfectoma expressing pSVG-V kappa 3 and pRTM1 containing a rearranged VH4-59 (V71-4) gene isolated from a chronic lymphocytic leukemia B cell population, designated WIL, produced IgM kappa antibodies that had no detectable anti-i binding activity. However, transfectomas expressing VH 4-21 fused onto the Ig heavy-chain third complementarity determining region (CDR3) of WIL are found to make anti-B cell autoantibodies with anti-i activity. These studies indicate that VH 4-21 genes rearranged in human fetal B cell ontogeny can encode anti-B cell autoantibodies with a binding specificity that does not require in vivo somatic selection. PMID:7805720

Parr, T B; Johnson, T A; Silberstein, L E; Kipps, T J

1994-12-01

112

Variant translocation of the bcl-2 gene to immunoglobulin. lambda. light chain gene in chronic lymphocytic leukemia  

SciTech Connect

The bcl-2 gene has been identified as a gene directly involved in the consistent chromosome translocation t(14;18), which is found in {approx} 90% of human follicular lymphoma cases, and is a prime candidate for the oncogene playing a crucial role in follicular lymphomagenesis. In this paper, the authors describe a case of chronic lymphocytic leukemia showing the juxtaposition of the bcl-2 gene on chromosome 18 to immunoglobulin {lambda} light chain (Ig{lambda}) gene on chromosome 22 in a head-to-head configuration. Sequencing analysis of the joining site of the bcl-2 gene and Ig{lambda} gene has shown that the breakpoint is within the 5{prime} flanking region of the bcl-2 gene and about 2.2 kilobases 5{prime} to the joining segment of Ig{lambda} locus in a germ-line configuration. The extranucleotide, commonly appearing at the joining site of the t(14;18) translocation involving the IgH locus, is absent from the joining site of bcl-2 and Ig{lambda}. The lack of extranucleotide suggests that the juxtaposition of the bcl-2 and Ig{lambda} genes occurred during physiological rearrangement of the Ig{lambda} gene since it has been shown that the rearrangement of the Ig{lambda} locus is not accompanied by extranucleotides.

Adachi, M.; Cossman, J.; Longo, D.; Croce, C.M.; Tsujimoto, Y. (Wistar Institute of Anatomy and Biology, Philadelphia, PA (USA))

1989-04-01

113

Mutations in the Human l 5\\/14.1 Gene Result in B Cell Deficiency and Agammaglobulinemia  

Microsoft Academic Search

Summary B cell precursors transiently express a pre-B cell receptor complex consisting of a rearranged mu heavy chain, a surrogate light chain composed of l 5\\/14.1 and VpreB, and the immunoglobulin (Ig)-associated signal transducing chains, Ig a and Ig b . Mutations in the mu heavy chain are as- sociated with a complete failure of B cell development in both

Yoshiyuki Minegishi; Elaine Coustan-Smith; Yui-Hsi Wang; Max D. Cooper; Dario Campana; Mary Ellen Conley

114

Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution.  

PubMed

B cell antigen receptor (BCR) cross-linking promotes proliferation and survival of mature B cells. Phosphoinositide-3-kinase-mediated down-regulation of pro-apoptotic and anti-mitogenic genes such as the Foxo family of transcription factors is an important component of this process. Previously, we demonstrated that BCR signaling decreases expression of transcripts for Foxo1, Foxo3 and Foxo4. We now show that BCR-induced down-regulation of Foxo3 and Foxo4 mRNA expression occurs via distinct mechanisms from those established for Foxo1. While Foxo1, Foxo3 and Foxo4 bind the same DNA sequence, the differential control of their expression upon B cell activation suggests that they may have unique functions in the B lineage. To begin to address this issue, we evaluated B cell development and function in Foxo3-/- mice. No effect of Foxo3 deficiency was observed with respect to the following parameters in the splenic B cell compartment: sub-population distribution, proliferation, in vitro differentiation and expression of the Foxo target genes cyclin G2 and B cell translocation gene 1. However, Foxo3-/- mice demonstrated increased basal levels of IgG2a, IgG3 and IgA. A significant reduction in pre-B cell numbers was also observed in Foxo3-/- bone marrow. Finally, recirculating B cells in the bone marrow and peripheral blood were decreased in Foxo3-/- mice, perhaps due to lower than normal expression of receptor for sphingosine-1 phosphate, which mediates egress from lymphoid organs. Thus, Foxo3 makes a unique contribution to B cell development, B cell localization and control of Ig levels. PMID:19502585

Hinman, Rochelle M; Nichols, Whitney A; Diaz, Tracy M; Gallardo, Teresa D; Castrillon, Diego H; Satterthwaite, Anne B

2009-07-01

115

Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction  

PubMed Central

Gene-expression profiling has identified 3 major subgroups of diffuse large B-cell lymphoma (DLBCL): germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal DLBCL (PMBCL). Using comparative genomic hybridization (CGH), we investigated the genetic alterations of 224 cases of untreated DLBCL (87 GCB-DLBCL, 77 ABC-DLBCL, 19 PMBCL, and 41 unclassified DLBCL) previously characterized by gene-expression profiling. The DLBCL subgroups differed significantly in the frequency of particular chromosomal aberrations. ABC-DLBCL had frequent trisomy 3, gains of 3q and 18q21-q22, and losses of 6q21-q22, whereas GCB-DLBCL had frequent gains of 12q12, and PMBCL had gains of 9p21-pter and 2p14-p16. Parallel analysis of CGH alterations, locus-specific gene-expression profiles, and global gene-expression signatures revealed that DNA amplifications and gains had a substantial impact on the expression of genes in the involved chromosomal regions, and some genes were overexpressed in a DLBCL subgroup-specific fashion. Unexpectedly, specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. In addition, gains involving the chromosomal region 3p11-p12 provided prognostic information that was statistically independent of the previously defined gene-expression-based survival model, thereby improving its predictive power. PMID:16046532

Bea, Silvia; Zettl, Andreas; Wright, George; Salaverria, Itziar; Jehn, Philipp; Moreno, Victor; Burek, Christof; Ott, German; Puig, Xavier; Yang, Liming; Lopez-Guillermo, Armando; Chan, Wing C.; Greiner, Timothy C.; Weisenburger, Dennis D.; Armitage, James O.; Gascoyne, Randy D.; Connors, Joseph M.; Grogan, Thomas M.; Braziel, Rita; Fisher, Richard I.; Smeland, Erlend B.; Kvaloy, Stein; Holte, Harald; Delabie, Jan; Simon, Richard; Powell, John; Wilson, Wyndham H.; Jaffe, Elaine S.; Montserrat, Emili; Muller-Hermelink, Hans-Konrad; Staudt, Louis M.; Campo, Elias; Rosenwald, Andreas

2005-01-01

116

Switch recombination in a transfected plasmid occurs preferentially in a B cell line that undergoes switch recombination of its chromosomal Ig heavy chain genes  

Microsoft Academic Search

Ab class switching is induced upon B cell activation in vivo by immunization or infection or in vitro by treatment with mitogens, e. g. LPS, and results in the expression of different heavy chain constant region (CH) genes without a change in the Ab variable region. This DNA recombination event allows Abs to alter their biological activity while maintaining their

Janet Stavnezer; Sean P. Bradley; Norman Rousseau; Todd Pearson; Ananth Shanmugam; Debra J. Waite; Paul R. Rogers; Amy L. Kenter

1999-01-01

117

Expression of Recombination Activating Genes in Germinal Center B Cells: Involvement of Interleukin 7 (IL7) and the IL7 Receptor  

Microsoft Academic Search

Summary Mouse germinal center (GC) B cells have been shown to undergo secondary V(D)J (V, vari- able; D, diversity; J, joining) recombination (receptor editing) mediated by the reexpressed products of recombination activating gene ( RAG ) -1 and RAG-2 . We show here that interleu- kin (IL)-7 as well as IL-4 was effective in inducing functional RAG products in mouse

Masaki Hikida; Yasunori Nakayama; Yumi Yamashita; Yoshio Kumazawa; Shin-Ichi Nishikawa; Hitoshi Ohmori

2010-01-01

118

Transcription of the tumor necrosis factor alpha gene is rapidly induced by anti-immunoglobulin and blocked by cyclosporin A and FK506 in human B cells.  

PubMed Central

The human tumor necrosis factor alpha (TNF-alpha) gene encodes a cytokine whose activities have been implicated in many immunopathological processes, including the activation and differentiation of lymphocytes. Originally identified as a monocyte factor, our studies and those of others have demonstrated that B and T lymphocytes produce TNF-alpha when stimulated by a variety of inducers. We report here that TNF-alpha gene transcription is rapidly and highly induced in three independently derived human Burkitt lymphoma cell lines, as well as in freshly isolated human splenic B cells, activated by antibodies to surface immunoglobulin. This burst in TNF-alpha gene transcription is associated with an induction of TNF-alpha bioactivity in the culture supernatants from stimulated splenic B cells. Moreover, induction of TNF-alpha gene transcription by anti-immunoglobulin was blocked by the immunosuppressants cyclosporin A and FK506. These studies demonstrate that TNF-alpha production is an early event in B-cell activation and they establish the efficacy of using immunosuppressants as probes in dissecting transcriptional activation pathways in human B cells. Images PMID:1281550

Goldfeld, A E; Flemington, E K; Boussiotis, V A; Theodos, C M; Titus, R G; Strominger, J L; Speck, S H

1992-01-01

119

The role of H-2-linked genes in helper T-cell function. I. In vitro expression in B cells of immune response genes controlling helper T-cell activity  

PubMed Central

The ability of murine helper T cells primed to the antigen, sheep erythrocytes (SRBC) to cross-react with burro erythrocytes (BRBC) in the in vitro anti-trinitrophenol (TNP) response to TNP-RBC was shown to be under genetic control. Although non-H-2 genes were shown to influence the absolute level of helper activity assayed after SRBC priming, the extent of cross-reaction of SRBC-primed helpers with BRBC was shown to be controlled by an H-2-1inked Ir gene(s). H-2 haplotypes were identified which determined high, intermediate, or low response to the cross- reacting determinants and the gene(s) controlling the cross-reaction tentatively mapped to the K through I-E end of the H-2 complex. Helpers primed in F(1) mice of high x intermediate or high x low responder parents were tested for cross-reaction using B cells and macrophages (M?) of parental haplotypes. In each case the extent of cross-reaction was predicted by the H-2 haplotype of the B cells and M?, establishing the expression of the Ir gene(s) in B cells and/or M? a t least, but not ruling out its expression in T cells as well. The low cross-reaction seen when T cells from F(1) mice of high × low responder parents were tested on low responder B cells and M? was not increased by the presence of high responder M?, indicating the Ir gene(s) is expressed in the B cell a t least although it may be expressed in M? as well. These and our previously reported experiments are consistent with the hypothesis that helper T cells recognize antigen bound to the surface of B cells and M? in association with the product(s) of Ir gene(s) expressed on the B cell and M?. PMID:411877

Kappler, JW; Marrack, P

1977-01-01

120

Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging.  

PubMed

Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis. Indeed, several of the so-called tumor specific translocations have been detected in peripheral blood of healthy individuals, finding a higher frequency of some of them with aging. The inappropriate repair of DNA double strand breaks by the nonhomologous end joining (NHEJ) pathway is one of the reasons for a translocation to occur. Moreover, fidelity of this pathway has been shown to decline with age. Although the mechanism underlying this inefficacy is unknown, other repair pathways are inactivated by methylation with aging. In this study, we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age. To this aim, we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes. We found higher frequency of BCL2-JH and BCR-ABL (major) translocations with aging. In addition, we detected that two NHEJ genes (LIG4 and XRCC6) presented age-dependent promoter methylation changes. However, we did not observe a correlation between the increase of translocations and methylation, indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging. PMID:25399073

Martín-Guerrero, Idoia; de Prado, Elena; Lopez-Lopez, Elixabet; Ardanaz, Maite; Vitoria, Juan Carlos; Parada, Luis A; García-Orad, Cristina; García-Orad, Africa

2014-12-01

121

BCL2 antibodies targeted at different epitopes detect varying levels of protein expression and correlate with frequent gene amplification in diffuse large B-cell lymphoma.  

PubMed

Patients with aggressive, BCL2 protein-positive (+) diffuse large B-cell lymphoma (DLBCL) often experience rapid disease progression that is refractory to standard therapy. However, there is potential for false-negative staining of BCL2 using the standard monoclonal mouse 124 antibody that hinders the identification of these high-risk DLBCL patients. Herein, we compare 2 alternative rabbit monoclonal antibodies (E17 and SP66) to the 124 clone in staining for BCL2 in formalin-fixed, paraffin-embedded DLBCL tissues. Overall, in 2 independent DLBCL cohorts, E17 and SP66 detected BCL2 expression more frequently than 124. In the context of MYC expression, cases identified as BCL2 (+) with SP66 demonstrated the strongest correlation with worse overall survival. The 124 clone failed to detect BCL2 expression in the majority of translocation (+), amplification (+), and activated B-cell DLBCL cases in which high levels of BCL2 protein are expected. Using dual in situ hybridization as a new tool to detect BCL2 translocation and amplification, we observed similar results as previously reported for fluorescence in situ hybridization for translocation but a higher amplification frequency, indicating that BCL2 amplification may be underreported in DLBCL. Among the discrepant cases, phosphorylation of BCL2 at T69 and/or S70 was more common than in the concordant cases and may contribute to the 124 false negatives, in addition to previously associated mutations within the epitope region. The accurate detection of BCL2 expression is important in the prognosis and treatment of DLBCL particularly with new anti-BCL2 therapies. PMID:25090918

Kendrick, Samantha L; Redd, Lucas; Muranyi, Andrea; Henricksen, Leigh A; Stanislaw, Stacey; Smith, Lynette M; Perry, Anamarija M; Fu, Kai; Weisenburger, Dennis D; Rosenwald, Andreas; Ott, German; Gascoyne, Randy D; Jaffe, Elaine S; Campo, Elías; Delabie, Jan; Braziel, Rita M; Cook, James R; Tubbs, Raymond R; Staudt, Louis M; Chan, Wing Chung; Steidl, Christian; Grogan, Thomas M; Rimsza, Lisa M

2014-10-01

122

Pretransplant Mobilization with Granulocyte Colony-Stimulating Factor Improves B-Cell Reconstitution by Lentiviral Vector Gene Therapy in SCID-X1 Mice.  

PubMed

Abstract Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg(-/-) mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin(-)) cells or Il2rg(-/-) Lin(-) cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2?Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning. PMID:25222508

Huston, Marshall W; Riegman, Adriaan R A; Yadak, Rana; van Helsdingen, Yvette; de Boer, Helen; van Til, Niek P; Wagemaker, Gerard

2014-10-01

123

Expression of human {beta}-defensin-2 gene induced by CpG-DNA in human B cells  

SciTech Connect

Defensins have a broad range of antimicrobial activity against bacteria, fungi, and viruses. The expression of human {beta}-defensin-2 (hBD-2) is prevalently observed in epithelial cells and is induced by bacterial infection. Here, we have shown that the expression of the hBD-2 gene and release of hBD-2 protein into the medium is up-regulated in response to CpG-DNA in human B cell line RPMI 8226. The induction of hBD-2 was dependent on CG sequence and phosphorothioate backbone-modification. This was also confirmed in primary human lymphocytes. To shed light on the molecular mechanism involved in hBD-2 induction by CpG-DNA, we examined the contribution of the NF-{kappa}B signaling pathway in RPMI 8226 cells. Suppression of MyD88 function and inhibition of NF-{kappa}B nuclear localization blocked hBD-2 induction. The NF-{kappa}B pathway inhibitors also abolished hBD-2 induction. These results may contribute to a better understanding on the therapeutic effects of CpG-DNA against infectious diseases.

Han, Su Ho [Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of)] [Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of); Kim, Young-Eun; Park, Jeong-A [Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Chungbuk 361-763 (Korea, Republic of)] [Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Chungbuk 361-763 (Korea, Republic of); Park, Jae-Bong [Department of Biochemistry, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of)] [Department of Biochemistry, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of); Kim, Yong-Sun [Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of)] [Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of); Lee, Younghee [Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Chungbuk 361-763 (Korea, Republic of)] [Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Chungbuk 361-763 (Korea, Republic of); Choi, Ihn-Geun [Department of Neuropsychiatry, Hallym University, Han-Gang Sacred Heart Hospital, Seoul 150-719 (Korea, Republic of)] [Department of Neuropsychiatry, Hallym University, Han-Gang Sacred Heart Hospital, Seoul 150-719 (Korea, Republic of); Kwon, Hyung-Joo, E-mail: hjookwon@hallym.ac.kr [Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of) [Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of); Center for Medical Science Research, College of Medicine, Hallym University, Gangwon-do 200-702 (Korea, Republic of)

2009-11-20

124

Tyrosine kinase chromosomal translocations mediate distinct and overlapping gene regulation events  

PubMed Central

Background Leukemia is a heterogeneous disease commonly associated with recurrent chromosomal translocations that involve tyrosine kinases including BCR-ABL, TEL-PDGFRB and TEL-JAK2. Most studies on the activated tyrosine kinases have focused on proximal signaling events, but little is known about gene transcription regulated by these fusions. Methods Oligonucleotide microarray was performed to compare mRNA changes attributable to BCR-ABL, TEL-PDGFRB and TEL-JAK2 after 1 week of activation of each fusion in Ba/F3 cell lines. Imatinib was used to control the activation of BCR-ABL and TEL-PDGFRB, and TEL-JAK2-mediated gene expression was examined 1 week after Ba/F3-TEL-JAK2 cells were switched to factor-independent conditions. Results Microarray analysis revealed between 800 to 2000 genes induced or suppressed by two-fold or greater by each tyrosine kinase, with a subset of these genes commonly induced or suppressed among the three fusions. Validation by Quantitative PCR confirmed that eight genes (Dok2, Mrvi1, Isg20, Id1, gp49b, Cxcl10, Scinderin, and collagen V?1(Col5a1)) displayed an overlapping regulation among the three tested fusion proteins. Stat1 and Gbp1 were induced uniquely by TEL-PDGFRB. Conclusions Our results suggest that BCR-ABL, TEL-PDGFRB and TEL-JAK2 regulate distinct and overlapping gene transcription profiles. Many of the genes identified are known to be involved in processes associated with leukemogenesis, including cell migration, proliferation and differentiation. This study offers the basis for further work that could lead to an understanding of the specificity of diseases caused by these three chromosomal translocations. PMID:22204395

2011-01-01

125

A rapid and quantitative method for the evaluation of V gene usage, specificities and the clonal size of B cell repertoires.  

PubMed

The quantitative simultaneous description of both variable region gene usage and antigen specificity of immunoglobulin repertoires is a major goal in immunology. Current quantitative assays are labor intensive and depend on extensive gene expression cloning prior to screening for antigen specificity. Here we describe an alternative method based on high efficiency single B cell cultures coupled with RT-PCR that can be used for rapid characterization of immunoglobulin gene segment usage, clonal size and antigen specificity. This simplified approach should facilitate the study of antibody repertoires expressed by defined B cell subpopulations, the analysis of immune responses to self and nonself-antigens, the development and screening of synthetic antibodies and the accelerated study and screening of neutralizing antibodies to pathogenic threats. PMID:22226792

Vale, A M; Foote, J B; Granato, A; Zhuang, Y; Pereira, R M S; Lopes, U G; Bellio, M; Burrows, P D; Schroeder, H W; Nobrega, A

2012-02-28

126

A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-? nuclear translocation  

PubMed Central

Nocturnin (NOC) is a circadian-regulated protein related to the yeast family of transcription factors involved in the cellular response to nutrient status. In mammals, NOC functions as a deadenylase but lacks a transcriptional activation domain. It is highly expressed in bone-marrow stromal cells (BMSCs), hepatocytes, and adipocytes. In BMSCs exposed to the PPAR-? (peroxisome proliferator-activated receptor-?) agonist rosiglitazone, Noc expression was enhanced 30-fold. Previously, we reported that Noc?/? mice had low body temperature, were protected from diet-induced obesity, and most importantly exhibited absence of Pparg circadian rhythmicity on a high-fat diet. Consistent with its role in influencing BMSCs allocation, Noc?/? mice have reduced bone marrow adiposity and high bone mass. In that same vein, NOC overexpression enhances adipogenesis in 3T3-L1 cells but negatively regulates osteogenesis in MC3T3-E1 cells. NOC and a mutated form, which lacks deadenylase activity, bind to PPAR-? and markedly enhance PPAR-? transcriptional activity. Both WT and mutant NOC facilitate nuclear translocation of PPAR-?. Importantly, NOC-mediated nuclear translocation of PPAR-? is blocked by a short peptide fragment of NOC that inhibits its physical interaction with PPAR-?. The inhibitory effect of this NOC-peptide was partially reversed by rosiglitazone, suggesting that effect of NOC on PPAR-? nuclear translocation may be independent of ligand-mediated PPAR-? activation. In sum, Noc plays a unique role in the regulation of mesenchymal stem-cell lineage allocation by modulating PPAR-? activity through nuclear translocation. These data illustrate a unique mechanism whereby a nutrient-responsive gene influences BMSCs differentiation, adipogenesis, and ultimately body composition. PMID:20498072

Kawai, Masanobu; Green, Carla B.; Lecka-Czernik, Beata; Douris, Nicholas; Gilbert, Misty R.; Kojima, Shihoko; Ackert-Bicknell, Cheryl; Garg, Neha; Horowitz, Mark C.; Adamo, Martin L.; Clemmons, David R.; Rosen, Clifford J.

2010-01-01

127

High Basal Expression of Interferon-Stimulated Genes in Human Bronchial Epithelial (BEAS-2B) Cells Contributes to Influenza A Virus Resistance  

PubMed Central

Respiratory epithelial cells play a key role in influenza A virus (IAV) pathogenesis and host innate response. Transformed human respiratory cell lines are widely used in the study of IAV?host interactions due to their relative convenience, and inherent difficulties in working with primary cells. Transformed cells, however, may have altered susceptibility to virus infection. Proper characterization of different respiratory cell types in their responses to IAV infection is therefore needed to ensure that the cell line chosen will provide results that are of relevance in vivo. We compared replication kinetics of human H1N1 (A/USSR/77) IAVs in normal primary human bronchial epithelial (NHBE) and two commonly used respiratory epithelial cell lines namely BEAS-2B and A549 cells. We found that IAV replication was distinctly poor in BEAS-2B cells in comparison with NHBE, A549 and Madin-Darby canine kidney (MDCK) cells. IAV resistance in BEAS-2B cells was accompanied by an activated antiviral state with high basal expression of interferon (IFN) regulatory factor-7 (IRF-7), stimulator of IFN genes (STING) and IFN stimulated genes (ISGs). Treatment of BEAS-2B cells with a pan-Janus-activated-kinase (JAK) inhibitor decreased IRF-7 and ISG expression and resulted in increased IAV replication. Therefore, the use of highly resistant BEAS-2B cells in IAV infection may not reflect the cytopathogenicity of IAV in human epithelial cells in vivo. PMID:25313647

Seng, Lai-Giea; Daly, Janet; Chang, Kin-Chow; Kuchipudi, Suresh V.

2014-01-01

128

Gene delivery in malignant B cells using the combination of lentiviruses conjugated to anti-transferrin receptor antibodies and an immunoglobulin promoter  

PubMed Central

Background We previously developed an antibody-avidin fusion protein (ch128.1Av) specific for the human transferrin receptor 1 (TfR1; CD71) to be used as a delivery vector for cancer therapy and showed that ch128.1Av delivers the biotinylated plant toxin saporin-6 into malignant B cells. However, due to widespread expression of TfR1, delivery of the toxin to normal cells is a concern. Therefore, we explored the potential of dual targeted lentiviral-mediated gene therapy approaches to restrict gene expression to malignant B cells. Targeting occurs through the use of ch128.1Av or its parental antibody without avidin (ch128.1) and through transcriptional regulation using an immunoglobulin promoter. Methods Flow cytometry was used to detect the expression of enhanced green fluorescent protein (EGFP) in a panel of cell lines. Cell viability after specific delivery of the therapeutic gene FCU1, a chimeric enzyme consisting of cytosine deaminase genetically fused to uracil phosphoribosyltransferse that converts the 5-fluorocytosine (5-FC) prodrug into toxic metabolites, was monitored by an MTS assay. Results We found that EGFP was specifically expressed in a panel of human malignant B cells, but not in human T cell lines. EGFP expression was observed in all cell lines when a ubiquitous promoter was used. Furthermore, we show the decrease of cell viability in malignant plasma cells in the presence of 5-FC. Conclusions These studies demonstrate that gene expression can be restricted to malignant B cells and suggest that this dual targeted gene therapy strategy may help to circumvent the potential side effects of certain TfR1-targeted protein delivery approaches. PMID:24436117

Leoh, Lai Sum; Morizono, Kouki; Kershaw, Kathleen M.; Chen, Irvin S. Y.; Penichet, Manuel L.; Daniels-Wells, Tracy R.

2014-01-01

129

Rgs13 Constrains Early B Cell Responses and Limits Germinal Center Sizes  

PubMed Central

Germinal centers (GCs) are microanatomic structures that develop in secondary lymphoid organs in response to antigenic stimulation. Within GCs B cells clonally expand and their immunoglobulin genes undergo class switch recombination and somatic hypermutation. Transcriptional profiling has identified a number of genes that are prominently expressed in GC B cells. Among them is Rgs13, which encodes an RGS protein with a dual function. Its canonical function is to accelerate the intrinsic GTPase activity of heterotrimeric G-protein ? subunits at the plasma membrane, thereby limiting heterotrimeric G-protein signaling. A unique, non-canonical function of RGS13 occurs following translocation to the nucleus, where it represses CREB transcriptional activity. The functional role of RGS13 in GC B cells is unknown. To create a surrogate marker for Rgs13 expression and a loss of function mutation, we inserted a GFP coding region into the Rgs13 genomic locus. Following immunization GFP expression rapidly increased in activated B cells, persisted in GC B cells, but declined in newly generated memory B and plasma cells. Intravital microscopy of the inguinal lymph node (LN) of immunized mice revealed the rapid appearance of GFP+ cells at LN interfollicular regions and along the T/B cell borders, and eventually within GCs. Analysis of WT, knock-in, and mixed chimeric mice indicated that RGS13 constrains extra-follicular plasma cell generation, GC size, and GC B cell numbers. Analysis of select cell cycle and GC specific genes disclosed an aberrant gene expression profile in the Rgs13 deficient GC B cells. These results indicate that RGS13, likely acting at cell membranes and in nuclei, helps coordinate key decision points during the expansion and differentiation of naive B cells. PMID:23533672

Hwang, Il-Young; Hwang, Kyung-Sun; Park, Chung; Harrison, Kathleen A.; Kehrl, John H.

2013-01-01

130

Model for MLL translocations in therapy-related leukemia involving topoisomerase II?-mediated DNA strand breaks and gene proximity  

PubMed Central

Topoisomerase poisons such as the epipodophyllotoxin etoposide are widely used effective cytotoxic anticancer agents. However, they are associated with the development of therapy-related acute myeloid leukemias (t-AMLs), which display characteristic balanced chromosome translocations, most often involving the mixed lineage leukemia (MLL) locus at 11q23. MLL translocation breakpoints in t-AMLs cluster in a DNase I hypersensitive region, which possesses cryptic promoter activity, implicating transcription as well as topoisomerase II activity in the translocation mechanism. We find that 2–3% of MLL alleles undergoing transcription do so in close proximity to one of its recurrent translocation partner genes, AF9 or AF4, consistent with their sharing transcription factories. We show that most etoposide-induced chromosome breaks in the MLL locus and the overall genotoxicity of etoposide are dependent on topoisomerase II?, but that topoisomerase II? and -? occupancy and etoposide-induced DNA cleavage data suggest factors other than local topoisomerase II concentration determine specific clustering of MLL translocation breakpoints in t-AML. We propose a model where DNA double-strand breaks (DSBs) introduced by topoisomerase II? into pairs of genes undergoing transcription within a common transcription factory become stabilized by antitopoisomerase II drugs such as etoposide, providing the opportunity for illegitimate end joining and translocation. PMID:22615413

Cowell, Ian G.; Sondka, Zbyslaw; Smith, Kayleigh; Lee, Ka Cheong; Manville, Catriona M.; Sidorczuk-Lesthuruge, Malgorzata; Rance, Holly Ashlene; Padget, Kay; Jackson, Graham Hunter; Adachi, Noritaka; Austin, Caroline A.

2012-01-01

131

Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment.  

PubMed

Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL. PMID:21670469

Alizadeh, Ash A; Gentles, Andrew J; Alencar, Alvaro J; Liu, Chih Long; Kohrt, Holbrook E; Houot, Roch; Goldstein, Matthew J; Zhao, Shuchun; Natkunam, Yasodha; Advani, Ranjana H; Gascoyne, Randy D; Briones, Javier; Tibshirani, Robert J; Myklebust, June H; Plevritis, Sylvia K; Lossos, Izidore S; Levy, Ronald

2011-08-01

132

Noncoding RNA transcription targets AID to divergently transcribed loci in B cells.  

PubMed

The vast majority of the mammalian genome has the potential to express noncoding RNA (ncRNA). The 11-subunit RNA exosome complex is the main source of cellular 3'-5' exoribonucleolytic activity and potentially regulates the mammalian noncoding transcriptome. Here we generated a mouse model in which the essential subunit Exosc3 of the RNA exosome complex can be conditionally deleted. Exosc3-deficient B cells lack the ability to undergo normal levels of class switch recombination and somatic hypermutation, two mutagenic DNA processes used to generate antibody diversity via the B-cell mutator protein activation-induced cytidine deaminase (AID). The transcriptome of Exosc3-deficient B cells has revealed the presence of many novel RNA exosome substrate ncRNAs. RNA exosome substrate RNAs include xTSS-RNAs, transcription start site (TSS)-associated antisense transcripts that can exceed 500 base pairs in length and are transcribed divergently from cognate coding gene transcripts. xTSS-RNAs are most strongly expressed at genes that accumulate AID-mediated somatic mutations and/or are frequent translocation partners of DNA double-strand breaks generated at Igh in B cells. Strikingly, translocations near TSSs or within gene bodies occur over regions of RNA exosome substrate ncRNA expression. These RNA exosome-regulated, antisense-transcribed regions of the B-cell genome recruit AID and accumulate single-strand DNA structures containing RNA-DNA hybrids. We propose that RNA exosome regulation of ncRNA recruits AID to single-strand DNA-forming sites of antisense and divergent transcription in the B-cell genome, thereby creating a link between ncRNA transcription and overall maintenance of B-cell genomic integrity. PMID:25119026

Pefanis, Evangelos; Wang, Jiguang; Rothschild, Gerson; Lim, Junghyun; Chao, Jaime; Rabadan, Raul; Economides, Aris N; Basu, Uttiya

2014-10-16

133

Overexpression of full-length ETV1 transcripts in clinical prostate cancer due to gene translocation.  

PubMed

ETV1 is overexpressed in a subset of clinical prostate cancers as a fusion transcript with many different partners. However, ETV1 can also be overexpressed as a full-length transcript. Full-length ETV1 protein functions differently from truncated ETV1 produced by fusion genes. In this study we describe the genetic background of full-length ETV1 overexpression and the biological properties of different full-length ETV1 isoforms in prostate cancer. Break-apart FISH showed in five out of six patient samples with overexpression of full-length ETV1 a genomic rearrangement of the gene, indicating frequent translocation. We were able to study the rearrangements in more detail in two tumors. In the first tumor 5'-RACE on cDNA showed linkage of the complete ETV1 transcript to the first exon of a prostate-specific two exon ncRNA gene that maps on chromosome 14 (EST14). This resulted in the expression of both full-length ETV1 transcripts and EST14-ETV1 fusion transcripts. In chromosome spreads of a xenograft derived from the second prostate cancer we observed a complex ETV1 translocation involving a chromosome 7 fragment that harbors ETV1 and fragments of chromosomes 4 and 10. Further studies revealed the overexpression of several different full-length transcripts, giving rise to four protein isoforms with different N-terminal regions. Even the shortest isoform synthesized by full-length ETV1 stimulated in vitro anchorage-independent growth of PNT2C2 prostate cells. This contrasts the lack of activity of even shorter N-truncated ETV1 produced by fusion transcripts. Our findings that in clinical prostate cancer overexpression of full-length ETV1 is due to genomic rearrangements involving different chromosomes and the identification of a shortened biologically active ETV1 isoform are highly relevant for understanding the mechanism of ETV1 function in prostate cancer. PMID:21298110

Gasi, Delila; van der Korput, Hetty A; Douben, Hannie C; de Klein, Annelies; de Ridder, Corrina M; van Weerden, Wytske M; Trapman, Jan

2011-01-01

134

Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in  

E-print Network

-Greenwood Pacific Biomedical Research Center, University of Hawaii, Honolulu, Hawaii 96822, USA 1 Imgenex Inc., 1175 D Bryant-Greenwood; Email: gbg@pbrc.hawaii.edu) ABSTRACT Pre-B-cell colony enhancing factor (PBEF of the amnion and chorion and the maternal decidua of the membranes, and to the invading neutrophils

Bryant-Greenwood, Gillian D.

135

Pre-B and B cells in rabbits. Ontogeny and allelic exclusion of kappa light chain genes  

PubMed Central

Pre-B cells in developing rabbits were identified by immunofluorescence as cells containing small amounts of cytoplasmic IgM (cIgM) but lacking surface immunoglobulin (sIg). During ontogeny the first pre-B cells appeared in fetal liver at 23 days gestation, 2 days before the appearance of sIgM+ B lymphocytes. Pre-B cells were relatively frequent in fetal and adult bone marrow, but were not found in other tissues except rarely in fetal spleen. Allelic exclusion is apparently established at this early stage of development, because individual pre- B cells and B lymphocytes from heterozygous rabbits expressed only one of the alternative alleles in amounts sufficient for detection. Development of isotype diversity among rabbit B lymphocytes followed the general pattern seen in mouse and man. sIgM+ cells were detected before birth. Expression of sIgG was detected in neonatal rabbits on cells which were also sIgM+ but in older animals most sIgG+ cells lacked sIgM. Cells bearing sIgA were not found until 5-6 days of age, and had no other isotype on their surface. PMID:102726

1978-01-01

136

DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes  

PubMed Central

Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies. PMID:22314321

Hakim, Ofir; Resch, Wolfgang; Yamane, Arito; Klein, Isaac; Kieffer-Kwon, Kyong-Rim; Jankovic, Mila; Oliveira, Thiago; Bothmer, Anne; Voss, Ty C.; Ansarah-Sobrinho, Camilo; Mathe, Ewy; Liang, Genqing; Cobell, Jesse; Nakahashi, Hirotaka; Robbiani, Davide F.; Nussenzweig, Andre; Hager, Gordon L.; Nussenzweig, Michel C.; Casellas, Rafael

2012-01-01

137

Fine mapping of the EDA gene: a translocation breakpoint is associated with a CpG island that is transcribed.  

PubMed Central

In order to identify the gene for human X-linked anhidrotic ectodermal dysplasia (EDA), a translocation breakpoint in a female with t(X;1)(q13.1;p36.3) and EDA (patient AK) was finely mapped. The EDA region contains five groups of rare-cutter restriction sites that define CpG islands. The two more centromeric of these islands are associated with transcripts of 3.5 kb and 1.8 kb. The third CpG island maps within <1 kb of the translocation breakpoint in patient AK, as indicated by a genomic rearrangement, and approximately 100 kb centromeric from another previously mapped translocation breakpoint (patient AnLy). Northern analysis with a probe from this CpG island detected an approximately 6-kb mRNA in several fetal tissues tested. An extended YAC contig of 1,200 kb with an average of fivefold coverage was constructed. The two most telomeric CpG islands map 350 kb telomeric of the two translocations. Taken together, the results suggest that the CpG island just proximal of the AK translocation breakpoint lies at the 5' end of a candidate gene for EDA. Images Figure 2 Figure 3 Figure 4 PMID:8554048

Srivastava, A. K.; Montonen, O.; Saarialho-Kere, U.; Chen, E.; Baybayan, P.; Pispa, J.; Limon, J.; Schlessinger, D.; Kere, J.

1996-01-01

138

Analysis of Mutations in Immunoglobulin Heavy Chain Variable Region Genes of Microdissected Marginal Zone (MGZ) B Cells Suggests that the MGZ of Human Spleen Is a Reservoir of Memory B Cells  

Microsoft Academic Search

Summary The splenic marginal zone (MGZ), which surrounds the mantle zone (MTZ) in human splenic white pulp, contains a phenotypically and morphologically distinct population of B cells. The origin of MGZ B cells is .uncertain. Whereas some experiments in rodents have suggested that they are a distinct cell lineage responsible for the immune response to T-independent type 2 an- tigens,

Deborah K. Dunn-Walters; Peter G. Isaacson; Jo Spencer

139

The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain  

PubMed Central

The murine pre-B cell-specific genes VpreB and lambda 5, as well as the murine gene for mu heavy chain, were introduced into Ltk- fibroblast cells which normally do not express these genes. Stable transfectants carrying these genes produced the corresponding proteins of 15.5, 21.5, and 75 kD. They secreted the three proteins as a triple complex that could be immunoprecipitated by mu heavy chain-specific antibodies, consisting of one VpreB, one lambda 5, and one mu heavy chain. The mu heavy chain and lambda 5 were disulfide-bonded with each other, while the VpreB protein was noncovalently associated. These experiments proved that the VpreB, lambda 5 and mu H chain proteins can form a heavy/light chain-like heterocomplex. PMID:2117638

1990-01-01

140

Comparative Gene Expression Profiling Identifies Common Molecular Signatures of NF-?B Activation in Canine and Human Diffuse Large B Cell Lymphoma (DLBCL)  

PubMed Central

We present the first comparison of global transcriptional changes in canine and human diffuse large B-cell lymphoma (DLBCL), with particular reference to the nuclear factor-kappa B (NF-?B) pathway. Microarray data generated from canine DLBCL and normal lymph nodes were used for differential expression, co-expression and pathway analyses, and compared with analysis of microarray data from human healthy and DLBCL lymph nodes. The comparisons at gene level were performed by mapping the probesets in canine microarrays to orthologous genes in humans and vice versa. A considerable number of differentially expressed genes between canine lymphoma and healthy lymph node samples were also found differentially expressed between human DLBCL and healthy lymph node samples. Principal component analysis using a literature-derived NF-?B target gene set mapped to orthologous canine array probesets and human array probesets clearly separated the healthy and cancer samples in both datasets. The analysis demonstrated that for both human and canine DLBCL there is activation of the NF-?B/p65 canonical pathway, indicating that canine lymphoma could be used as a model to study NF-?B-targeted therapeutics for human lymphoma. To validate this, tissue arrays were generated for canine and human NHL and immunohistochemistry was employed to assess NF-?B activation status. In addition, human and canine B-cell lymphoma lines were assessed for NF-?B activity and the effects of NF-?B inhibition. PMID:24023754

Mudaliar, Manikhandan A. V.; Haggart, Ross D.; Miele, Gino; Sellar, Grant; Tan, Karen A. L.; Goodlad, John R.; Milne, Elspeth; Vail, David M.; Kurzman, Ilene

2013-01-01

141

Human mb-1 gene: Complete cDNA sequence and its expression in B cells bearing membrane Ig of various isotypes  

SciTech Connect

The transmembrane protein, IgM-[alpha], a product of mb-1 gene, has been shown to be specifically associated with membrane-bound IgM on the plasma membrane of B lymphocytes. Recent studies have suggested that IgM-[alpha] may play a role in transducing signals from the Ag receptors during the activation of B cells. A large amount of information has been obtained in the mouse system regarding IgM-[alpha] and other components of the newly conceived B cell Ag receptor complex. Here, the authors report the cloning and the nucleotide sequencing of cDNA clones of human mb-1, covering the entire length of the mRNA. At the amino acid sequence level, human and murine mb-1 share a high homology in their transmembrane and intracytoplasmic segments, suggesting an important biologic function for these regions of mb-1. A major difference, mainly in the 3[prime] untranslated part, exits between the authors' cDNA sequence and the published partial human mb-1 cDNA sequence. It has also been observed that human mb-1 is expressed not only by B cell lines expressing membrane-bound Ig of [mu] and [sigma] isotypes but also those expressing membrane-bound Ig of [alpha] and [gamma] isotypes. 24 refs., 5 figs.

Yu, Li-Ming; Chang, Tse Wen (Tanox Biosystems Inc., Houston, TX (United States))

1992-01-15

142

Nuclear translocation uncovers the amyloid peptide A?42 as a regulator of gene transcription.  

PubMed

Although soluble species of the amyloid-? peptide A?42 correlate with disease symptoms in Alzheimer disease, little is known about the biological activities of amyloid-? (A?). Here, we show that A? peptides varying in lengths from 38 to 43 amino acids are internalized by cultured neuroblastoma cells and can be found in the nucleus. By three independent methods, we demonstrate direct detection of nuclear A?42 as follows: (i) biochemical analysis of nuclear fractions; (ii) detection of biotin-labeled A? in living cells by confocal laser scanning microscopy; and (iii) transmission electron microscopy of A? in cultured cells, as well as brain tissue of wild-type and transgenic APPPS1 mice (overexpression of amyloid precursor protein and presenilin 1 with Swedish and L166P mutations, respectively). Also, this study details a novel role for A?42 in nuclear signaling, distinct from the amyloid precursor protein intracellular domain. Chromatin immunoprecipitation showed that A?42 specifically interacts as a repressor of gene transcription with LRP1 and KAI1 promoters. By quantitative RT-PCR, we confirmed that mRNA levels of the examined candidate genes were exclusively decreased by the potentially neurotoxic A?42 wild-type peptide. Shorter peptides (A?38 or A?40) and other longer peptides (nontoxic A?42 G33A substitution or A?43) did not affect mRNA levels. Overall, our data indicate that the nuclear translocation of A?42 impacts gene regulation, and deleterious effects of A?42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes. PMID:24878959

Barucker, Christian; Harmeier, Anja; Weiske, Joerg; Fauler, Beatrix; Albring, Kai Frederik; Prokop, Stefan; Hildebrand, Peter; Lurz, Rudi; Heppner, Frank L; Huber, Otmar; Multhaup, Gerhard

2014-07-18

143

FOXP1 molecular cytogenetics and protein expression analyses in primary cutaneous large B cell lymphoma, leg-type.  

PubMed

FOXP1 protein is expressed in normal activated B cells and overexpressed in a subset of diffuse large B-cell lymphomas, including primary cutaneous large B-cell lymphomas (PCLBCL), leg type. High expression of FOXP1 has been associated to an unfavourable prognosis with independent survival significance. However, little is known regarding the mechanisms underlying the overexpression of FOXP1 in PCLBCL, leg type. Our aims were to analyze FOXP1 cytogenetic status and protein expression in a series of PCLBCL, leg type. Finally, we compared the observed results with those obtained in a group of patients with primary cutaneous follicle centre lymphoma (PCFCL). Fifteen patients with PCLBCL, leg type and nine patients with primary cutaneous follicle centre lymphoma (PCFCL) were included in the study. For each biopsy specimen, FOXP1 translocation and copy number changes were evaluated by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC). Immunohistochemistry showed FOXP1 staining in 13 PCLBCL, leg type, whereas all PCFCL were negative. FISH analysis disclosed no translocations involving FOXP1 gene in any of the cases. However, FOXP1 gene gains (3 to 4 copies) were observed in 82% of samples of PCLBCL, leg type and in 37% of PCFCL. FOXP1 expression was independent from FOXP1 translocation. Our results confirm that overexpression of FOXP1 is present in a considerable proportion of PCLBCL, leg type and might indicate an unfavourable prognosis. Mechanisms not related to translocation seem to be responsible for this overexpression. PMID:21154235

Espinet, Blanca; García-Herrera, Adriana; Gallardo, Fernando; Baró, Cristina; Salgado, Rocío; Servitje, Octavio; Estrach, Teresa; Colomo, Lluís; Romagosa, Vicenç; Barranco, Carlos; Serrano, Sergi; Campo, Elias; Pujol, Ramon Ma; Solé, Francesc

2011-02-01

144

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification.  

PubMed

MYC is a potent oncogene initially identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. MYC gene alterations have been identified in other mature B-cell neoplasms that are usually associated with an aggressive clinical behavior. Most of these tumors originate in cells that do not normally express MYC protein. The oncogenic events leading to MYC up-regulation seem to overcome the inhibitory effect of physiological repressors such as BCL6 or BLIMP1. Aggressive lymphomas frequently carry additional oncogenic alterations that cooperate with MYC dysregulation, likely counteracting its proapoptotic function. The development of FISH probes and new reliable antibodies have facilitated the study of MYC gene alterations and protein expression in large series of patients, providing new clinical and biological perspectives regarding MYC dysregulation in aggressive lymphomas. MYC gene alterations in large B-cell lymphomas are frequently associated with BCL2 or BCL6 translocations conferring a very aggressive behavior. Conversely, MYC protein up-regulation may occur in tumors without apparent gene alterations, and its association with BCL2 overexpression also confers a poor prognosis. In this review, we integrate all of this new information and discuss perspectives, challenges, and open questions for the diagnosis and management of patients with MYC-driven aggressive B-cell lymphomas. PMID:24319234

Ott, German; Rosenwald, Andreas; Campo, Elias

2013-01-01

145

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification.  

PubMed

MYC is a potent oncogene initially identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. MYC gene alterations have been identified in other mature B-cell neoplasms that are usually associated with an aggressive clinical behavior. Most of these tumors originate in cells that do not normally express MYC protein. The oncogenic events leading to MYC up-regulation seem to overcome the inhibitory effect of physiological repressors such as BCL6 or BLIMP1. Aggressive lymphomas frequently carry additional oncogenic alterations that cooperate with MYC dysregulation, likely counteracting its proapoptotic function. The development of FISH probes and new reliable antibodies have facilitated the study of MYC gene alterations and protein expression in large series of patients, providing new clinical and biological perspectives regarding MYC dysregulation in aggressive lymphomas. MYC gene alterations in large B-cell lymphomas are frequently associated with BCL2 or BCL6 translocations conferring a very aggressive behavior. Conversely, MYC protein up-regulation may occur in tumors without apparent gene alterations, and its association with BCL2 overexpression also confers a poor prognosis. In this review, we integrate all of this new information and discuss perspectives, challenges, and open questions for the diagnosis and management of patients with MYC-driven aggressive B-cell lymphomas. PMID:24009228

Ott, German; Rosenwald, Andreas; Campo, Elias

2013-12-01

146

Identification of BSAP (Pax-5) target genes in early B-cell development by loss- and gain-of-function experiments.  

PubMed

The Pax-5 gene codes for the transcription factor BSAP which is essential for the progression of adult B lymphopoiesis beyond an early progenitor (pre-BI) cell stage. Although several genes have been proposed to be regulated by BSAP, CD19 is to date the only target gene which has been genetically confirmed to depend on this transcription factor for its expression. We have now taken advantage of cultured pre-BI cells of wild-type and Pax-5 mutant bone marrow to screen a large panel of B lymphoid genes for additional BSAP target genes. Four differentially expressed genes were shown to be under the direct control of BSAP, as their expression was rapidly regulated in Pax-5-deficient pre-BI cells by a hormone-inducible BSAP-estrogen receptor fusion protein. The genes coding for the B-cell receptor component Ig-alpha (mb-1) and the transcription factors N-myc and LEF-1 are positively regulated by BSAP, while the gene coding for the cell surface protein PD-1 is efficiently repressed. Distinct regulatory mechanisms of BSAP were revealed by reconstituting Pax-5-deficient pre-BI cells with full-length BSAP or a truncated form containing only the paired domain. IL-7 signalling was able to efficiently induce the N-myc gene only in the presence of full-length BSAP, while complete restoration of CD19 synthesis was critically dependent on the BSAP protein concentration. In contrast, the expression of the mb-1 and LEF-1 genes was already reconstituted by the paired domain polypeptide lacking any transactivation function, suggesting that the DNA-binding domain of BSAP is sufficient to recruit other transcription factors to the regulatory regions of these two genes. In conclusion, these loss- and gain-of-function experiments demonstrate that BSAP regulates four newly identified target genes as a transcriptional activator, repressor or docking protein depending on the specific regulatory sequence context. PMID:9545244

Nutt, S L; Morrison, A M; Dörfler, P; Rolink, A; Busslinger, M

1998-04-15

147

Ectopic Expression of Homeobox Gene NKX2-1 in Diffuse Large B-Cell Lymphoma Is Mediated by Aberrant Chromatin Modifications  

PubMed Central

Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2-1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies. PMID:23637834

Nagel, Stefan; Ehrentraut, Stefan; Tomasch, Jurgen; Quentmeier, Hilmar; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G.; MacLeod, Roderick A. F.

2013-01-01

148

Translocation of the c-myc Gene into the Immunoglobulin Heavy Chain Locus in Human Burkitt Lymphoma and Murine Plasmacytoma Cells  

Microsoft Academic Search

The consistent appearance of specific chromosomal translocations in human Burkitt lymphomas and murine plasmacytomas has suggested that these translocations might play a role in malignant transformation. Here we show that transformation of these cells is frequently accompanied by the somatic rearrangement of a cellular analogue of an avian retrovirus transforming gene, c-myc. Moreover, we map c-myc to human chromosome 8

R. Taub; I. Kirsch; C. Morton; G. Lenoir; D. Swan; S. Tronick; S. Aaronson; P. Leder

1982-01-01

149

Immunoglobulin genes undergo legitimate repair in human B cells not only after cis- but also frequent trans-class switch recombination.  

PubMed

Immunoglobulin (Ig) genes specifically recruit activation-induced deaminase (AID) for 'on-target' DNA deamination, initiating either variable (V) region somatic hypermutation, or double-strand break intermediates of class switch recombination (CSR). Such breaks overwhelmingly undergo legitimate intra-Ig repair rather than rare illegitimate and potentially oncogenic junctions outside of Ig loci. We show that in human B cells, legitimate synapsis and repair efficiently join Ig genes whether physically linked on one chromosome or located apart on both alleles. This indicates mechanisms faithfully recognizing and/or pairing loci with homology in structure and accessibility, thus licensing interchromosomal trans-CSR junctions while usually preventing illegitimate interchromosomal recombination with AID off-target genes. Physical linkage of IgH genes in cis on the same allele just increases the likelihood of legitimate repair by another fourfold. The strongest force driving CSR might thus be recognition of legitimate target genes. Formation of IgH intra-allelic loops along this process would then constitute a consequence rather than a pre-requisite of this gene-pairing process. PMID:24848929

Laffleur, B; Bardet, S M; Garot, A; Brousse, M; Baylet, A; Cogné, M

2014-01-01

150

Germline variations of the MALT1 gene as risk factors in the development of primary gastric B-cell lymphoma.  

PubMed

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a histologically distinct tumour derived from MALT acquired as a result of Helicobacter pylori infection. The genetic susceptibility to develop primary gastric B-cell lymphoma in patients with chronic H. pylori infection is unknown. MALT1 plays a key role in malignant B-cell transformation and lymphoma progression. Thus, we investigated germline variations of MALT1 as risk factors for gastric lymphoma in a large cohort from a European multicentre study and in total 214 lymphoma patients, 593 H. pylori infected controls and 348 healthy blood donors were genotyped for four single nucleotide polymorphisms (SNPs) covering the MALT1 locus by Taqman technology. Haplotype and single marker analyses were conducted for association testing in a case-control setting. A distinct haplotype was identified that showed a trend towards protection from high-grade and low-grade lymphomas. In single marker analysis individuals homozygous for the rare allele G of SNP3 (rs12969413) were significantly protected only from gastric high-grade lymphoma compared with controls (p=0.002, odds ratio (OR): 0.2, Wald 95% confidence interval (CI): 0.1

Hellmig, Stephan; Bartscht, Tobias; Fischbach, Wolfgang; Ott, Stephan Johannes; Rosenstiel, Philip; Klapper, Wolfram; Fölsch, Ulrich Robert; Schreiber, Stefan

2009-07-01

151

Situs ambiguus in a female fetus with balanced (X;21) translocation – evidence for functional nullisomy of the ZIC3 gene?  

Microsoft Academic Search

The human ZIC3 gene has been mapped to Xq26.2, the visceral heterotaxy locus HTX1, and has been shown to be mutated in X-linked situs ambiguus and\\/or complex heart defects. We report on a female fetus with situs ambiguus, asplenia and corrected transposition of the great arteries, displaying a (X;21) translocation. The balanced state of the t(X;21)(q26;p13) was verified by FISH

Barbara Fritz; Jürgen Kunz; Gun Peggy Strømstad Knudsen; Frank Louwen; Ingo Kennerknecht; Bernd Eiben; Karen Helene Ørstavik; Ursula Friedrich; Helga Rehder

2005-01-01

152

B cells in autoimmunity  

PubMed Central

B-cell development is tightly regulated, including the induction of B-cell memory and antibody-secreting plasmablasts and plasma cells. In the last decade, we have expanded our understanding of effector functions of B cells as well as their roles in human autoimmune diseases. The current review addresses the role of certain stages of B-cell development as well as plasmablasts/plasma cells in immune regulation under normal and autoimmune conditions with particular emphasis on systemic lupus erythematosus. Based on preclinical and clinical data, B cells have emerged increasingly as both effector cells as well as cells with immunoregulatory potential. PMID:19849820

2009-01-01

153

What is the relevance of Ikaros gene deletions as a prognostic marker in pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia?  

PubMed Central

New prognostic markers are needed for upfront identification of patients with acute lymphocytic leukemia with a high risk of relapse or who are not likely to respond to the most aggressive chemotherapy. We focused our analysis on Ikaros (IKZF1) gene deletions in a homogeneous cohort of 410 pediatric patients with Philadelphia chromosome-negative, B-cell precursor acute lymphoblastic leukemia enrolled in Italy into the AIEOP-BFM ALL2000 study. We confirm their reported poor prognostic value, although the associated event-free survival was relatively high (approximately 70%). The difference in the cumulative incidence of relapse between patients positive or not for IKZF1 deletions was not marked: 24.2% (5.9) versus 13.1% (1.8) overall and 23.9% (6.6) versus 16.5% (2.5) in the intermediate-risk subgroup. In line with this, IKZF1 deletions were not an independent prognostic factor for the hazard of relapse. Most IKZF1-deleted cases stratified in the high-risk group relapsed, suggesting that once identified, patients with these deletions require an alternative treatment. In conclusion, the need of and benefit from introducing IKZF1 deletions as an additional stratification marker for patients with Philadelphia-negative B-cell precursor acute lymphoblastic leukemia remain questionable. PMID:23585525

Palmi, Chiara; Valsecchi, Maria Grazia; Longinotti, Giulia; Silvestri, Daniela; Carrino, Valentina; Conter, Valentino; Basso, Giuseppe; Biondi, Andrea; Kronnie, Geertruy Te; Cazzaniga, Giovanni

2013-01-01

154

1,25-dihydroxyvitamin D{sub 3} impairs NF-{kappa}B activation in human naive B cells  

SciTech Connect

Highlights: {yields} In naive B cells, VDR activation by calcitriol results in reduced NF-{kappa}B p105 and p50 protein expression. {yields} Ligating the VDR with calcitriol causes reduced nuclear translocation of NF-{kappa}B p65. {yields} Reduced nuclear amount of p65 after calcitriol incubation results in reduced binding of p65 on the p105 promoter. {yields} Thus, vitamin D receptor signaling may reduce or prevent activation of B cells and unwanted immune responses, e.g. in IgE dependent diseases such as allergic asthma. -- Abstract: 1{alpha},25-dihydroxyvitamin D{sub 3} (calcitriol), the bioactive metabolite of vitamin D, modulates the activation and inhibits IgE production of anti-CD40 and IL-4 stimulated human peripheral B cells. Engagement of CD40 results in NF-{kappa}B p50 activation, which is essential for the class switch to IgE. Herein, we investigated by which mechanism calcitriol modulates NF-{kappa}B mediated activation of human naive B cells. Naive B cells were predominantly targeted by calcitriol in comparison with memory B cells as shown by pronounced induction of the VDR target gene cyp24a1. Vitamin D receptor activation resulted in a strongly reduced p105/p50 protein and mRNA expression in human naive B cells. This effect is mediated by impaired nuclear translocation of p65 and consequently reduced binding of p65 to its binding site in the p105 promoter. Our data indicate that the vitamin D receptor reduces NF-{kappa}B activation by interference with NF-{kappa}B p65 and p105. Thus, the vitamin D receptor inhibits costimulatory signal transduction in naive B cells, namely by reducing CD40 signaling.

Geldmeyer-Hilt, Kerstin, E-mail: kerstin.hilt@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany)] [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Heine, Guido, E-mail: guido.heine@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany) [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Hartmann, Bjoern, E-mail: bjoern.hartmann@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany)] [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Baumgrass, Ria, E-mail: baumgrass@drfz.de [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany)] [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Radbruch, Andreas, E-mail: radbruch@drfz.de [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany)] [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Worm, Margitta, E-mail: margitta.worm@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany)] [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany)

2011-04-22

155

Molecular cloning and characterization of genes for antibodies generated by orbital tissue-infiltrating B-cells in Graves` ophthalmopathy  

SciTech Connect

Graves` ophthalmopathy is a distressing autoimmune disease of unknown etiology. Analysis of the genes for antibodies secreted by orbital tissue-infiltrating plasma cells might provide insight into the pathogenesis of this disease. The authors, therefore, constructed an immunoglobulin heavy (H) chain and an immunoglobulin k light (L) chain cDNA library from the orbital tissue of a patient with active Graves` ophthalmopathy. Analysis of 15 H (IgG1) and 15 L (k) chains revealed a restricted spectrum of variable region genes. Fourteen of 15 variable k genes were about 94% homologous to the closest known germline gene, KL012. Thirteen of 15 H chain genes were 91% and 90% homologous to the closest germline genes, DP10 and hv1263, respectively. Remarkably, these germline genes also code for other autoantibodies to striated muscle (KL012) and thyroid peridase (KL012 and hv1263). These studies raise the possibility that particular germline genes may be associated with autoimmunity in humans. Further, the present study opens the way to identifying ocular autoantigens that may be the target of an humoral immune response. 29 refs., 4 figs., 1 tab.

Jaume, J.C.; Portolano, S.; Prummel, M.F.; McLachlan, S.M.; Rapoport, B. [Univ. of California, San Francisco, CA (United States)] [Univ. of California, San Francisco, CA (United States)

1994-02-01

156

The 3;21 Translocation in Myelodysplasia Results in a Fusion Transcript Between the AML1 Gene and the Gene for EAP, a Highly Conserved Protein Associated with the Epstein-Barr Virus Small RNA EBER 1  

Microsoft Academic Search

In the 8;21 translocation, the AML1 gene, located at chromosome band 21q22, is translocated to chromosome 8 (q22), where it is fused to the ETO gene and transcribed as a chimeric gene. AML1 is the human homolog of the recently cloned mouse gene pebp2alphaB, homologous to the DNA binding alpha subunit of the polyoma enhancer factor pebp2. AML1 is also

Giuseppina Nucifora; Catherine R. Begy; Paul Erickson; Harry A. Drabkin; Janet D. Rowley

1993-01-01

157

Control of Translocations between Highly Diverged Genes by Sgs1, the Saccharomyces cerevisiae Homolog of the Bloom's Syndrome Protein  

PubMed Central

Sgs1 is a RecQ family DNA helicase required for genome stability in Saccharomyces cerevisiae whose human homologs BLM, WRN, and RECQL4 are mutated in Bloom's, Werner, and Rothmund Thomson syndromes, respectively. Sgs1 and mismatch repair (MMR) are inhibitors of recombination between similar but divergent (homeologous) DNA sequences. Here we show that SGS1, but not MMR, is critical for suppressing spontaneous, recurring translocations between diverged genes in cells with mutations in the genes encoding the checkpoint proteins Mec3, Rad24, Rad9, or Rfc5, the chromatin assembly factors Cac1 or Asf1, and the DNA helicase Rrm3. The S-phase checkpoint kinase and telomere maintenance factor Tel1, a homolog of the human ataxia telangiectasia (ATM) protein, prevents these translocations, whereas the checkpoint kinase Mec1, a homolog of the human ATM-related protein, and the Rad53 checkpoint kinase are not required. The translocation structures observed suggest involvement of a dicentric intermediate and break-induced replication with multiple cycles of DNA template switching. PMID:16809776

Schmidt, Kristina H.; Wu, Joann; Kolodner, Richard D.

2006-01-01

158

A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma  

PubMed Central

The characterization of immunoglobulin heavy chain (IGH) translocations provides information on the diagnosis and guides therapeutic decisions in mature B-cell malignancies while enhancing our understanding of normal and malignant B-cell biology. However, existing methodologies for the detection of IGH translocations are labor intensive, often require viable cells, and are biased toward known IGH fusions. To overcome these limitations, we developed a capture sequencing strategy for the identification of IGH rearrangements at nucleotide level resolution and tested its capabilities as a diagnostic and discovery tool in 78 primary diffuse large B-cell lymphomas (DLBCLs). We readily identified IGH-BCL2, IGH-BCL6, IGH-MYC, and IGH-CCND1 fusions and discovered IRF8, EBF1, and TNFSF13 (APRIL) as novel IGH partners in these tumors. IRF8 and TNFSF13 expression was significantly higher in lymphomas with IGH rearrangements targeting these loci. Modeling the deregulation of IRF8 and EBF1 in vitro defined a lymphomagenic profile characterized by up-regulation of AID and/or BCL6, down-regulation of PRMD1, and resistance to apoptosis. Using a capture sequencing strategy, we discovered the B-cell relevant genes IRF8, EBF1, and TNFSF13 as novel targets for IGH deregulation. This methodology is poised to change how IGH translocations are identified in clinical settings while remaining a powerful tool to uncover the pathogenesis of B-cell malignancies. PMID:23775715

Bouamar, Hakim; Abbas, Saman; Lin, An-Ping; Wang, Long; Jiang, Daifeng; Holder, Kenneth N.; Kinney, Marsha C.; Hunicke-Smith, Scott

2013-01-01

159

Clonal Progression during the T Cell-Dependent B Cell Antibody Response Depends on the Immunoglobulin DH Gene Segment Repertoire  

PubMed Central

The diversity of the third complementarity determining region of the IgH chain is constrained by natural selection of immunoglobulin diversity (DH) sequence. To test the functional significance of this constraint in the context of thymus-dependent (TD) immune responses, we immunized BALB/c mice with WT or altered DH sequence with 2-phenyloxazolone-coupled chicken serum albumin (phOx-CSA). We chose this antigen because studies of the humoral immune response to the hapten phOx were instrumental in the development of the current theoretical framework on which our understanding of the forces driving TD responses is based. To allow direct comparison, we used the classic approach of generating monoclonal Ab (mAb) from various stages of the immune response to phOx to assess the effect of changing the sequence of the DH on clonal expansion, class switching, and affinity maturation, which are hallmarks of TD responses. Compared to WT, TD-induced humoral IgM as well as IgG antibody production in the D-altered ?D-D?FS and ?D-iD strains were significantly reduced. An increased prevalence of IgM-producing hybridomas from late primary, secondary, and tertiary memory responses suggested either impaired class switch recombination (CSR) or impaired clonal expansion of class switched B cells with phOx reactivity. Neither of the D-altered strains demonstrated the restriction in the VH/VL repertoire, the elimination of VH1 family-encoded antibodies, the focusing of the distribution of CDR-H3 lengths, or the selection for the normally dominant Ox1 clonotype, which all are hallmarks of the anti-phOx response in WT mice. These changes in clonal selection and expansion, as well as CSR indicate that the genetic constitution of the DH locus, which has been selected by evolution, can strongly influence the functional outcome of a TD humoral response. PMID:25157256

Trad, Ahmad; Tanasa, Radu Iulian; Lange, Hans; Zemlin, Michael; Schroeder, Harry W.; Lemke, Hilmar

2014-01-01

160

Curcumin regulates gene expression of insulin like growth factor, B-cell CLL/lymphoma 2 and antioxidant enzymes in streptozotocin induced diabetic rats  

PubMed Central

Background The effects of curcumin on the activities and gene expression of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (G-ST), B-cell CLL/lymphoma 2 (Bcl-2) and insulin like growth factor-1 (IGF-1) in diabetic rats were studied. Methods Twenty four rats were assigned to three groups (8 rats for each). Rats of first group were non diabetic and rats of the second group were rendered diabetic by streptozotocin (STZ). Both groups received vehicle, corn oil only (5 ml/kg body weight) and served as negative and positive controls, respectively. Rats of the third group were rendered diabetic and received oral curcumin dissolved in corn oil at a dose of 15 mg/5 ml/kg body weight for 6 weeks. Results Diabetic rats showed significant increase of blood glucose, thiobarbituric acid reactive substances (TBARS) and activities of all antioxidant enzymes with significant reduction of reduced glutathione (GSH) compare to the control non diabetic group. Gene expression of Bcl2, SOD, CAT, GPX and GST was increased significantly in diabetic untreated rats compare to the control non diabetic group. The administration of curcumin to diabetic rats normalized significantly their blood sugar level and TBARS values and increased the activities of all antioxidant enzymes and GSH concentration. In addition, curcumin treated rats showed significant increase in gene expression of IGF-1, Bcl2, SOD and GST compare to non diabetic and diabetic untreated rats. Conclusion Curcumin was antidiabetic therapy, induced hypoglycemia by up-regulation of IGF-1 gene and ameliorate the diabetes induced oxidative stress via increasing the availability of GSH, increasing the activities and gene expression of antioxidant enzymes and Bcl2. Further studies are required to investigate the actual mechanism of action of curcumin regarding the up regulation of gene expression of examined parameters. PMID:24364912

2013-01-01

161

B-cell Lymphoma  

Cancer.gov

B-cell Lymphoma Lymphomas are cancers that arise from lymphoid cells, which are part of the immune system. The World Health Organization currently recognizes about 70 different types of lymphoma and divides them into four major groups: mature B-cell neoplasms,

162

MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program  

PubMed Central

Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)–like and unfavorable activated B-cell (ABC)–like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP. PMID:23449635

Hu, Shimin; Xu-Monette, Zijun Y.; Tzankov, Alexander; Green, Tina; Wu, Lin; Balasubramanyam, Aarthi; Liu, Wei-min; Visco, Carlo; Li, Yong; Miranda, Roberto N.; Montes-Moreno, Santiago; Dybkaer, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W. L.; Zhao, Xiaoying; van Krieken, J. Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andres J. M.; Zhou, Fan; Slack, Graham W.; Gascoyne, Randy D.; Tu, Meifeng; Variakojis, Daina; Chen, Weina; Go, Ronald S.; Piris, Miguel A.; M?ller, Michael B.; Medeiros, L. Jeffrey; Young, Ken H.

2013-01-01

163

Reciprocal translocations  

SciTech Connect

Chapter 26, describes reciprocal translocations of chromosomes: their occurrence, breakpoints, and multiple rearrangements. In addition, phenotypes of balanced and unbalanced translocation carriers and fetal death are discussed. Examples of translocation families are given. Meiosis and genetic risk in translocation carriers is presented. Finally, sperm chromosomes in meiotic segregation analysis is mentioned. 39 refs., 3 figs., 1 tab.

NONE

1993-12-31

164

The zntA gene of Escherichia coli encodes a Zn(II)-translocating P-type ATPase.  

PubMed

The first Zn(II)-translocating P-type ATPase has been identified as the product of o732, a potential gene identified in the sequencing of the Escherichia coli genome. This gene, termed zntA, was disrupted by insertion of a kanamycin gene through homologous recombination. The mutant strain exhibited hypersensitivity to zinc and cadmium salts but not salts of other metals, suggesting a role in zinc homeostasis in E. coli. Everted membrane vesicles from a wild-type strain accumulated 65Zn(II) and 109Cd(II) by using ATP as an energy source. Transport was sensitive to vanadate, an inhibitor of P-type ATPases. Membrane vesicles from the zntA::kan strain did not accumulate those metal ions. Both the sensitive phenotype and transport defect of the mutant were complemented by expression of zntA on a plasmid. PMID:9405611

Rensing, C; Mitra, B; Rosen, B P

1997-12-23

165

Effects of B-Cell Lymphoma 2 Gene Transfer to Myoblast Cells on Skeletal Muscle Tissue Formation Using Magnetic Force-Based Tissue Engineering  

PubMed Central

Tissue-engineered skeletal muscle should possess a high cell-dense structure with unidirectional cell alignment. However, limited nutrient and/or oxygen supply within the artificial tissue constructs might restrict cell viability and muscular functions. In this study, we genetically modified myoblast cells with the anti-apoptotic B-cell lymphoma 2 (Bcl-2) gene and evaluated their function in artificial skeletal muscle tissue constructs. Magnetite cationic liposomes were used to magnetically label C2C12 myoblast cells for the construction of skeletal muscle bundles by applying a magnetic force. Bcl-2-overexpressing muscle bundles formed highly cell-dense and viable tissue constructs, while muscle bundles without Bcl-2 overexpression exhibited substantial necrosis/apoptosis at the central region of the bundle. Bcl-2-overexpressing muscle bundles contracted in response to electrical pulses and generated a significantly higher physical force. These findings indicate that the incorporation of anti-apoptotic gene-transduced myoblast cells into tissue constructs significantly enhances skeletal muscle formation and function. PMID:23088454

Sato, Masanori; Ito, Akira; Akiyama, Hirokazu; Kawabe, Yoshinori

2013-01-01

166

The Histological and Biological Spectrum of Diffuse Large B-cell Lymphoma in the WHO Classification  

PubMed Central

Diffuse large B cell lymphomas (DLBCL) are aggressive B-cell lymphomas that are clinically, pathologically and genetically diverse, in part reflecting the functional diversity of the B-cell system. The focus in recent years has been towards incorporation of clinical features, morphology, immunohistochemistry and ever evolving genetic data into the classification scheme. The 2008 WHO classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling (GEP) heralded a new era with a focus on pathways of transformation as well as a promise of more targeted therapies, directed at specific pathways. Some DLBCLs exhibit unique clinical characteristics with a predilection for specific anatomic sites; the anatomic site often reflects underlying biological distinctions. Recently, the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression has been better characterized; most of these occur in patients of advanced age, and include EBV-positive large B-cell lymphoma of the elderly. HHV-8 is involved in the pathogenesis of primary effusion lymphoma, which can present as a “solid variant.” Two borderline categories were created; one deals with tumors at the interface between classical Hodgkin lymphoma (cHL) and DLBCL. The second confronts the interface between Burkitt Lymphoma (BL) and DLBCL, so called “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma” in the 2008 classification. Most cases harbor both MYC and BCL2 translocations, and are highly aggressive. Another interesting entity is ALK+ DLBCL, which renders itself potentially targetable by ALK inhibitors. Ongoing investigations at the genomic level, with both exome and whole genome sequencing, are sure to reveal new pathways of transformation in the future. PMID:23006945

Menon, Madhu P.; Pittaluga, Stefania; Jaffe, Elaine S.

2012-01-01

167

Translin binds to the sequences adjacent to the breakpoints of the TLS and CHOP genes in liposarcomas with translocation t(12;16)  

Microsoft Academic Search

Myxoid and round-cell liposarcomas share the translocation t(12;16)(q13;p11) creating the TLS-CHOP fusion gene as a common genetic alteration. We previously reported several unique characteristics of genomic sequences around the breakpoints in the TLS and CHOP loci, and among them was the presence of consensus recognition motifs of Translin, a protein that associates with chromosomal translocations of lymphoid neoplasms. We further

Taisuke Hosaka; Hiroshi Kanoe; Tomitaka Nakayama; Hiroshi Murakami; Hiroshi Yamamoto; Takeharu Nakamata; Tadao Tsuboyama; Masanori Oka; Masataka Kasai; Masao S Sasaki; Takashi Nakamura; Junya Toguchida; J Toguchida

2000-01-01

168

DNA markers closely linked to nematode resistance genes in sugar beet ( Beta vulgaris L.) mapped using chromosome additions and translocations originating from wild beets of the Procumbentes section  

Microsoft Academic Search

Genes conferring resistance to the beet cyst nematode (Heterodera schachtii Schm.) have been transferred to sugar beet (Beta vulgaris L.) from three wild species of the Procumbentes section using monosomic addition and translocation lines, because no meiotic recombination occurs between chromosomes of cultured and wild species. In the course of a project to isolate the nematode resistance genes by strategies

C. Jung; R. Koch; F. Fischer; A. Branded; G. Wrickel; R. G. Herrmann

1992-01-01

169

Analysis of Host Gene Expression Changes Reveals Distinct Roles for the Cytoplasmic Domain of the Epstein-Barr Virus Receptor/CD21 in B-Cell Maturation, Activation, and Initiation of Virus Infection  

PubMed Central

ABSTRACT Epstein-Barr virus (EBV) attachment to human CD21 on the B-cell surface initiates infection. Whether CD21 is a simple tether or conveys vital information to the cell interior for production of host factors that promote infection of primary B cells is controversial, as the cytoplasmic fragment of CD21 is short, though highly conserved. The ubiquity of CD21 on normal B cells, the diversity of this population, and the well-known resistance of primary B cells to gene transfer technologies have all impeded resolution of this question. To uncover the role(s) of the CD21 cytoplasmic domain during infection initiation, the full-length receptor (CD21 = CR), a mutant lacking the entire cytoplasmic tail (CT), and a control vector (NEO) were stably expressed in two pre-B-cell lines that lack endogenous receptor. Genome-wide transcriptional analysis demonstrated that stable CD21 surface expression alone (either CR or CT) produced multiple independent changes in gene expression, though both dramatically decreased class I melanoma-associated antigen (MAGE) family RNAs and upregulated genes associated with B-cell differentiation (e.g., C2TA, HLA-II, IL21R, MIC2, CD48, and PTPRCAP/CD45-associated protein). Temporal analysis spanning 72 h revealed that not only CR- but also CT-expressing lines initiated latency. In spite of this, the number and spectrum of transcripts altered in CR- compared with CT-bearing lines at 1 h after infection further diverged. Differential modulation of immediate early cellular transcripts (e.g., c-Jun and multiple histones), both novel and previously linked to CD21-initiated signaling, as well as distinct results from pathway analyses support a separate role for the cytoplasmic domain in initiation of intracellular signals. IMPORTANCE Membrane proteins that mediate virus attachment tether virus particles to the cell surface, initiating infection. In addition, upon virus interaction such proteins may transmit signals to the interior of the cell that support subsequent steps in the infection process. Here we show that expression of the Epstein-Barr virus B-cell attachment receptor, CD21, in B cells that lack this receptor results in significant changes in gene expression, both before and rapidly following EBV-CD21 interaction. These changes translate into major signaling pathway alterations that are predicted to support stable infection. PMID:24600013

Arredouani, Mohamed S.; Bhasin, Manoj K.; Sage, David R.; Dunn, Laura K.; Gill, Michael B.; Agnani, Deep; Libermann, Towia A.

2014-01-01

170

Evaluation of the NOD/SCID xenograft model for glucocorticoid-regulated gene expression in childhood B-cell precursor acute lymphoblastic leukemia  

PubMed Central

Background Glucocorticoids such as prednisolone and dexamethasone are critical drugs used in multi-agent chemotherapy protocols used to treat acute lymphoblastic leukemia (ALL), and response to glucocorticoids is highly predictive of outcome. The NOD/SCID xenograft mouse model of ALL is a clinically relevant model in which the mice develop a systemic leukemia which retains the fundamental biological characteristics of the original disease. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Cells from a glucocorticoid-sensitive xenograft derived from a child with B-cell precursor ALL were inoculated into NOD/SCID mice. When highly engrafted the mice were randomized into groups of 4 to receive dexamethasone 15 mg/kg by intraperitoneal injection or vehicle control. Leukemia cells were harvested from mice spleens at 0, 8, 24 or 48 hours thereafter, and gene expression analyzed on Illumina WG-6_V3 chips, comparing all groups to time 0 hours. Results The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes, with fewer observed at the 24 and 48 hour timepoints, and with minimal changes seen across the time-matched controls. When compared to publicly available datasets of glucocorticoid-induced gene expression from an in vitro cell line study and from an in vivo study of patients with ALL, at the level of pathways, expression changes in the 8 hour xenograft samples showed a similar response to patients treated with glucocorticoids. Replicate analysis revealed that at the 8 hour timepoint, a dataset with high signal and differential expression, using data from 3 replicates instead of 4 resulted in excellent recovery scores of > 0.9. However at other timepoints with less signal very poor recovery scores were obtained with 3 replicates. Conclusions The NOD/SCID xenograft mouse model provides a reproducible experimental system in which to investigate clinically-relevant mechanisms of drug-induced gene regulation in ALL; the 8 hour timepoint provides the highest number of significantly differentially expressed genes; time-matched controls are redundant and excellent recovery scores can be obtained with 3 replicates. PMID:22093874

2011-01-01

171

Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours  

Microsoft Academic Search

EWING'S sarcoma and related subtypes of primitive neuroectodermal tumours share a recurrent and specific t(ll;22) (q24;q12) chromosome translocation1-8, the breakpoints of which have recently been cloned9. Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions

Olivier Delattre; Jessica Zucman; Béatrice Plougastel; Chantal Desmaze; Thomas Melot; Martine Peter; Heinrich Kovar; Isabelle Joubert; Pieter de Jong; Guy Rouleau; Alain Aurias; Gilles Thomas

1992-01-01

172

An unbalanced translocation unmasks a recessive mutation in the follicle-stimulating hormone receptor (FSHR) gene and causes FSH resistance  

PubMed Central

Follicle-stimulating hormone (FSH) mediated by its receptor (FSHR) is pivotal for normal gametogenesis. Inactivating FSHR mutations are known to cause hypergonadotropic hypogonadism with disturbed follicular maturation in females. So far, only very few recessive point mutations have been described. We report on a 17-year-old female with primary amenorrhea, hypergonadotropic hypogonadism and disturbed folliculogenesis. Chromosome analysis detected a seemingly balanced translocation 46,XX,t(2;8)(p16.3or21;p23.1)mat. FSHR sequence analysis revealed a novel non-synonymous point mutation in exon 10 (c.1760C>A, p.Pro587His), but no wild-type allele. The mutation was also found in the father, but not in the mother. Furthermore, molecular-cytogenetic analyses of the breakpoint region on chromosome 2 showed the translocation to be unbalanced, containing a deletion with one breakpoint within the FSHR gene. The deletion size was narrowed down by array analysis to approximately 163?kb, involving exons 9 and 10 of the FSHR gene. Functional studies of the mutation revealed the complete lack of signal transduction presumably caused by a changed conformational structure of transmembrane helix 6. To our knowledge, this is the first description of a compound heterozygosity of an inactivating FSHR point mutation unmasked by a partial deletion. This coincidence of two rare changes caused clinical signs consistent with FSH resistance. PMID:20087398

Kuechler, Amla; Hauffa, Berthold P; Koninger, Angela; Kleinau, Gunnar; Albrecht, Beate; Horsthemke, Bernhard; Gromoll, Jorg

2010-01-01

173

B Cell Maturation  

NSDL National Science Digital Library

This Flash animation shows intracellular and extracellular interactions that illustrate the maturation stages of B cells in the bone marrow. It uses sound and mouse-over identification to help students learn more and retain the information.

American Society For Microbiology;

2003-05-12

174

PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor.  

PubMed

The transcription factor PU.1 has been shown to be crucial for the early stages of B cell development but its function at later stages of B cell development is less well known. We observed previously that PU.1 is expressed uniformly throughout the mature pre-plasma cell B cell population, the only exception being a subpopulation of germinal centre (GC) cells which showed exceptionally high expression of PU.1. This suggested that PU.1 may also have a role in GC B cell biology. To test this hypothesis and to screen for possible genes regulated by PU.1, we first evaluated semi-quantitatively the possible co-expression of PU.1 with proteins known to be upregulated or downregulated during GC B cell development. Normal lymphoid tissues and 255 B cell non-Hodgkin lymphomas of putative GC B cell origin were evaluated. PU.1 expression was positively associated with CD10 (p < 0.0001), CD20 (p = 0.043), CD22 (p = 0.005), CD79a (p = 0.024) and Bcl-6 (p < 0.0001) and negatively associated with cytoplasmic immunoglobulin light-chain expression (p = 0.036) in diffuse large B cell lymphoma. Identical or nearly identical associations were found in follicular lymphoma. Since CD20 is known to be partly regulated by PU.1 and putative PU.1-binding sites have been described in the regulatory regions of the CD22, CD79a and CD10 genes, we looked for putative PU.1 binding sites in the BCL6 promotor. Four such putative PU.1 binding sites were identified. Further analysis by gel-shift electromobility essay showed that PU.1 protein binds to three of the four putative binding sites in the BCL6 promotor. PU.1 and Bcl-6 were also found to be upregulated in centroblasts in the normal GC, but jointly downregulated in a subpopulation of centrocytes. Our findings support the contention that PU.1 may also have an important role in GC B cell development. PMID:15892171

Torlakovic, Emina; Malecka, Agnieszka; Myklebust, June H; Tierens, Anne; Aasheim, Hans-Christian; Nesland, Jahn M; Smeland, Erlend; Kvaløy, Stein; Delabie, Jan

2005-07-01

175

EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts.  

PubMed

The genes involved in the t(12;22)(q13;q12) translocation found recurrently in malignant melanoma of soft parts have been characterized and shown to form, in four cases studied, hybrid transcripts. The deduced chimaeric protein encoded by the der(22) chromosome consists of the N-terminal domain of EWS linked to the bZIP domain of ATF-1, a transcription factor which may normally be regulated by cAMP. ATF-1 has not previously been implicated in oncogenesis. EWS was first identified as forming a hybrid transcript in Ewing's sarcoma, which links its N-terminal domain to the DNA binding domain of the FLI-1 gene. Thus the oncogenic conversion of EWS follows a common scheme of activation, exchanging its putative RNA binding domain with different DNA binding domains that appear to be tumour-specific. PMID:8401579

Zucman, J; Delattre, O; Desmaze, C; Epstein, A L; Stenman, G; Speleman, F; Fletchers, C D; Aurias, A; Thomas, G

1993-08-01

176

Evidence for a wide occurrence of proton-translocating pyrophosphatase genes in parasitic and free-living protozoa.  

PubMed

Proton-translocating inorganic pyrophosphatases (H(+)-PPase, EC 3.6.1.1) are integral membrane proteins that have been extensively studied in higher plants, the photosynthetic bacterium Rhodospirillum rubrum and, more recently, in some human pathogenic protozoa. By using a PCR-based approach, fragments of genes coding for H(+)-PPases in a number of protists, both free-living and parasites of animals and plants, that belong to diverse taxonomic groups (trypanosomatids, ciliates, apicomplexans, euglenoids, amoeboid mycetozoa, heterokonts) have been isolated. The experimental procedure involved the use of degenerate oligonucleotides designed from protein domains conserved in H(+)-PPases from plants and bacteria. The PCR-amplified DNA fragments exhibited the characteristic genomic structure and codon usage of the corresponding protozoan group. Paralogous genes were found in some species suggesting the occurrence of protein isoforms. These results indicate that H(+)-PPases are more widely distributed among protozoa than previously thought. PMID:12056804

Pérez-Castiñeira, José R; Alvar, Jorge; Ruiz-Pérez, Luis M; Serrano, Aurelio

2002-06-14

177

Promiscuity of translocation partners in multiple myeloma.  

PubMed

Multiple myeloma (MM) is characterized by karyotypic instability, including chromosomal translocations involving the IGH locus. MM cells display a promiscuity of translocation partners, only some of which are recurrent. We propose that several factors, including temporal and spatial nuclear positioning of potential partner loci, "off-target" IGH diversification mechanisms, and aberrant repair pathways contribute to the promiscuity of translocation partners in MM. We speculate that in MM, IGH diversification processes [V(D)J recombination, somatic hypermutation, and class switch recombination] in B cells may not be restricted to specific stages of B-cell development or within specific immune tissues, but may occur in different temporal "windows." Before or during MM evolution, off-target activities of the enzymes involved in IGH modification processes may contribute to the generation of double-strand breaks (DSB) in translocation partner loci. In the parent B cells from which MM originates, spatial proximity within the nucleus of IGH and potential translocation partners contributes to the selection of a translocation partner and the clinical frequency at which a specific translocation occurs. The spatial proximity of IGH and specific translocation partners may be temporal and contribute not only to partner selection but also to the promiscuity of partners seen in MM. Lastly, aberrant repair mechanisms in MM progenitors (including the possibility that a Ku 86 variant allows for positional instability at DSBs) may also contribute to the promiscuity of chromosome translocation partners in MM. PMID:20127714

Martin, Lorri D; Belch, Andrew R; Pilarski, Linda M

2010-04-15

178

Distinguishing primary and secondary translocations in multiple myeloma.  

PubMed

Multiple myeloma (MM) is a malignant post-germinal center tumor of somatically-mutated, isotype-switched plasma cells that accumulate in the bone marrow. It often is preceded by a stable pre-malignant tumor called monoclonal gammopathy of undetermined significance (MGUS), which can sporadically progress to MM. Five recurrent primary translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 have been identified in MGUS and MM tumors. The five partner loci include 11q13, 6p21, 4p16, 16q23, and 20q12, with corresponding dysregulation of CYCLIN D1, CYCLIN D3, FGFR3/MMSET, c-MAF, and MAFB, respectively, by strong enhancers in the IgH locus. The five recurrent translocations, which are present in 40% of MM tumors, typically are simple reciprocal translocations, mostly having breakpoints within or near IgH switch regions but sometimes within or near VDJ or JH sequences. It is thought that these translocations are caused by aberrant IgH switch recombination, and possibly by aberrant somatic hypermutation in germinal center B cells, thus providing an early and perhaps initiating event in transformation. A MYC gene is dysregulated by complex translocations and insertions as a very late event during the progression of MM tumors. Since the IgH switch recombination and somatic hypermutation mechanism are turned off in plasma cells and plasma cell tumors, the MYC rearrangements are thought to be mediated by unknown mechanisms that contribute to structural genomic instability in all kinds of tumors. These rearrangements, which often but not always juxtapose MYC near one of the strong immunoglobulin enhancers, provide a paradigm for secondary translocations. It is hypothesized that secondary translocations not involving a MYC gene can occur at any stage of tumorigenesis, including in pre-malignant MGUS tumor cells. PMID:16829212

Gabrea, Ana; Leif Bergsagel, P; Michael Kuehl, W

2006-09-01

179

Spin90 deficiency increases CXCL13-mediated B cell migration.  

PubMed

SPIN90 regulates actin dynamics, which is important for cell migration control. CXCL13-mediated B cell migration is essential for B cell immune responses. In this study, we investigated the role of SPIN90 in CXCL13-mediated B cell migration using Spin90 gene-deficient mice. Our chemokinesis analysis and transwell cell migration assay showed that SPIN90 is involved in CXCL13-mediated B cell migration. Moreover, the level of CXCR5, which is CXCL13 receptor, was increased in SPIN90-deficient B cells compared with wild-type B cells. Overall, our data suggest that SPIN90 plays an important role in B cell immune responses through the regulation of CXCL13-mediated B cell migration. PMID:24965518

Park, S-H; Kim, H-R; Jun, C-D; Song, W K; Park, S-G

2014-09-01

180

Primary Mediastinal (Thymic) B-Cell Lymphoma Is Characterized by Gains of Chromosomal Material Including 9p and Amplification of the REL Gene  

Microsoft Academic Search

RIMARY MEDIASTINAL (thymic) B-cell lymphoma is a tumor with clinical, immunologic, and histologic features that, in their combination, are quite unique. It occurs in all age groups but predominates in young ad~1ts.l.~ Typi- cally, it is localized in the anterior mediastinum, and a thymic involvement has been repeatedly shown. Accordingly, it is assumed that this B-cell lymphoma is a primary

Stefan Joos; Marta I. Otafio-Joos; Susanne Ziegler; Silke Bruderlein; Martin Bentz; Peter Moller; Peter Lichter

1996-01-01

181

Translocation-Capture Sequencing Reveals the Extent and Nature of Chromosomal Rearrangements in B Lymphocytes  

PubMed Central

Summary Chromosomal rearrangements, including translocations, require formation and joining of DNA double strand breaks (DSBs). These events disrupt the integrity of the genome and are frequently involved in producing leukemias, lymphomas and sarcomas. Despite the importance of these events, current understanding of their genesis is limited. To examine the origins of chromosomal rearrangements we developed Translocation Capture Sequencing (TC-Seq), a method to document chromosomal rearrangements genome-wide, in primary cells. We examined over 180,000 rearrangements obtained from 400 million B lymphocytes, revealing that proximity between DSBs, transcriptional activity and chromosome territories are key determinants of genome rearrangement. Specifically, rearrangements tend to occur in cis and to transcribed genes. Finally, we find that activation-induced cytidine deaminase (AID) induces the rearrangement of many genes found as translocation partners in mature B cell lymphoma. PMID:21962510

Klein, Isaac A.; Resch, Wolfgang; Jankovic, Mila; Oliveira, Thiago; Yamane, Arito; Nakahashi, Hirotaka; Di Virgilio, Michela; Bothmer, Anne; Nussenzweig, Andre; Robbiani, Davide F.; Casellas, Rafael; Nussenzweig, Michel C.

2011-01-01

182

A phylogeny of the temperate seabasses (Moronidae) characterized by a translocation of the mt-nd6 gene.  

PubMed

The entire mitochondrial genome of the striped bass Morone saxatilis was sequenced together with the mitochondrial (mt) control regions of the white bass Morone chrysops, white perch Morone americana, yellow bass Morone mississippiensis, spotted seabass Dicentrarchus punctatus, European seabass Dicentrarchus labrax and the Japanese seabass Lateolabrax japonicus. The resultant 17 580 base pair circular genome of M. saxatilis contains 38 genes (13 proteins, 23 transfer RNAs and two ribosomal RNAs) and a control region bordered by the proline and phenylalanine mitochondrial tRNAs. Gene arrangement was similar to other vertebrates, except that the mt-nd6 gene was found within the control region rather than the canonical position between the mt-nd5 and mt-cyb genes. This translocation was found in all the Morone and Dicentrarchus species studied without functional copies or pseudogenes in the ancestral position. In L. japonicus, the mt-nd6 gene was found in the canonical position without evidence of an mt-nd6 gene in the control region. A Bayesian analysis of these and published mt-nd6 sequences from 45 other Perciformes grouped the Morone and Dicentrarchus species monophyletically with a probability of 1·00 with respect to L. japonicus and all other perciforms, and placed the Dicentrarchus species in the basal position. These data reinforce current placement of L. japonicus outside the Moronidae and provide a clear evolutionary character to define this family. The phylogeny of the Moronidae presented here also supports the hypothesis of an anadromous common ancestor to this family that gave rise to the North American estuarine and freshwater species. A series of tandem repeats previously reported in M. saxatilis was found in the control region of all Morone species between the mt-nd6 and mt-rnr1 genes, but not in either Dicentrarchus species, which reinforces the continued use of these two separate genera. PMID:22220893

Williams, E P; Peer, A C; Miller, T J; Secor, D H; Place, A R

2012-01-01

183

Cooperation of Six and Eya in Activation of Their Target Genes through Nuclear Translocation of Eya  

Microsoft Academic Search

Drosophila sine oculis and eyes absent genes synergize in compound-eye formation. The murine homologues of these genes, Six and Eya, respectively, show overlapping expression patterns during development. We hypothesized that Six and Eya proteins cooperate to regulate their target genes. Cotransfection assays were performed with various combinations of Six and Eya to assess their effects on a potential natural target,

HIROMI OHTO; SAYAKA KAMADA; KENJI TAGO; SHIN-ICHI TOMINAGA; HIDENORI OZAKI; SHIGERU SATO; KIYOSHI KAWAKAMI

1999-01-01

184

Reversing B cell aging  

PubMed Central

Age-related alterations in the cellular composition of the B lineage are a major cause of the poor antibody response to vaccination and to infectious agents among the elderly population. The mechanisms leading to these changes are poorly understood. Recently, we have shown that these changes reflect, at least in part, homeostatic pressures imposed by long-lived B cells that accumulate with aging, and that aging in the B lineage can be reversed upon alteration of B cell homeostasis by depletion. Here we discuss homeostatic causes for B lineage immunosenescence, and the potential for its rejuvenation. PMID:21483035

Mehr, Ramit; Melamed, Doron

2011-01-01

185

Cytoprotective effect of kaempferol on paraquat-exposed BEAS-2B cells via modulating expression of MUC5AC.  

PubMed

Mucins are highly glycosylated secretary proteins produced by most epithelial cells. Hypersecretion of mucins is one of the prominent symptoms of several airway diseases, including asthma, cystic fibrosis, nasal allergy, rhinitis, and sinusitis. Paraquat (PQ), a common herbicide, has been associated with pulmonary damage and is a potent reactive oxygen species (ROS) producer. However, until now the role of PQ on mucin overproduction has not been studied. The aim of this study is to explore how kaempferol (KM), a widely used dietary flavonoid, affects the protection of human PQ-exposed bronchial epithelium BEAS-2B cells by suppressing Mucin gene expression via nuclear factor-kappa B (NF-?B). We observed that PQ generates intracellular ROS, and also induces lipid peroxidation in BEAS-2B cells. Additionally, we found that PQ effectively induces the expression of the MUC5AC gene; however, co-treatment of PQ with KM drastically reduces its expression. Furthermore, we observed that PQ activates NF-?B, while co-treatment with KM occludes its nuclear translocation, and additionally KM repressed the PQ phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in BEAS-2B cells. Based on our data, we believe that KM can suppress the over-expression of the MUC5AC gene. This would contribute to the protection of PQ cytotoxicity to exposed BEAS-2B cells, and allow further study toward a better understanding of ROS-associated diseases. PMID:25177032

Podder, Biswajit; Song, Kyoung Seob; Song, Ho-Yeon; Kim, Yong-Sik

2014-01-01

186

Identification of COL3A1 and RAB2A as novel translocation partner genes of PLAG1 in lipoblastoma.  

PubMed

Lipoblastoma is a rapidly growing, benign neoplasm in children. Surgical excision is usually curative, with a recurrence rate of about 20%. Because the histology of lipoblastoma is heterogeneous and overlaps with other lipomatous tumors, some lipoblastoma cases have been difficult to diagnose. The detection of PLAG1 gene rearrangement is useful for the diagnosis of lipoblastoma. Three fusion partner genes are known in relation to PLAG1 in lipoblastoma HAS2 at 8q24.1, COL1A2 at 7q22, and RAD51L1 at 14q24. Herein, we describe another two novel fusion genes in lipoblastoma tumor specimens. We checked six tumors for the presence of two known fusion genes, HAS2-PLAG1 and COL1A2-PLAG1. Only HAS2-PLAG1 was found in one of the cases. Next, we attempted to identify potential PLAG1 fusion partners using 5'RACE. Sequence analysis revealed two novel fusion genes, COL3A1-PLAG1 in three cases and RAB2A-PLAG1 in one case, respectively. As a result of the translocations, the constitutively active promoter of the partner gene drives the ectopic expression of PLAG1. We also evaluated whether a high level of PLAG1 expression can be used to help differentiate lipomatous tumors. PLAG1 expression was evaluated by real-time PCR in five lipoblastoma tumor specimens. The expressions were 70-150 times higher in lipoblastomas than in human adipocytes. However, PLAG1 expression was low in one case of lipoma. These results demonstrate that PLAG1 overexpression is a potential marker of lipoblastoma. Our findings, in agreement with previous studies, show that lipoblastoma is a group of lipomatous tumors with PLAG1 rearrangement and overexpression. © 2014 Wiley Periodicals, Inc. PMID:24700772

Yoshida, Hideki; Miyachi, Mitsuru; Ouchi, Kazutaka; Kuwahara, Yasumichi; Tsuchiya, Kunihiko; Iehara, Tomoko; Konishi, Eiichi; Yanagisawa, Akio; Hosoi, Hajime

2014-07-01

187

The expression of 16 genes related to the cell of origin and immune response predicts survival in elderly patients with diffuse large B-cell lymphoma treated with CHOP and rituximab  

Microsoft Academic Search

Gene expression profiles have been associated with clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-containing chemotherapy. Using Affymetrix HU133A microarrays, we analyzed the lymphoma transcriptional profile of 30 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 23 patients treated with rituximab (R)-CHOP in the Groupe d'Etude des Lymphomes de l'Adulte clinical centers. We used

J-P Jais; C Haioun; T J Molina; D S Rickman; A de Reynies; F Berger; C Gisselbrecht; J Brière; F Reyes; P Gaulard; P Feugier; E Labouyrie; H Tilly; C Bastard; B Coiffier; G Salles; K Leroy

2008-01-01

188

Chromosome translocations: Dangerous liaisons  

Microsoft Academic Search

Many chromosome abnormalities, especially translocations or inversions, are closely associated with a particular morphologic or phenotypic subtype of leukemia, lymphoma, or sarcoma. Cloning the genes at the breakpoints of these rearrangements has provided critical tools for more-precise diagnosis; in some cases the particular diagnosis has prognostic implications. In addition, many of the genes had not been previously identified; their discovery

Janet D. Rowley

1998-01-01

189

Identification and mapping of molecular markers linked to rust resistance genes located on chromosome 1RS of rye using wheat-rye translocation lines  

Microsoft Academic Search

The short arm of rye (Secale cereale) chromosome 1 has been widely used in breeding programs to incorporate new disease resistance genes into wheat. Using wheat-rye translocation and recombinant lines, molecular markers were isolated and mapped within chromosomal regions of 1RS carrying rust resistance genes Lr26, Sr31, Yr9 from 'Petkus' and SrR from 'Imperial' rye. RFLP markers previously mapped to

R. Mago; W. Spielmeyer; G. Lawrence; E. Lagudah; J. Ellis; A. Pryor

2002-01-01

190

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.  

PubMed

The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q. PMID:24398325

Salaverria, Itziar; Martin-Guerrero, Idoia; Wagener, Rabea; Kreuz, Markus; Kohler, Christian W; Richter, Julia; Pienkowska-Grela, Barbara; Adam, Patrick; Burkhardt, Birgit; Claviez, Alexander; Damm-Welk, Christine; Drexler, Hans G; Hummel, Michael; Jaffe, Elaine S; Küppers, Ralf; Lefebvre, Christine; Lisfeld, Jasmin; Löffler, Markus; Macleod, Roderick A F; Nagel, Inga; Oschlies, Ilske; Rosolowski, Maciej; Russell, Robert B; Rymkiewicz, Grzegorz; Schindler, Detlev; Schlesner, Matthias; Scholtysik, René; Schwaenen, Carsten; Spang, Rainer; Szczepanowski, Monika; Trümper, Lorenz; Vater, Inga; Wessendorf, Swen; Klapper, Wolfram; Siebert, Reiner

2014-02-20

191

The product of the Herpes simplex virus 1 UL7 gene interacts with a mitochondrial protein, adenine nucleotide translocator 2  

PubMed Central

The herpes simplex virus 1 (HSV-1) UL7 gene is highly conserved among herpesviridae. Since the construction of recombinant HSV-1 with a mutation in the UL7 gene has not been reported, the involvement of HSV-1 UL7 in viral replication has been unclear. In this study, we succeeded in generating a UL7 null HSV-1 mutant virus, MT102, and characterized it. Our results were as follows. (i) In Vero cells, MT102 was replication-competent, but formed smaller plaques and yielded 10- to 100-fold fewer progeny than the wild-type virus, depending on the multiplicity of infection. (ii) Using mass spectrometry-based proteomics technology, we identified a cellular mitochondrial protein, adenine nucleotide translocator 2 (ANT2), as a UL7-interacting partner. (iii) When ANT2 was transiently expressed in COS-7 cells infected with HSV-1, ANT2 was specifically co-precipitated with UL7. (iv) Cell fractionation experiments with HSV-1-infected cells detected the UL7 protein in both the mitochondrial and cytosolic fractions, whereas ANT2 was detected only in the mitochondrial fraction. These results indicate the importance of HSV-1 UL7's involvement in viral replication and demonstrate that it interacts with ANT2 in infected cells. The potential biological significance of the interaction between UL7 and ANT2 is discussed. PMID:18940012

Tanaka, Michiko; Sata, Tetsutaro; Kawaguchi, Yasushi

2008-01-01

192

ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements.  

PubMed

ALK-positive large B-cell lymphoma is an aggressive lymphoid neoplasm characterized by a monomorphic proliferation of immunoblast-like cells expressing a plasmablastic phenotype and carrying ALK rearrangements. MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown. MYC expression is downregulated by BLIMP1, a master modulator of plasma cell differentiation. BLIMP1 and MYC are upregulated by STAT3, a signal transducer activated by ALK. To determine the role of BLIMP1, MYC and STAT3 in the pathogenesis of ALK-positive large B-cell lymphomas, we investigated MYC rearrangement and the expression of MYC, phosphorylated STAT3, BLIMP1, PAX5 and XBP1 in 12 ALK-positive large B-cell lymphomas. All cases expressed ALK with a granular cytoplasmic pattern. Nine cases had a split signal consistent with an ALK rearrangement. Three additional cases showed a deletion of the 5' or 3' end of the ALK probe consistent with cryptic translocation. PAX5 was virtually negative in all cases tested, whereas BLIMP1 was expressed in all tumors and XBP1 in 11 of 12. Phosphorylated STAT3 was observed in all cases with a strong and diffuse nuclear pattern. MYC rearrangements were not identified in any tumor, but MYC gains and amplification were detected in six cases and one case, respectively. MYC protein was expressed in all tumors independently of MYC gene alterations. These results indicate that ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but, contrary to plasmablastic lymphomas, do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression in these tumors. The relevance of the ALK/STAT3 pathway in the pathogenesis of ALK-positive large B-cell lymphomas may offer an attractive target for new therapies. PMID:23599149

Valera, Alexandra; Colomo, Lluis; Martínez, Antonio; de Jong, Daphne; Balagué, Olga; Matheu, Gabriel; Martínez, Mónica; Taddesse-Heath, Lekidelu; Jaffe, Elaine S; Bacchi, Carlos E; Campo, Elías

2013-10-01

193

Dissecting teleost B cell differentiation using transcription factors.  

PubMed

B cell developmental pathways in teleost fishes are poorly understood. In the absence of serological reagents, an alternative approach to dissecting teleost B cell development is to use transcription factors that are differentially expressed during B cell development. This review discusses the structure and function of six transcription factors that play essential roles during teleost B cell development: Ikaros, E2A, EBF, Pax5, Blimp1, and XbpI. Research on alternative splicing of both the Ikaros and Pax5 genes in rainbow trout is presented, including their functional significance. An application is discussed that should aid in elucidating teleost B cell development and activation, by using transcription factors as developmental markers in flow cytometric analysis. Possible future studies in teleost B cell development are suggested in the context of gene regulation. Lastly, broader impacts and practical applications are discussed. PMID:21251922

Zwollo, Patty

2011-09-01

194

Lon protease inactivation, or translocation of the lon gene, potentiate bacterial evolution to antibiotic resistance.  

PubMed

Previous work demonstrated that selection for Escherichia coli mutants with low antibiotic resistance frequently resulted in co-selection of lon mutations and that lon(-) mutants evolved higher-level resistance faster than a lon(+) strain. Here we show that lon mutation causes a very low multidrug resistance by inducing the AcrAB-TolC pump via stabilization of the acrAB transcriptional activators MarA and SoxS, which are substrates of the Lon protease. Fast evolution of lon(-) mutants towards higher resistance involves selection of frequent next-step mutations consisting of large duplications including acrAB and the mutated lon gene. Resistance results from the combined effects of acrAB duplication and lon mutation increasing dosage of efflux pump. In contrast, when acrAB duplication occurs as the first step mutation, increased Lon activity caused by lon(+) co-duplication mitigates the effect of acrAB duplication on resistance, and faster evolution towards higher resistance is not observed. As predicted, when the functional lon gene is relocated far from acrAB to prevent their co-duplication, first-step acrAB duplication confers higher resistance, which then allows selection of frequent next-step mutations and results in faster evolution towards higher resistance. Our results demonstrate how order of appearance of mutations and gene location can influence the rate of resistance evolution. PMID:24325250

Nicoloff, Hervé; Andersson, Dan I

2013-12-01

195

Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders. Implications for lymphomagenesis  

PubMed Central

AIDS (acquired immune deficiency syndrome) and ARC (AIDS-related complex) are associated with a spectrum of lymphoproliferative disorders ranging from lymphadenopathy syndrome (LAS), an apparently benign polyclonal lymphoid hyperplasia, to B cell non-Hodgkin's lymphoma (B-NHL), i.e., malignant, presumably monoclonal B cell proliferations. To gain insight into the process of lymphomagenesis in AIDS and to investigate a possible pathogenetic relationship between LAS and NHL, we investigated the clonality of the B or T lymphoid populations by Ig or T beta gene rearrangement analysis, the presence of rearrangements involving the c-myc oncogene locus, and the presence of human immunodeficiency virus (HIV) sequences in both LAS and B-NHL biopsies. Our data indicate that multiple clonal B cell expansions are present in a significant percentage of LAS (approximately 20%) and B- NHL (60%) biopsies. c-myc rearrangements/translocations are detectable in 9 of our 10 NHLs, but not in any of the LAS cases. However, only one of the B cell clones, identified by Ig gene rearrangements carries a c- myc gene rearrangement, suggesting that only one clone carries the genetic abnormality associated with malignant B cell lymphoma. Furthermore, the frequency of detection of c-myc rearrangements in AIDS- associated NHLs of both Burkitt and non-Burkitt type suggest that the biological alterations present in AIDS favor the development of lymphomas carrying activated c-myc oncogenes. Finally, our data show that HIV DNA sequences are not detectable in LAS nor in NHL B cell clones, suggesting that HIV does not play a direct role in NHL development. Taken together, these observations suggest a model of multistep lymphomagenesis in AIDS in which LAS would represent a predisposing condition to NHL. Immunosuppression and EBV infection present in LAS can favor the expansion of B cell clones, which in turn may increase the probability of occurrence of c-myc rearrangements leading to malignant transformation. PMID:3491176

1986-01-01

196

B Cell Aortic Homing and Atheroprotection Depend on Id3  

PubMed Central

Rationale B cells are abundant in the adventitia of normal and diseased vessels. Yet, the molecular and cellular mechanisms mediating homing of B cells to the vessel wall and B cell effects on atherosclerosis are poorly understood. Inhibitor of Differentiation-3 (Id3), is important for atheroprotection in mice and polymorphism in the human ID3 gene has been implicated as a potential risk marker of atherosclerosis in humans. Yet the role of Id3 in B cell regulation of atherosclerosis is unknown. Objective To determine if Id3 regulates B cell homing to the aorta and atheroprotection, and identify molecular and cellular mechanisms mediating this effect. Methods and Results Loss of Id3 in Apoe?/? mice resulted in early and increased atherosclerosis. Flow cytometry revealed a defect in Id3?/? Apoe?/? mice in the number of B cells in the aorta, but not the spleen, lymph nodes and circulation. Similarly, B cells transferred from Id3?/? Apoe?/? mice into B cell deficient micereconstituted spleen, lymph node and blood similarly to B cells from Id3+/+ Apoe?/? mice, but aortic reconstitution and B cell-mediated inhibition of diet-induced atherosclerosis was significantly impaired. In addition to retarding initiation of atherosclerosis, B cells homed to regions of existing atherosclerosis, reduced macrophage content in plaque and attenuated progression of disease. The chemokine receptor, CCR6, was identified as an important Id3 target mediating aortic homing and atheroprotection. Conclusions Together, these results are the first to identify the Id3-CCR6 pathway in B cells and demonstrate its role in aortic B cell homing and B cell mediated protection from early atherosclerosis. PMID:22034493

Doran, Amanda C.; Lipinski, Michael J.; Oldham, Stephanie N.; Garmey, James C.; Campbell, Kirsti A.; Skaflen, Marcus D.; Cutchins, Alexis; Lee, Daniel J.; Glover, David K.; Kelly, Kimberly A.; Galkina, Elena V.; Ley, Klaus; Witztum, Joseph L.; Tsimikas, Sotirios; Bender, Timothy P.; McNamara, Coleen A.

2011-01-01

197

In vivo control of B-cell survival and antigen-specific B-cell responses.  

PubMed

Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes controlling B-cell survival and responsiveness, but also from the manipulation of antigen specificity made possible by targeting endogenous immunoglobulin loci. In this review, we discuss recent results obtained from our laboratory using gene-targeted mouse models to investigate the in vivo regulation of B-cell survival and responsiveness. The control of BAFF-dependent survival signals by the TRAF2- and TRAF3-signaling proteins is discussed as is the potential involvement of these molecules in B-lineage malignancies. We also outline the development and use of the SW(HEL) model for analyzing antigen-specific B-cell responses in vivo. This includes insights into the control of early decision-making during T-dependent B-cell differentiation, the affinity maturation and plasma cell differentiation of germinal center B cells, and the identification of EBI2 as a key regulator of B-cell migration and differentiation. PMID:20727031

Chan, Tyani D; Gardam, Sandra; Gatto, Dominique; Turner, Vivian M; Silke, John; Brink, Robert

2010-09-01

198

Targeted Deletion of the Gene Encoding the La Autoantigen (Sjögren's Syndrome Antigen B) in B Cells or the Frontal Brain Causes Extensive Tissue Loss  

PubMed Central

La antigen (Sjögren's syndrome antigen B) is a phosphoprotein associated with nascent precursor tRNAs and other RNAs, and it is targeted by autoantibodies in patients with Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Increased levels of La are associated with leukemias and other cancers, and various viruses usurp La to promote their replication. Yeast cells (Saccharomyces cerevisiae and Schizosaccharomyces pombe) genetically depleted of La grow and proliferate, whereas deletion from mice causes early embryonic lethality, raising the question of whether La is required by mammalian cells generally or only to surpass a developmental stage. We developed a conditional La allele and used it in mice that express Cre recombinase in either B cell progenitors or the forebrain. B cell Mb1Cre La-deleted mice produce no B cells. Consistent with ?CamKII Cre, which induces deletion in hippocampal CA1 cells in the third postnatal week and later throughout the neocortex, brains develop normally in La-deleted mice until ?5 weeks and then lose a large amount of forebrain cells and mass, with evidence of altered pre-tRNA processing. The data indicate that La is required not only in proliferating cells but also in nondividing postmitotic cells. Thus, La is essential in different cell types and required for normal development of various tissue types. PMID:24190965

Gaidamakov, Sergei; Maximova, Olga A.; Chon, Hyongi; Blewett, Nathan H.; Wang, Hongsheng; Crawford, Amanda K.; Day, Amanda; Tulchin, Natalie; Crouch, Robert J.; Morse, Herbert C.; Blitzer, Robert D.

2014-01-01

199

A case of anaplastic lymphoma kinase-positive large B-cell lymphoma: aspiration cytology findings.  

PubMed

Anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma (LBCL) is a rare subtype of non-Hodgkin B-cell lymphoma that exhibits a more aggressive clinical course and poorer prognosis than the typical diffuse large B-cell lymphoma. In this study, we report the case of a 67-year-old man with left cervical lymph node swelling. Aspiration cytology revealed many clusters of cohesive, large, and solitary cells. The tumor cells had abundant cytoplasm and large round-to-oval nuclei with prominent nucleoli. The Giemsa staining specimens exhibited amorphous global bodies adjacent to some clusters. Histologically, large tumor cells occupied the lymph nodes in a sinusoidal pattern, and immunohistochemically, these cells were cytokeratin-, CD19(-), CD20(-), CD79a(-), CD3(-), CD30(-), CD138(+), IgG(-), IgA(+), and ALK(+). Chromogenic in situ hybridization revealed restricted immunoglobulin light-chain expression. Fluorescent in situ hybridization demonstrated translocation of the ALK gene. The tumor cells were negative for Epstein-Barr virus and human herpesvirus 8. It is important to differentiate ALK+LBCL from metastatic carcinoma and other lymphoma subtypes with similar histological features to ensure a proper treatment strategy and prediction of prognosis. PMID:23457005

Nakatsuka, Shin-ichi; Oku, Kazuko; Nagano, Teruaki; Kimura, Hayato; Hanamoto, Atsushi; Ito, Mahito; Hashimoto, Koji

2014-01-01

200

The Majority of Human Memory B Cells Recognizing RhD and Tetanus Resides in IgM+ B Cells  

PubMed Central

B cell memory to T cell–dependent (TD) Ags are considered to largely reside in class-switched CD27+ cells. However, we previously observed that anti-RhD (D) Igs cloned from two donors, hyperimmunized with D+ erythrocytes, were predominantly of the IgM isotype. We therefore analyzed in this study the phenotype and frequency of D- and tetanus toxoid–specific B cells by culturing B cells in limiting dilution upon irradiated CD40L-expressing EL4.B5 cells and testing the culture supernatant. Most Ag-specific B cells for both TD Ags were found to reside in the IgM-expressing B cells, including CD27? B cells, in both hyperimmunized donors and nonhyperimmunized volunteers. Only shortly after immunization a sharp increase in Ag-specific CD27+IgG+ B cells was observed. Next, B cells were enriched with D+ erythrocyte ghosts and sorted as single cells. Sequencing of IGHV, IGLV, IGKV, and BCL6 genes from these D-specific B cell clones demonstrated that both CD27?IgM+ and CD27+IgM+ B cells harbored somatic mutations, documenting their Ag-selected nature. Furthermore, sequencing revealed a clonal relationship between the CD27?IgM+, CD27+IgM+, and CD27+IgG+ B cell subsets. These data strongly support the recently described multiple layers of memory B cells to TD Ags in mice, where IgM+ B cells represent a memory reservoir which can re-enter the germinal center and ensure replenishment of class-switched memory CD27+ B cells from Ag-experienced precursors. PMID:24965774

Della Valle, Luciana; Dohmen, Serge E.; Verhagen, Onno J. H. M.; Berkowska, Magdalena A.; Vidarsson, Gestur

2014-01-01

201

The majority of human memory B cells recognizing RhD and tetanus resides in IgM+ B cells.  

PubMed

B cell memory to T cell-dependent (TD) Ags are considered to largely reside in class-switched CD27(+) cells. However, we previously observed that anti-RhD (D) Igs cloned from two donors, hyperimmunized with D(+) erythrocytes, were predominantly of the IgM isotype. We therefore analyzed in this study the phenotype and frequency of D- and tetanus toxoid-specific B cells by culturing B cells in limiting dilution upon irradiated CD40L-expressing EL4.B5 cells and testing the culture supernatant. Most Ag-specific B cells for both TD Ags were found to reside in the IgM-expressing B cells, including CD27(-) B cells, in both hyperimmunized donors and nonhyperimmunized volunteers. Only shortly after immunization a sharp increase in Ag-specific CD27(+)IgG(+) B cells was observed. Next, B cells were enriched with D(+) erythrocyte ghosts and sorted as single cells. Sequencing of IGHV, IGLV, IGKV, and BCL6 genes from these D-specific B cell clones demonstrated that both CD27(-)IgM(+) and CD27(+)IgM(+) B cells harbored somatic mutations, documenting their Ag-selected nature. Furthermore, sequencing revealed a clonal relationship between the CD27(-)IgM(+), CD27(+)IgM(+), and CD27(+)IgG(+) B cell subsets. These data strongly support the recently described multiple layers of memory B cells to TD Ags in mice, where IgM(+) B cells represent a memory reservoir which can re-enter the germinal center and ensure replenishment of class-switched memory CD27(+) B cells from Ag-experienced precursors. PMID:24965774

Della Valle, Luciana; Dohmen, Serge E; Verhagen, Onno J H M; Berkowska, Magdalena A; Vidarsson, Gestur; Ellen van der Schoot, C

2014-08-01

202

Invasin of Yersinia pseudotuberculosis activates human peripheral B cells.  

PubMed Central

The Yersinia pseudotuberculosis cell surface-located protein invasin was found to promote binding between the pathogen and resting peripheral B cells via beta 1 integrin receptors (CD29). B cells responded by expressing several activation markers and by growing, In contrast, T cells did not react, although these cells express CD29. An isogenic invA mutant failed to activate B cells. The mutation could be complemented by providing the invA+ gene in trans. Purified invasin alone did not activate B cells, although it was able to block the binding of bacteria to the cells. PMID:8641788

Lundgren, E; Carballeira, N; Vazquez, R; Dubinina, E; Branden, H; Persson, H; Wolf-Watz, H

1996-01-01

203

Attenuation of Recombinant Vesicular Stomatitis Virus-Human Immunodeficiency Virus Type 1 Vaccine Vectors by Gene Translocations and G Gene Truncation Reduces Neurovirulence and Enhances Immunogenicity in Mice?  

PubMed Central

Recombinant vesicular stomatitis virus (rVSV) has shown great potential as a new viral vector for vaccination. However, the prototypic rVSV vector described previously was found to be insufficiently attenuated for clinical evaluation when assessed for neurovirulence in nonhuman primates. Here, we describe the attenuation, neurovirulence, and immunogenicity of rVSV vectors expressing human immunodeficiency virus type 1 Gag. These rVSV vectors were attenuated by combinations of the following manipulations: N gene translocations (N4), G gene truncations (CT1 or CT9), noncytopathic M gene mutations (Mncp), and positioning of the gag gene into the first position of the viral genome (gag1). The resulting N4CT1-gag1, N4CT9-gag1, and MncpCT1-gag1 vectors demonstrated dramatically reduced neurovirulence in mice following direct intracranial inoculation. Surprisingly, in spite of a very high level of attenuation, the N4CT1-gag1 and N4CT9-gag1 vectors generated robust Gag-specific immune responses following intramuscular immunization that were equivalent to or greater than immune responses generated by the more virulent prototypic vectors. MncpCT1-gag1 also induced Gag-specific immune responses following intramuscular immunization that were equivalent to immune responses generated by the prototypic rVSV vector. Placement of the gag gene in the first position of the VSV genome was associated with increased in vitro expression of Gag protein, in vivo expression of Gag mRNA, and enhanced immunogenicity of the vector. These findings demonstrate that through directed manipulation of the rVSV genome, vectors that have reduced neurovirulence and enhanced immunogenicity can be made. PMID:17942549

Cooper, David; Wright, Kevin J.; Calderon, Priscilla C.; Guo, Min; Nasar, Farooq; Johnson, J. Erik; Coleman, John W.; Lee, Margaret; Kotash, Cheryl; Yurgelonis, Irene; Natuk, Robert J.; Hendry, R. Michael; Udem, Stephen A.; Clarke, David K.

2008-01-01

204

Differential Programming of B Cells in AID Deficient Mice  

PubMed Central

The Aicda locus encodes the activation induced cytidine deaminase (AID) and is highly expressed in germinal center (GC) B cells to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes. Besides these Ig specific activities in B cells, AID has been implicated in active DNA demethylation in non-B cell systems. We here determined a potential role of AID as an epigenetic eraser and transcriptional regulator in B cells. RNA-Seq on different B cell subsets revealed that Aicda?/? B cells are developmentally affected. However as shown by RNA-Seq, MethylCap-Seq, and SNP analysis these transcriptome alterations may not relate to AID, but alternatively to a CBA mouse strain derived region around the targeted Aicda locus. These unexpected confounding parameters provide alternative, AID-independent interpretations on genotype-phenotype correlations previously reported in numerous studies on AID using the Aicda?/? mouse strain. PMID:23922811

Hogenbirk, Marc A.; Heideman, Marinus R.; Velds, Arno; van den Berk, Paul CM.; Kerkhoven, Ron M.; van Steensel, Bas; Jacobs, Heinz

2013-01-01

205

The 3; 21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER 1  

SciTech Connect

In the 8;21 translocation, the AML1 gene, located at chromosome band 21q22, is translocated to chromosome 8 (q22), where it is fused to the ETO gene and transcribed as a chimeric gene. AML1 is the human homolog of the recently cloned mouse gene pebp2[alpha]B, homologous to the DNA binding [alpha] subunit of the polyoma enhancer factor pebp2. AML1 is also involved in a translocation with chromosome 3 that is seen in patients with therapy-related acute myeloid leukemia and myelodysplastic syndrome and in chronic myelogenous leukemia in blast crisis. The authors have isolated a fusion cDNA clone from a t(3;21) library derived from a patient with therapy-related myelodysplastic syndrome; this clone contains sequences from AML1 and from EAP, which have now been localized to ban 3q26. EAP has previously been characterized as a highly expressed small nuclear protein of 128 residues (EBER 1) associated with Epstein-Barr virus small RNA. The fusion clone contains the DNA binding 5[prime] part of AML1 that is fused to ETO in the t(8;21) and, in addition, at least one other exon. The translocation replaces the last nine codons of AML1 with the last 96 codons of EAP. The fusion does not maintain the correct reading frame of EAP and may not lead to a functional chimeric protein. 23 refs., 6 figs.

Nucifora, G.; Begy, C.R.; Rowley, J.D. (Univ. of Chicago, IL (United States)); Erickson, P.; Drabkin, H.A. (Univ. of Colorado Health Sciences Center, Denver, CO (United States))

1993-08-15

206

Usefulness of long-distance inverse polymerase chain reaction for molecular detection of 14q32 translocation in a clinical setting.  

PubMed

All mature B-cell leukaemias and lymphomas have a clonal Ig gene recombination, and half of them have a reciprocal chromosomal translocation involving the 14q32 locus. The 14q32 translocation partners are variable, such as BCL-2, BCL-1 and BCL-6, thus accounting for the difficulty in molecular detection by the current genomic polymerase chain reaction (PCR) method. To identify B-cell clones efficiently with an Ig gene rearrangement and reciprocal inter-chromosomal translocation, we verified the usefulness, in a practical laboratory setting, of our modified long-distance inverse (LDI) PCR method for detecting IgH gene rearrangements involving inter- and intra-chromosomal segments. The total run time of this LDI PCR method was 5.5 h. Using 24 samples of mature B-cell leukaemias and lymphomas, the modified LDI PCR gave clonally rearranged amplicons in 83 % (20/24) of cases. Direct sequencing results of the amplicons revealed inter-chromosomal translocations in 5 cases (25 %) and intra-chromosomal rearrangements in the remaining 15 cases (75 %). The partners of the inter-chromosomal translocation consisted of the 11q13.3 segment containing a partial BCL1 sequence in 3 cases; 18q21.3 segment containing a partial BCL2 sequence in one case; and a segment of 7ql1.2 in one case. We present an LDI PCR-based methodology for the efficient identification of 14q32 translocations, with modifications to reduce the total run time to within one day. PMID:19378422

Ishizaki, Akiko; Sugahara, Kazuyuki; Tsuruda, Kazuto; Hasegawa, Hiroo; Yanagihara, Katsunori; Tsukasaki, Kunihiro; Yamada, Yasuaki; Kamihira, Shimeru

2008-01-01

207

B-cell selection and the development of autoantibodies  

PubMed Central

The clearest evidence that B cells play an important role in human autoimmunity is that immunotherapies that deplete B cells are very effective treatments for many autoimmune diseases. All people, healthy or ill, have autoreactive B cells, but not at the same frequency. A number of genes influence the level of these autoreactive B cells and whether they are eliminated or not during development at a central checkpoint in the bone marrow (BM) or at a later checkpoint in peripheral lymphoid tissues. These genes include those encoding proteins that regulate signaling through the B-cell receptor complex such as Btk and PTPN22, proteins that regulate innate signaling via Toll-like receptors (TLRs) such as MyD88 and interleukin-1 receptor-associated kinase 4, as well as the gene encoding the activation-induced deaminase (AID) essential for B cells to undergo class switch recombination and somatic hypermutation. Recent studies have revealed that TLR signaling elements and AID function not only in peripheral B cells to help mediate effective antibody responses to foreign antigens, but also in the BM to help remove autoreactive B-lineage cells at a very early point in B-cell development. Newly arising B cells that leave the BM and enter the blood and splenic red pulp can express both AID and TLR signaling elements like TLR7, and thus are fully equipped to respond rapidly to antigens (including autoantigens), to isotype class switch, and to undergo somatic hypermutation. These red pulp B cells may thus be an important source of autoantibody-producing cells arising particularly in extrafollicular sites, and indeed may be as significant a source of autoantibody-producing cells as B cells arising from germinal centers. PMID:23281837

2012-01-01

208

Ibrutinib for B cell malignancies  

PubMed Central

Research over the role of Bruton’s agammaglobulinemia tyrosine kinase (BTK) in B-lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site of BTK (TH/SH1 domain) and inhibits BTK phosphorylation on Tyr223. This review discussed in details the role of BTK in B-cell signaling, molecular interactions between B cell lymphoma/leukemia cells and their microenvironment. Clinical trials of the novel BTK inhibitor, ibrutinib (PCI-32765), in B cell malignancies were summarized. PMID:24472371

2014-01-01

209

Entropic effects in formation of chromosome territories: towards understanding of radiation-induced gene translocation frequency  

NASA Astrophysics Data System (ADS)

A detailed understanding of structural organization of biological target, such as geometry of an inter-phase chromosome, is an essential prerequisite for gaining deeper insight into relationship between radiation track structure and radiation-induced biological damage [1]. In particular, coupling of biophysical models aimed to describe architecture of chromosomes and their positioning in a cell nucleus [2-4] with models of local distribution of ionizations caused by passing projectiles, are expected to result in more accurate estimates of aberration induction caused by radiation. There is abundant experimental evidence indicating that arrangements of chromosomes in eukaryotic cell nucleus is non-random and has been evolutionary conserved in specific cell types. Moreover, the radial position of a given chromosome territory (CT) within the cell nucleus has been shown to correlate with its size and gene density. Usually it is assumed that chromosomal geometry and positioning result from the action of specific forces acting locally, such as hydrogen bonds, electrostatic, Van der Waals or hydrophobic interactions operating between nucleosomes and within their interiors. However, it is both desirable and instructive to learn to what extend organization of inter-phase chromosomes is affected by nonspecific entropic forces. In this study we report results of a coarse-grained analysis of a chromatin structure modeled by two distinct approaches. In the first method, we adhere to purely statistical analysis of chromatin packing within a chromosome territory. On the basis of the polymer theory, the chromatin fiber of diameter 30nm is approximated by a chain of spheres, each corresponding to about 30 kbp. Random positioning of the center of the domain is repeated for 1000 spherical nuclei. Configuration of the domain is determined by a random packing of a polymer (a string of identical beads) in estimated fraction of space occupied by a chromosome of a given length and mass. The degree of condensation of the chromatin fiber is modeled by changing length of the string: e.g. loosening of the structure is achieved by distributing the chromosome mass into a higher number of smaller beads and tighter configuration corresponds to a lower number of fragments (balls) with a bigger radius. Additionally, for each configuration, a degree of possible overlapping between domains is assumed. This procedure effectively intensifies loosening/tightening of the chromosome structure by changing the radial dimension of the domain while keeping a constant volume of the polymer chain. Such a positioning model is confronted with a minimalistic molecular dynamics model [5] on a similar structure, in which a chain of beads becomes connected by entropic spring energy and subjected to thermal fluctuations. Comparison of both Monte Carlo models allows to discuss variability of possible configurations as observed in static and dynamic models of chromosome territories along with the effect of compaction and relative arrangements of territorial polymer structures. Acknowledgements: Project is operated within the Foundation for Polish Science International Ph.D. Projects Programme co-financed by the European Regional Development Fund covering, under the agreement no. MPD/2009/6, the Jagiellonian University International Ph.D. Studies in Physics of Complex Systems. References: [1] F. Ballarini, M. Biaggi, and A. Ottolenghi, Radiation Protection Dosimetry 99, 175 (2002). [2] M. Nicodemi and A. Prisco, Biophysical Journal 96, 2168 (2009). [3] P. Cook and D. Marenduzzo, Journal of Cell Biology 186, 825 (2009). [4] M. Tark-Dame, R. van Driel, and D. Heermann, Journal of Cell Science 124, 839 (2011). [5] W. Swope, H. Andersen, P. Berens, and K. Wilson, J. Chem. Phys. 76, 637 (1982).

Gudowska-Nowak, Ewa; Ritter, Sylvia; Durante, Marco; Deperas-Standylo, Joanna; Ciesla, Michal

2012-07-01

210

Translocations in epithelial cancers  

PubMed Central

Genomic translocations leading to the expression of chimeric transcripts characterize several hematologic, mesenchymal and epithelial malignancies. While several gene fusions have been linked to essential molecular events in hematologic malignancies, the identification and characterization of recurrent chimeric transcripts in epithelial cancers has been limited. However, the recent discovery of the recurrent gene fusions in prostate cancer has sparked a revitalization of the quest to identify novel rearrangements in epithelial malignancies. Here, the molecular mechanisms of gene fusions that drive several epithelial cancers and the recent technological advances that increase the speed and reliability of recurrent gene fusion discovery are explored. PMID:19406209

Chad Brenner, J.; Chinnaiyan, Arul M.

2009-01-01

211

Mechanisms of oncogenic chromosomal translocations.  

PubMed

Chromosome translocations are caused by inappropriate religation of two DNA double-strand breaks (DSBs) in heterologous chromosomes. These DSBs can be generated by endogenous or exogenous sources. Endogenous sources of DSBs leading to translocations include inappropriate recombination activating gene (RAG) or activation-induced deaminase (AID) activity during immune receptor maturation. Endogenous DSBs can also occur at noncanonical DNA structures or at collapsed replication forks. Exogenous sources of DSBs leading to translocations include ionizing radiation (IR) and cancer chemotherapy. Spatial proximity of the heterologous chromosomes is also important for translocations. While three distinct pathways for DNA DSB repair exist, mounting evidence supports alternative nonhomologous end joining (aNHEJ) as the predominant pathway through which the majority of translocations occur. Initiated by poly (ADP-ribose) polymerase 1 (PARP1), aNHEJ is utilized less frequently in DNA DSB repair than other forms of DSB repair. We recently found that PARP1 is essential for chromosomal translocations to occur and that small molecule PARP1 inhibitors, already in clinical use, can inhibit translocations generated by IR or topoisomerase II inhibition. These data confirm the central role of PARP1 in aNHEJ-mediated chromosomal translocations and raise the possibility of using clinically available PARP1 inhibitors in patients who are at high risk for secondary oncogenic chromosomal translocations. PMID:24528169

Byrne, Michael; Wray, Justin; Reinert, Brian; Wu, Yuehan; Nickoloff, Jac; Lee, Suk-Hee; Hromas, Robert; Williamson, Elizabeth

2014-03-01

212

Single nucleotide polymorphisms at erythropoietin, superoxide dismutase 1, splicing factor, arginine/serin-rich 15 and plasmacytoma variant translocation genes association with diabetic nephropathy.  

PubMed

A number of genes have been identified in diabetic nephropathy. Association between diabetes-associated nephropathy and polymorphisms in the erythropoietin (EPO) gene, variants in the superoxide dismutase 1 (SOD1) gene and plasmacytoma variant translocation 1 (PVT1) gene have been identified. The EPO, SOD1:SFRS15 and PVT1 genes were genotyped using the single nucleotide polymorphism (SNP) technique in 38 diabetic nephropathy patients (Group 1) compared with 64 diabetic type 2 subjects without nephropathy (Group 2) at the Mubarak Alkabeer Hospital, Kuwait. The frequency of the risk allele T of the EPO (rs1617640) gene was high in both groups (0.96 in Group 1 and 0.92 in Group 2). Similarly, SNPs of the PVT1 (rs2720709) gene showed a higher frequency of the risk allele G in both groups (0.70 in the Group 1 and 0.68 in Group 2). Although the frequency of the risk allele A was higher than the frequency of the non-risk allele C of the SOD1:SFRS15 gene in both groups, the lowest probability value was observed in those gene SNPs (P = 0.05). We observed that the A allele of the SOD1:SFRS15 gene (rs17880135) was more frequently present in Group 1 (0.75) compared with Group 2 (0.62). Susceptibility to diabetes-associated nephropathy is partially mediated by genetic predisposition, and screening tests may open the gate for new therapeutic approaches. PMID:24821155

Alwohhaib, Maisaa; Alwaheeb, Salah; Alyatama, Nour; Dashti, Ali A; Abdelghani, Amal; Hussain, Naser

2014-05-01

213

Situs ambiguus in a female fetus with balanced (X;21) translocation--evidence for functional nullisomy of the ZIC3 gene?  

PubMed

The human ZIC3 gene has been mapped to Xq26.2, the visceral heterotaxy locus HTX1, and has been shown to be mutated in X-linked situs ambiguus and/or complex heart defects. We report on a female fetus with situs ambiguus, asplenia and corrected transposition of the great arteries, displaying a (X;21) translocation. The balanced state of the t(X;21)(q26;p13) was verified by FISH on metaphase chromosomes of the fetus using DOP-PCR products of the microdissected der(21) and Xq-subtelomere specific sequences, and by PRINS with beta-satellite specific sequences. Examination with polymorphic markers flanking ZIC3 on DOP-PCR products of the microdissected der(21) chromosome evidenced that the complete copy of the ZIC3 gene was translocated to chromosome 21. Mutations in the fetal and parental ZIC3 genes were excluded by sequencing. Paternal origin of the der(X) and der(21) chromosomes was confirmed by use of polymorphic microsatellite markers from chromosome 21 and from the chromosomal region Xq26, respectively. X chromosome inactivation analysis using a PCR of a polymorphic (CAG)(n) repeat in the first exon of the androgen receptor gene showed a completely skewed X inactivation pattern with the paternal X as the active X chromosome, thus excluding functional disomy of distal Xq. A positional effect caused by the balanced (X;21) translocation may be responsible for functional nullisomy of ZIC3 and thus explain the situs and cardiac abnormalities in the fetus. PMID:15470371

Fritz, Barbara; Kunz, Jürgen; Knudsen, Gun Peggy Strømstad; Louwen, Frank; Kennerknecht, Ingo; Eiben, Bernd; Orstavik, Karen Helene; Friedrich, Ursula; Rehder, Helga

2005-01-01

214

Relapse kinetics in acute myeloid leukaemias with MLL translocations or partial tandem duplications within the MLL gene.  

PubMed

Correct action upon re-emergence of minimal residual disease in acute myeloid leukaemia (AML) patients has not yet been established. The applicability of demethylating agents and use of allogeneic stem cell transplantation will be dependent on pre-relapse AML growth rates. We here delineate molecular growth kinetics of AML harbouring MLL partial tandem duplication (MLL-PTD; 37 cases) compared to those harbouring MLL translocations (43 cases). The kinetics of MLL-PTD relapses was both significantly slower than those of MLL translocation positive ones (median doubling time: MLL-PTD: 24 d, MLL-translocations: 12 d, P = 0·015, Wilcoxon rank sum test), and displayed greater variation depending on additional mutations. Thus, MLL-PTD+ cases with additional RUNX1 mutations or FLT3-internal tandem duplication relapsed significantly faster than cases without one of those two mutations (Wilcoxon rank sum test, P = 0·042). As rapid relapses occurred in all MLL subgroups, frequent sampling are necessary to obtain acceptable relapse detection rates and times from molecular relapse to haematological relapse (blood sampling every second month: MLL-PTD: 75%/50 d; MLL translocations: 85%/25 d). In conclusion, in this cohort relapse kinetics is heavily dependent on AML subtype as well as additional genetic aberrations, with possibly great consequences for the rational choice of pre-emptive therapies. PMID:24611505

Ommen, Hans B; Hokland, Peter; Haferlach, Torsten; Abildgaard, Lotte; Alpermann, Tamara; Haferlach, Claudia; Kern, Wolfgang; Schnittger, Susanne

2014-06-01

215

Detection of the bcl-2 t(14;18) Translocation and Proto-Oncogene Expression in Primary Intraocular Lymphoma  

PubMed Central

PURPOSE Primary intraocular lymphoma (PIOL) is a diffuse large B cell lymphoma that initially infiltrates the retina, vitreous, or optic nerve head, with or without central nervous system involvement. This study examined the expression of the bcl-2 t(14;18) translocation, the bcl-10 gene, and high expression of bcl-6 mRNA in PIOL cells. METHODS Microdissection and PCR analysis were used to examine vitreous specimens in patients with PIOL for the presence of bcl-2 t(14;18) translocations, the bcl-10 gene, and expression of bcl-6 mRNA. A medical record review was also conducted to determine whether the bcl-2 t(14;18) translocation correlated with prognosis. RESULTS Forty of 72 (55%) PIOL patients expressed the bcl-2 t(14;18) translocation at the major breakpoint region. Fifteen of 68 (22%) patients expressed the translocation at the minor cluster region. The bcl-10 gene was detected in 6 of 26 (23%) patients, whereas 4 of 4 (100%) PIOL patients expressed higher levels of bcl-6 mRNA compared with inflammatory lymphocytes. An analysis of clinical outcome in 23 PIOL patients revealed no significant association between bcl-2 t(14;18) translocations and survival or relapse. However, patients with the translocation were significantly younger. CONCLUSIONS PIOL has unique molecular patterns of bcl-2, bcl-10, and bcl-6 when compared with other systemic lympho-mas. This study lays the foundation for future studies aimed at exploring the genotypic classification of PIOL based on the quantitative molecular framework of gene expression profil-ing, with the goal of providing useful adjuncts to the pathologic diagnosis of this complex disease. PMID:16799010

Wallace, Dana J.; Shen, DeFen; Reed, George F.; Miyanaga, Masaru; Mochizuki, Manabu; Sen, H. Nida; Dahr, Samuel S.; Buggage, Ronald R.; Nussenblatt, Robert B.; Chan, Chi-Chao

2007-01-01

216

Molecular cytogenetics of IGH rearrangements in non-Hodgkin B-cell lymphoma.  

PubMed

Rearrangements involving the IGH gene have been identified in about 50% of non-Hodgkin B-cell lymphomas (NHLs) and correlated to clinically relevant subgroups. However, the detection rate largely varied with the technique used. We analyzed the incidence of IGH rearrangements using several fluorescence in situ hybridization (FISH) techniques on metaphases obtained from 96 patients with nodal NHL. An IGH rearrangement was identified in 71 cases (74%). A t(14;18)(q32;q21) was found in 37 of the 42 follicular lymphomas (88.1%) studied and a t(11;14)(q13;q32) in 12 of the 14 mantle cell lymphomas (85.7%). IGH rearrangements were identified in 21 of the 40 diffuse large B-cell lymphomas (52.5%), including seven t(14;18)(q32;q21) and four t(3;14)(q27;q32). Conventional cytogenetics was uninformative in several cases. However, the complemented analysis using 24-color FISH, chromosomal whole paints, telomeric probes and locus specific identifiers enabled us to characterize complex and/or masked IGH translocations in follicular lymphomas and mantle cell lymphomas and to identify all the chromosomal partners involved in IGH rearrangements in diffuse large B-cell lymphomas. This study shows the interest of using metaphase FISH in addition to conventional cytogenetics. Following banding techniques, FISH with the IGH dual color probe can be the first approach in NHL, after which chromosome painting and 24-color FISH can be used to identify the chromosomal partners involved in IGH rearrangements. The identification of these genes is of utmost importance for a better understanding of the molecular mechanisms involved in the genesis of lymphoma. PMID:18000389

Bernicot, I; Douet-Guilbert, N; Le Bris, M-J; Herry, A; Morel, F; De Braekeleer, M

2007-01-01

217

Nucleotide sequence of the afimbrial-adhesin-encoding afa-3 gene cluster and its translocation via flanking IS1 insertion sequences.  

PubMed Central

The afa gene clusters encode afimbrial adhesins (AFAs) that are expressed by uropathogenic and diarrhea-associated Escherichia coli strains. The plasmid-borne afa-3 gene cluster is responsible for the biosynthesis of the AFA-III adhesin that belongs to the Dr family of hemagglutinins. Reported in this work is the nucleotide sequence of the 9.2-kb insert of the recombinant plasmid pILL61, which contains the afa-3 gene cluster cloned from a cystitis-associated E. coli strain (A30). The afa-3 gene cluster was shown to contain six open reading frames, designated afaA to afaF. It was organized in two divergent transcriptional units. Five of the six Afa products showed marked homologies with proteins encoded by previously described adhesion systems that allowed us to attribute to each of them a putative function in the biogenesis of the AFA-III adhesin. AfaE was identified as the structural adhesin product, whereas AfaB and AfaC were recognized as periplasmic chaperone and outer membrane anchor proteins, respectively. The AfaA and AfaF products were shown to be homologous to the PapI-PapB transcriptional regulatory proteins. No function could be attributed to the AfaD product, the gene of which was previously shown to be dispensable for the synthesis of a functional adhesin. Upstream of the afa-3 gene cluster, a 1.2-kb region was found to be 96% identical to the RepFIB sequence of one of the enterotoxigenic E. coli plasmids (P307), suggesting a common ancestor plasmid. This region contains an integrase-like gene (int). Sequence analysis revealed the presence of an IS1 element between the int gene and the afa-3 gene cluster. Two other IS1 elements were detected and located in the vicinity of the afa-3 gene cluster by hybridization experiments. The afa-3 gene cluster was therefore found to be flanked by two IS1 elements in direct orientation and two in opposite orientations. The afa-3 gene cluster, flanked by two directly oriented IS1 elements, was shown to translocate from a recombinant plasmid to the E. coli chromosome. This translocation event occurred via IS1-specific recombination mediated by a recA-independent mechanism. Images PMID:8002584

Garcia, M I; Labigne, A; Le Bouguenec, C

1994-01-01

218

Human B cell defects in perspective.  

PubMed

While primary immune defects are generally considered to lead to severe and easily recognized disease in infants and children, a number of genetic defects impairing B cell function may not be clinically apparent or diagnosed until adult life. The commonest of these is common variable immune deficiency, the genetic origins of which are beginning to be at least partially understood. CVID affects ? 1/25,000 Caucasians and is characterized by a marked reduction in serum IgG, almost always in serum IgA, and reduced serum IgM in about half of all cases; these defects continue to provide an opportunity to investigate the genes necessary for B cell function in humans. Recently, a small number of genes necessary for normal B cell function have been identified in consanguineous families leading to varying degrees of hypogammaglobulinemia and loss of antibody production. In other studies, whole-exome sequencing and copy number variation, applied to large cohorts, have extended research into understanding both the genetic basis of this syndrome and the clinical phenotypes of CVID. PMID:22477523

Cunningham-Rundles, Charlotte

2012-12-01

219

Signaling circuits in early B-cell development.  

PubMed

Early B-cell development is an ordered and highly regulated process with alternating phases of cell proliferation and differentiation leading to B cells with the ability to recognize an extraordinarily large repertoire of different antigens. Here, we discuss what is currently known about the receptors in B-cell progenitors and how their signaling pathways influence immunoglobulin (Ig) gene rearrangement and the transcriptional program of early B cells. In particular, we address the interplay of the interleukin-7 receptor and the pre-B-cell receptor (preBCR) in shaping the survival, proliferation, and differentiation of early B cells. Each receptor addresses a unique set of signaling components but they also share signaling pathways, most prominently the MAPK/Erk and phosphoinositide-3 kinase pathways. The latter pathway regulates transcription factors of the FoxO family that play a central role in the proliferation to differentiation switch of pre-B cells. Interestingly, these two alternative cellular programs (proliferation and differentiation) are both controlled by the preBCR. Finally, we discuss how mutations or alterations of these pathways result in deregulated pre-B-cell expansion and leukemia. PMID:24507157

Reth, Michael; Nielsen, Peter

2014-01-01

220

Sequence based analysis of U-2973, a cell line established from a double-hit B-cell lymphoma with concurrent MYC and BCL2 rearrangements  

PubMed Central

Background Double-hit lymphoma is a complex and highly aggressive sub-type of B-cell lymphoma, which has recently been classified and is an area of active research interest due to the poor prognosis for patients with this disease. It is characterized by the presence of both an activating MYC chromosomal translocation and a simultaneous additional oncogenic translocation, often of the BCL2 gene. Recently, a cell line was established from a patient with this complex lymphoma and analyzed using conventional tools revealing it contains both MYC and BCL2 translocation events. Findings In this work, we reanalyzed the genome of the cell line using next generation whole genome sequencing technology in order to catalogue translocations, insertions and deletions which may contribute to the pathology of this lymphoma type. Conclusions We describe the cell line in much greater detail, and pinpoint the exact locations of the chromosomal breakpoints. We also find several rearrangements within cancer-associated genes, which were not found using conventional tools, suggesting that high throughput sequencing may reveal novel targets for therapy, which could be used concurrently with existing treatments. PMID:23171647

2012-01-01

221

Next-generation sequencing of translocation renal cell carcinoma reveals novel RNA splicing partners and frequent mutations of chromatin remodeling genes  

PubMed Central

Purpose MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated. Experimental design We performed RNA and exome sequencing on an exploratory set of TRCC (n=7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n=460). Results Using the TCGA dataset, we identified 7 TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP and KHDRBS2), which are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared to other RCC types, and showed activation of MITF, the transforming growth factor ?1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared to ccRCC, with frequent mutations in chromatin remodeling genes (six of eight cases, three of which from the TCGA). In two cases, we identified mutations in INO80D, an ATP-dependent chromatin remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3-TFE3 translocation. Conclusions This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin remodeling genes. PMID:24899691

Malouf, Gabriel G.; Su, Xiaoping; Yao, Hui; Gao, Jianjun; Xiong, Liangwen; He, Qiuming; Comperat, Eva; Couturier, Jerome; Molinie, Vincent; Escudier, Bernard; Camparo, Philippe; Doss, Denaha J.; Thompson, Erika J; Khayat, David; Wood, Christopher G.; Yu, Willie; Teh, Bin T.; Weinstein, John; Tannir, Nizar M.

2014-01-01

222

TLR2 activated B cells are phenotypically similar to the abnormal circulating B cells seen preceding the diagnosis of AIDS related non-Hodgkin lymphoma (NHL) diagnosis  

PubMed Central

Background AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is a common AIDS-defining cancer. Prior studies suggest that chronic B cell activation precedes AIDS-NHL diagnosis. Activation of B cells by multiple factors, including Toll-like receptor (TLR) signaling, leads to the expression of activation-induced cytidine deaminase (AID), a DNA mutating molecule that can contribute to oncogene translocations/mutations, leading to NHL. The goal of this study was to determine whether surface markers expressed on activated and/or germinal center (GC) B cells, and AID expression, were elevated on circulating B cells preceding AIDS-NHL, as well as to determine if TLR signaling contributes to this activated B cell phenotype. Methods Stored viable peripheral blood mononuclear cell (PBMC) specimens, obtained prior to AIDS-NHL diagnosis, were assessed by multi-color flow cytometry. Additionally, B cells isolated from PBMC were exposed to TLR ligands in vitro, after which B cell phenotype was assessed by flow cytometry. Results An elevated fraction of B cells expressing CD10, CD71, or CD86 was seen in those who went on to develop AIDS-NHL. AID expression was detected in some who developed AIDS-NHL, but not in HIV+ or HIV? controls. TLR2- stimulated purified B cells exhibited the activated B cell phenotype observed in HIV+ subjects prior to AIDS-NHL diagnosis. Conclusions These results indicate that an elevated fraction of B cells display an activated/GC phenotype in those HIV+ subjects who go on to develop AIDS-NHL, and suggest that TLR2-mediated activation may play a role in HIV infection-associated B cell activation, potentially contributing to the genesis of AIDS-NHL. PMID:23722608

Guo, Yu; Siewe, Basile; Epeldegui, Marta; Detels, Roger; Landay, Alan; Martinez-Maza, Otoniel

2013-01-01

223

E?-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-?B pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma  

PubMed Central

BCL10, required for nuclear factor ?B (NF-?B) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations. E?-driven human BCL10 transgenic (Tg) mice, which we created and characterize here, had expanded populations of MZ B cells and reduced follicular and B1a cells. Splenic B cells from Tg mice exhibited constitutive activation of both canonical and noncanonical NF-?B signaling pathways is associated with increased expression of NF-?B target genes. These genes included Tnfsf13b, which encodes the B-cell activating factor (BAFF). In addition, levels of BAFF were significantly increased in sera from Tg mice. MZ B cells of Tg mice exhibited reduced turnover in vivo and enhanced survival in vitro, indicative of lymphoaccumulation rather than lymphoproliferation as the cause of MZ expansion. In vivo antibody responses to both T-independent, and especially T-dependent, antigens were significantly reduced in Tg mice. Mortality was accelerated in Tg animals, and some mice older than 8 months had histologic and molecular findings indicative of clonal splenic MZ lymphoma. These results suggest that, in addition to constitutive activation of BCL10 in MZ B cells, other genetic factors or environmental influences are required for short latency oncogenic transformation. PMID:19696203

Li, Zhaoyang; Wang, Hongsheng; Xue, Liquan; Shin, Dong-Mi; Roopenian, Derry; Xu, Wu; Qi, Chen-Feng; Sangster, Mark Y.; Orihuela, Carlos J.; Tuomanen, Elaine; Rehg, Jerold E.; Cui, Xiaoli

2009-01-01

224

Characterization of IGH rearrangements in non-Hodgkin's B-cell lymphomas by fluorescence in situ hybridization.  

PubMed

Rearrangements involving the IGH gene have been identified in about 50% of non-Hodgkin's B-cell lymphomas (NHL) and correlated to clinical relevant subgroups. However, the detection rate varied greatly with the technique used. The incidence of IGH rearrangements was analyzed using several fluorescence in situ hybridization (FISH) techniques on metaphases obtained from 57 patients with nodal NHL. An IGH rearrangement was identified in 42 cases (73.7%). A t(14;18)(q32;q21) was found in 17 of the 20 follicular lymphomas (85%) studied and a t(11;14)(q13;q32) in 10 of the 11 mantle cell lymphomas (91%). IGH rearrangements were identified in 12 of the 26 diffuse large B-cell lymphomas (46%), including 5 t(14;18)(q32;q21) and 2 t(3;14)(q27;q32). Conventional cytogenetics was uninformative in several cases. However, the complemented analysis using Multi-FISH and/or chromosomal whole paint enabled the characterization of complex IGH translocations in follicular lymphomas and mantle cell lymphomas and the identification of all the chromosomal partners involved in the IGH rearrangement in diffuse large B-cell lymphomas. This study shows the interest of using metaphase FISH in addition to conventional cytogenetics. Following banding techniques, FISH with the IGH dual color probe could be the first approach in NHL, after which chromosome painting and M-FISH could be used to identify the chromosomal partner involved in the IGH rearrangement. PMID:16101124

Bernicot, Izabel; Douet-Guilbert, Nathalie; Le Bris, Marie-Josée; Morice, Patrick; Abgrall, Jean Francois; Berthou, Christian; Morel, Frédéric; De Braekeleer, Marc

2005-01-01

225

The Down-Regulation of Mt4-Like Genes by Phosphate Fertilization Occurs Systemically and Involves Phosphate Translocation to the Shoots1  

PubMed Central

Mt4 is a cDNA representing a phosphate-starvation-inducible gene from Medicago truncatula that is down-regulated in roots in response to inorganic phosphate (Pi) fertilization and colonization by arbuscular mycorrhizal fungi. Split-root experiments revealed that the expression of the Mt4 gene in M. truncatula roots is down-regulated systemically by both Pi fertilization and colonization by arbuscular mycorrhizal fungi. A comparison of Pi levels in these tissues suggested that this systemic down-regulation is not caused by Pi accumulation. Using a 30-bp region of the Mt4 gene as a probe, Pi-starvation-inducible Mt4-like genes were detected in Arabidopsis and soybean (Glycine max L.), but not in corn (Zea mays L.). Analysis of the expression of the Mt4-like Arabidopsis gene, At4, in wild-type Arabidopsis and pho1, a mutant unable to load Pi into the xylem, suggests that Pi must first be translocated to the shoot for down-regulation to occur. The data from the pho1 and split-root studies are consistent with the presence of a translocatable shoot factor responsible for mediating the systemic down-regulation of Mt4-like genes in roots. PMID:9880366

Burleigh, Stephen H.; Harrison, Maria J.

1999-01-01

226

Robertsonian translocations  

SciTech Connect

Chapter 27, describes the occurrence of Robertsonian translocations (RTs), which refer to the recombination of whole chromosome arms, in both monocentric and dicentric chromosomes. The nonrandom participation of acrocentric chromosomes in RTs is documented by various methods, including unbiased ascertainment and ascertainment through trisomy, infertility, unspecified mental retardation, and Prader-Willi syndrome. Causes of nonrandom participation of chromosomes in RTs is presented, as are the following topics: segregation in carriers of RTs and segregation in sperm cells of RT carriers, interchromosomal effects and conclusions. 48 refs., 3 figs., 2 tabs.

NONE

1993-12-31

227

Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus.  

PubMed

B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19(+)CD27(-) and CD19(+)IgM(+) B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19(+) B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients. PMID:25210799

Fan, H; Liu, F; Dong, G; Ren, D; Xu, Y; Dou, J; Wang, T; Sun, L; Hou, Y

2014-01-01

228

Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus  

PubMed Central

B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19+CD27- and CD19+IgM+ B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19+ B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients. PMID:25210799

Fan, H; Liu, F; Dong, G; Ren, D; Xu, Y; Dou, J; Wang, T; Sun, L; Hou, Y

2014-01-01

229

Multiple Translocation of the AVR-Pita Effector Gene among Chromosomes of the Rice Blast Fungus Magnaporthe oryzae and Related Species  

PubMed Central

Magnaporthe oryzae is the causal agent of rice blast disease, a devastating problem worldwide. This fungus has caused breakdown of resistance conferred by newly developed commercial cultivars. To address how the rice blast fungus adapts itself to new resistance genes so quickly, we examined chromosomal locations of AVR-Pita, a subtelomeric gene family corresponding to the Pita resistance gene, in various isolates of M. oryzae (including wheat and millet pathogens) and its related species. We found that AVR-Pita (AVR-Pita1 and AVR-Pita2) is highly variable in its genome location, occurring in chromosomes 1, 3, 4, 5, 6, 7, and supernumerary chromosomes, particularly in rice-infecting isolates. When expressed in M. oryzae, most of the AVR-Pita homologs could elicit Pita-mediated resistance, even those from non-rice isolates. AVR-Pita was flanked by a retrotransposon, which presumably contributed to its multiple translocation across the genome. On the other hand, family member AVR-Pita3, which lacks avirulence activity, was stably located on chromosome 7 in a vast majority of isolates. These results suggest that the diversification in genome location of AVR-Pita in the rice isolates is a consequence of recognition by Pita in rice. We propose a model that the multiple translocation of AVR-Pita may be associated with its frequent loss and recovery mediated by its transfer among individuals in asexual populations. This model implies that the high mobility of AVR-Pita is a key mechanism accounting for the rapid adaptation toward Pita. Dynamic adaptation of some fungal plant pathogens may be achieved by deletion and recovery of avirulence genes using a population as a unit of adaptation. PMID:21829350

Chuma, Izumi; Isobe, Chihiro; Hotta, Yuma; Ibaragi, Kana; Futamata, Natsuru; Kusaba, Motoaki; Yoshida, Kentaro; Terauchi, Ryohei; Fujita, Yoshikatsu; Nakayashiki, Hitoshi; Valent, Barbara; Tosa, Yukio

2011-01-01

230

TSPAN33 is a novel marker of activated and malignant B cells.  

PubMed

We have identified Tspan33 as a gene encoding a transmembrane protein exhibiting a restricted expression pattern including expression in activated B cells. TSPAN33 is a member of the tetraspanin family. TSPAN33 is not expressed in resting B cells, but is strongly induced in primary human B cells following activation. Human 2E2 cells, a Burkitt's lymphoma-derived B cell model of activation and differentiation, also upregulate TSPAN33 upon activation. TSPAN33 is expressed in several lymphomas including Hodgkin's and Diffuse large B cell lymphoma. TSPAN33 is also expressed in some autoimmune diseases where B cells participate in the pathology, including rheumatoid arthritis patients, systemic lupus erythematosus (SLE), and in spleen B cells from MRL/Fas(lpr/lpr) mice (a mouse model of SLE). We conclude that TSPAN33 may be used as a diagnostic biomarker or as a target for therapeutic antibodies for treatment of certain B cell lymphomas or autoimmune diseases. PMID:24211713

Luu, Van Phi; Hevezi, Peter; Vences-Catalan, Felipe; Maravillas-Montero, José Luis; White, Clayton Alexander; Casali, Paolo; Llorente, Luis; Jakez-Ocampo, Juan; Lima, Guadalupe; Vilches-Cisneros, Natalia; Flores-Gutiérrez, Juan Pablo; Santos-Argumedo, Leopoldo; Zlotnik, Albert

2013-12-01

231

Role of Peroxisome Proliferator-Activated Receptor ?/? and B-Cell Lymphoma-6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells  

PubMed Central

PPAR?/? is a ligand-activated transcription factor that regulates various cellular functions via induction of target genes directly or in concert with its associated transcriptional repressor, BCL-6. Matrix remodeling proteinases are frequently over-expressed in pancreatic cancer and are involved with metastasis. The present study tested the hypothesis that PPAR?/? is expressed in human pancreatic cancer cells and that its activation could regulate MMP-9, decreasing cancer cells ability to transverse the basement membrane. In human pancreatic cancer tissue there was significantly higher expression of MMP-9 and PPAR?/?, and lower levels of BCL-6 mRNA. PPAR?/? activation reduced the TNF?-induced expression of various genes implicated in metastasis and reduced the invasion through a basement membrane in cell culture models. Through the use of short hairpin RNA inhibitors of PPAR?/?, BCL-6, and MMP-9, it was evident that PPAR?/? was responsible for the ligand-dependent effects whereas BCL-6 dissociation upon GW501516 treatment was ultimately responsible for decreasing MMP-9 expression and hence invasion activity. These results suggest that PPAR?/? plays a role in regulating pancreatic cancer cell invasion through regulation of genes via ligand-dependent release of BCL-6 and that activation of the receptor may provide an alternative therapeutic method for controlling migration and metastasis. PMID:23737761

Coleman, Jeffrey D.; Thompson, Jerry T.; Smith, Russell W.; Prokopczyk, Bogdan; Vanden Heuvel, John P.

2013-01-01

232

UBE2QL1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene  

PubMed Central

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gene. PMID:24000165

Wake, Naomi C; Ricketts, Christopher J; Morris, Mark R; Prigmore, Elena; Gribble, Susan M; Skytte, Anne-Bine; Brown, Michael; Clarke, Noel; Banks, Rosamonde E; Hodgson, Shirley; Turnell, Andrew S; Maher, Eamonn R; Woodward, Emma R

2013-01-01

233

Evolution of B Cell Immunity  

PubMed Central

Two types of adaptive immune strategies are known to have evolved in vertebrates: the VLR-based system, which is present in jawless organisms and is mediated by VLRA and VLRB lymphocytes, and the BCR/TCR-based system, which is present in jawed species and is provided by B and T cell receptors expressed on B and T cells, respectively. Here we summarize features of B cells and their predecessors in the different animal phyla, focusing the review on B cells from jawed vertebrates. We point out the critical role of nonclassical species and comparative immunology studies in the understanding of B cell immunity. Because nonclassical models include species relevant to veterinary medicine, basic science research performed in these animals contributes to the knowledge required for the development of more efficacious vaccines against emerging pathogens. PMID:25340015

Sunyer, J. Oriol

2013-01-01

234

B Cell Superantigens Subvert Innate Functions of B Cells  

Microsoft Academic Search

Some infectious agents produce molecules capable of interacting specifically with the immunoglobulin variable regions, independently of the conventional binding site. They are referred to as B cell superantigens, and include protein A of Staphylococcus aureus, protein L of Peptostreptococcus magnus, and gp120 of HIV-1. To test their effects in vivo, we used transgenic mice whose immunoglobulin loci were inactivated and

M. Zouali

2007-01-01

235

Localisation of the gene for Saethre-Chotzen syndrome by FISH using four cases with apparently balanced translocations at 7p21.2  

SciTech Connect

Saethre-Chotzen is a common autosomal dominant form of craniosynostosis, which results in the premature fusion of cranial sutures. The Saethre-Chotzen gene locus has been mapped to 7p by linkage with genetic markers. We have analyzed four patients with Saethre-Chotzen syndrome associated with apparently balanced translocations involving band 7p21.2 and different reciprocal chromosomes. We have used YACs corresponding to the Genethon series of markers as probes for FISH, and in all four patients we show that the breakpoints in 7p are situated between D7S488 and D7S493, a maximum distance of 6 centimorgans. A previous patient has been described with a translocation t(6;7) and hemizygosity for D7S135. D7S135 is contained within the same YAC as D7S488, indicating that the breakpoint in the previous patient lies close to D7S488 and in the same region as the cases described here.

Rose, C.S.P.; King, A.A.J.; Winter, R.M. [Institute of Child Health, London (United Kingdom)] [and others

1994-09-01

236

MDM2 gene SNP309 T\\/G and p53 gene SNP72 G\\/C do not influence diffuse large B-cell non-Hodgkin lymphoma onset or survival in central European Caucasians  

Microsoft Academic Search

BACKGROUND: SNP309 T\\/G (rs2279744) causes higher levels of MDM2, the most important negative regulator of the p53 tumor suppressor. SNP72 G\\/C (rs1042522) gives rise to a p53 protein with a greatly reduced capacity to induce apoptosis. Both polymorphisms have been implicated in cancer. The SNP309 G-allele has recently been reported to accelerate diffuse large B-cell lymphoma (DLBCL) formation in pre-menopausal

Joerg Bittenbring; Frédérique Parisot; Alain Wabo; Monika Mueller; Lynn Kerschenmeyer; Markus Kreuz; Lorenz Truemper; Olfert Landt; Alain Menzel; Michael Pfreundschuh; Klaus Roemer

2008-01-01

237

Selective activation of VH3A10+ rheumatoid factor producing B cells by staphylococcal enterotoxin D.  

PubMed

Staphylococcal enterotoxin D (SED) is a T cell superantigen which selectively targets alpha beta TCRs bearing particular V beta elements. A second function of SED relates to the preferential activation of a B cell subset characterized by a high frequency of rheumatoid factor (RF) producing B cells. To define the molecular basis of the SED-induced B cell repertoire shift, we have analyzed Ig heavy chain genes in B cell clones expanded after SED stimulation and compared them with B cell clones established in the presence of anti-CD3 stimulated helper cells. Gene segments of the VH3 family were most frequently utilized under both stimulation conditions (42% anti-CD3; 47% SED). Sequence analysis of VH3 gene segments demonstrated that the repertoire of VH3 elements in B cell clones from SED driven and anti-CD3 driven cultures were distinct (P = 0.01). RF activity was closely associated with the expression of selected VH3 elements. B cell clones stimulated with SED preferentially expressed VH3A10, whereas VH26 was the gene segment dominantly used in B cell clones expanded with anti-CD3 stimulated helper cells. The usage of JH and DH elements was indistinguishable in SED and anti-CD3 driven B cell clones, suggesting that SED targets VH3+ B cells through a VH-specific mechanism. Comparison of the closely related sequences of the SED responsive VH3A10 and the SED non-responsive VH26 element suggested a role of a sequence polymorphism in the CDR2 reminiscent of B cell reactivity to conventional antigens. In contrast to conventional antigens, SED can induce differentiation of a high frequency of naive B cells. Thus, this staphylococcal enterotoxin combines selective activation of T cells with selective activation of B cells and might be able to direct T cell help to RF producing B cells. PMID:7794822

Xie, C; Brühl, H; He, X; Weyand, C M; Goronzy, J J

1995-03-01

238

IgVH genes mutation and usage, ZAP-70 and CD38 expression provide new insights on B-cell prolymphocytic leukemia (B-PLL).  

PubMed

B-prolymphocytic leukemia (B-PLL) is a rare disease with poor prognosis. To further characterize the biological features of this disease, we analyzed immunoglobulin heavy chain (IgVH) mutations, ZAP-70 and CD38 in 19 cases with de novo B-PLL. Immunoglobulin heavy chain genes analysis showed an unmutated pattern (>98% homology to germ line) in 9/17 cases (53%), with 100% homology in eight. In the remaining, it ranged from 90 to 97.4%, with three cases slightly mutated (98-95%) and five heavily mutated (<95%). All B-PLL utilized members of VH3 (11/17) and VH4 (6/17) families, with V3-23, V4-59 and V4-34 gene accounting for more than half of them, regardless of mutational status. ZAP-70, assessed by flow cytometry, ranged from 1 to 91% cells, being > or =20% in 57% of cases. CD38 ranged from 1 to 99% (median 21%). There was no correlation between IgVH status and ZAP-70 or CD38 expression, but male gender and del(17p) were more common in the unmutated group. Neither IgVH mutations, CD38 expression nor del(17p) influenced patients' outcome. Unexpectedly, ZAP-70+ B-PLL patients survived longer (40 months) than ZAP-70- B-PLL (8 months). B-PLL appears biologically heterogeneous regarding IgVH mutations, ZAP-70 and CD38 expression, showing a pattern distinct from that of other lymphoproliferative disorders. PMID:16642047

Del Giudice, I; Davis, Z; Matutes, E; Osuji, N; Parry-Jones, N; Morilla, A; Brito-Babapulle, V; Oscier, D; Catovsky, D

2006-07-01

239

Ten-Eleven Translocation 1 (Tet1) Is Regulated by O-Linked N-Acetylglucosamine Transferase (Ogt) for Target Gene Repression in Mouse Embryonic Stem Cells*  

PubMed Central

As a member of the Tet (Ten-eleven translocation) family proteins that can convert 5-methylcytosine (5mC) to 5-hydroxylmethylcytosine (5hmC), Tet1 has been implicated in regulating global DNA demethylation and gene expression. Tet1 is highly expressed in embryonic stem (ES) cells and appears primarily to repress developmental genes for maintaining pluripotency. To understand how Tet1 may regulate gene expression, we conducted large scale immunoprecipitation followed by mass spectrometry of endogenous Tet1 in mouse ES cells. We found that Tet1 could interact with multiple chromatin regulators, including Sin3A and NuRD complexes. In addition, we showed that Tet1 could also interact with the O-GlcNAc transferase (Ogt) and be O-GlcNAcylated. Depletion of Ogt led to reduced Tet1 and 5hmC levels on Tet1-target genes, whereas ectopic expression of wild-type but not enzymatically inactive Ogt increased Tet1 levels. Mutation of the putative O-GlcNAcylation site on Tet1 led to decreased O-GlcNAcylation and level of the Tet1 protein. Our results suggest that O-GlcNAcylation can positively regulate Tet1 protein concentration and indicate that Tet1-mediated 5hmC modification and target repression is controlled by Ogt. PMID:23729667

Shi, Feng-Tao; Kim, Hyeung; Lu, Weisi; He, Quanyuan; Liu, Dan; Goodell, Margaret A.; Wan, Ma; Songyang, Zhou

2013-01-01

240

Insulin-like Growth Factor-I Receptor (IGF-IR) Translocates to Nucleus and Autoregulates IGF-IR Gene Expression in Breast Cancer Cells  

PubMed Central

The insulin-like growth factor (IGF) system plays an important role in mammary gland biology as well as in the etiology of breast cancer. The IGF-I receptor (IGF-IR), which mediates the biological actions of IGF-I and IGF-II, has emerged in recent years as a promising therapeutic target. The IGF and estrogen signaling pathways act in a synergistic manner in breast epithelial cells. The present study was aimed at investigating 1) the putative translocation of IGF-IR and the related insulin receptor (IR) to the nucleus in breast cancer cells, 2) the impact of IGF-IR and IR levels on IGF-IR biosynthesis in estrogen receptor (ER)-positive and ER-depleted breast cancer cells, and 3) the potential transcription factor role of IGF-IR in the specific context of IGF-IR gene regulation. We describe here a novel mechanism of autoregulation of IGF-IR gene expression by cellular IGF-IR, which is seemingly dependent on ER status. Regulation of the IGF-IR gene by IGF-IR protein is mediated at the level of transcription, as demonstrated by 1) binding assays (DNA affinity chromatography and ChIP) showing specific IGF-IR binding to IGF-IR promoter DNA and 2) transient transfection assays showing transactivation of the IGF-IR promoter by exogenous IGF-IR. The IR is also capable of translocating to the nucleus and binding the IGF-IR promoter in ER-depleted, but not in ER-positive, cells. However, transcription factors IGF-IR and IR display diametrically opposite activities in the context of IGF-IR gene regulation. Thus, whereas IGF-IR stimulated IGF-IR gene expression, IR inhibited IGF-IR promoter activity. In summary, we have identified a novel mechanism of IGF-IR gene autoregulation in breast cancer cells. The clinical implications of these findings and, in particular, the impact of IGF-IR/IR nuclear localization on targeted therapy require further investigation. PMID:22128190

Sarfstein, Rive; Pasmanik-Chor, Metsada; Yeheskel, Adva; Edry, Liat; Shomron, Noam; Warman, Naama; Wertheimer, Efrat; Maor, Sharon; Shochat, Lea; Werner, Haim

2012-01-01

241

Insulin-like growth factor-I receptor (IGF-IR) translocates to nucleus and autoregulates IGF-IR gene expression in breast cancer cells.  

PubMed

The insulin-like growth factor (IGF) system plays an important role in mammary gland biology as well as in the etiology of breast cancer. The IGF-I receptor (IGF-IR), which mediates the biological actions of IGF-I and IGF-II, has emerged in recent years as a promising therapeutic target. The IGF and estrogen signaling pathways act in a synergistic manner in breast epithelial cells. The present study was aimed at investigating 1) the putative translocation of IGF-IR and the related insulin receptor (IR) to the nucleus in breast cancer cells, 2) the impact of IGF-IR and IR levels on IGF-IR biosynthesis in estrogen receptor (ER)-positive and ER-depleted breast cancer cells, and 3) the potential transcription factor role of IGF-IR in the specific context of IGF-IR gene regulation. We describe here a novel mechanism of autoregulation of IGF-IR gene expression by cellular IGF-IR, which is seemingly dependent on ER status. Regulation of the IGF-IR gene by IGF-IR protein is mediated at the level of transcription, as demonstrated by 1) binding assays (DNA affinity chromatography and ChIP) showing specific IGF-IR binding to IGF-IR promoter DNA and 2) transient transfection assays showing transactivation of the IGF-IR promoter by exogenous IGF-IR. The IR is also capable of translocating to the nucleus and binding the IGF-IR promoter in ER-depleted, but not in ER-positive, cells. However, transcription factors IGF-IR and IR display diametrically opposite activities in the context of IGF-IR gene regulation. Thus, whereas IGF-IR stimulated IGF-IR gene expression, IR inhibited IGF-IR promoter activity. In summary, we have identified a novel mechanism of IGF-IR gene autoregulation in breast cancer cells. The clinical implications of these findings and, in particular, the impact of IGF-IR/IR nuclear localization on targeted therapy require further investigation. PMID:22128190

Sarfstein, Rive; Pasmanik-Chor, Metsada; Yeheskel, Adva; Edry, Liat; Shomron, Noam; Warman, Naama; Wertheimer, Efrat; Maor, Sharon; Shochat, Lea; Werner, Haim

2012-01-20

242

B cell targets in rheumatoid arthritis  

Microsoft Academic Search

B cells are critical to the pathogenesis of rheumatoid arthritis (RA). There is substantial evidence of the efficacy of depletion\\u000a of B cells in many patients with RA using the first licensed agent, rituximab. Recent research has focused on enhancing efficacy\\u000a using other targets to inhibit B cell function, including other B cell-depleting antibodies and cytokines critical to B cell

Edward M. Vital; Shouvik Dass; Paul Emery

243

Functional characterisation of human cells harbouring a novel t(2p;7p) translocation involving TNS3 and EXOC6B genes  

PubMed Central

Background Tensin3 is an intracellular cytoskeleton-regulating protein, the loss of which is associated with increased cell motility, as has been observed in some human cancers. A novel chromosomal translocation, t(2;7)(p13;p12), present in a patient with a complex syndromic phenotype, directly involves Tensin3 (TNS3) and EXOC6B genes. This translocation could impair the expression of Tensin3 and ExoC6B proteins, and potentially produce two novel fusion transcripts. In the present study, we have investigated the expression and phenotypic features of these potential products in cultured cells from the proband. Methods Skin fibroblasts isolated from the proband as well as an age-matched control were grown in cell culture. Cells were used for quantitative RT-PCR, western blot and immunofluorescent confocal microscopy, which determined Tensin3 gene and protein expression. Phase-contrast and confocal microscopy additionally revealed cellular phenotype differences. A scratch wound assay monitored by live cell imaging measured cellular migration rates. Results The levels of Tensin3 at both mRNA and protein levels were lower in proband cells versus control fibroblasts. Proband cells displayed broader and shorter morphologies versus control fibroblasts, and immunofluorescent staining revealed additional Tensin3 expression along cytoskeletal filaments and the cell periphery only in control fibroblasts. In addition, proband fibroblasts showed a significantly higher migration rate than control cells over 24 h. Conclusions The phenotypic changes observed in proband cells may arise from TNS3 haploinsufficiency, causing partial loss of full-length Tensin3 protein. These results further expose a role for Tensin3 in cytoskeletal organisation and cell motility and may also help to explain the syndromic features observed in the patient. PMID:23809228

2013-01-01

244

Effect of shRNA targeting mouse CD99L2 gene in a murine B cell lymphoma in vitro and in vivo.  

PubMed

Mouse CD99 antigen-like 2 (mCD99L2) has previously been confirmed to be expressed in murine B lymphoma (A20) cells by our group. The present study aimed to establish a mCD99L2?downregulated A20 cell line and to investigate the effect of shRNA targeting mCD99L2 in A20 cells in vitro and in vivo. Four pLenti6/mCD99L2 expression vectors containing the mCD99L2 shRNA-expressing cassette were constructed, transfected into A20 cells and stable mCD99L2-downregulated A20 subclones, termed A20-mCD99L2- cells, were established and identified by quantitative PCR and western blot analysis. Light and transmission electron microscopy, MTT assay, flow cytometry and immunofluorenscence labeling were used to observe the morphological, biological and phenotypic characteristics in vitro. Some of the A20-mCD99L2- cells exhibited H/RS?cell like morphology, a decreased proliferative ability, a prolonged G2 phase and increased CD30 and CD15 expression. Upon injecting cells into nude or immunocompetent BALB/c mice, tumorigenesis, tumor growth, morphology and phenotypes in vivo were observed. A20-mCD99L2- cells induced tumors in nude and BALB/c mice, but with less potency in the latter compared with the controls. Similar morphological, biological and phenotypic characteristics were observed in the A20-mCD99L2- cell-induced tumors as those in vitro. Several cytokines including CD30T, IL-12p40/p70, IL-3, IFN-?, CXCL16, MIP-1? and CD40 were upregulated following mCD99L2 downregulation when detected using antibody arrays. The results from western blot analysis indicated that the regulation of mCD99L2 expression may involve the activated nuclear factor-?B pathway in the murine B lymphoma cells. The present study provides data for further investigation into the mCD99L2 gene in tumor cells. PMID:23338758

Liu, Fang; Zhang, Gong; Liu, Fanrong; Zhou, Xinhua; Chen, Xiaoyan; Han, Xiqun; Wu, Ziqing; Zhao, Tong

2013-04-01

245

Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma  

Microsoft Academic Search

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas fre- quently involved other thoracic structures but not extrathoracic sites

Andreas Rosenwald; George Wright; Karen Leroy; Xin Yu; Philippe Gaulard; Randy D. Gascoyne; Wing C. Chan; Tong Zhao; Corinne Haioun; Timothy C. Greiner; Dennis D. Weisenburger; James C. Lynch; Julie Vose; James O. Armitage; Erlend B. Smeland; Stein Kvaloy; Harald Holte; Jan Delabie; Elias Campo; Emili Montserrat; Armando Lopez-Guillermo; German Ott; H. Konrad Muller-Hermelink; Joseph M. Connors; Rita Braziel; Thomas M. Grogan; Richard I. Fisher; Thomas P. Miller; Michael LeBlanc; Michael Chiorazzi; Hong Zhao; Liming Yang; John Powell; Wyndham H. Wilson; Elaine S. Jaffe; Richard Simon; Richard D. Klausner; Louis M. Staudt

246

Interallelic class switch recombination contributes significantly to class switching in mouse B cells.  

PubMed

Except for the expression of IgM and IgD, DNA recombination is constantly needed for the expression of other Ig classes and subclasses. The predominant path of class switch recombination (CSR) is intrachromosomal, and the looping-out and deletion model has been abundantly documented. However, switch regions also occasionally constitute convenient substrates for interchromosomal recombination, since it is noticeably the case in a number of chromosomal translocations causing oncogene deregulation in the course of lymphoma and myeloma. Although asymmetric accessibility of Ig alleles should theoretically limit its occurrence, interallelic CSR was shown to occur at low levels during IgA switching in rabbit, where the definition of allotypes within both V and C regions helped identify interchromosomally derived Ig. Thus, we wished to evaluate precisely interallelic CSR frequency in mouse B cells, by using a system in which only one allele (of b allotype) could express a functional VDJ region, whereas only interallelic CSR could restore expression of an excluded (a allotype) allele. In our study, we show that interchromosomal recombination of V(H) and Cgamma or Calpha occurs in vivo in B cells at a frequency that makes a significant contribution to physiological class switching: trans-association of V(H) and C(H) genes accounted for 7% of all alpha mRNA, and this frequency was about twice higher for the gamma3 transcripts, despite the much shorter distance between the J(H) region and the Cgamma3 gene, thus confirming that this phenomenon corresponded to site-specific switching and not to random recombination between long homologous loci. PMID:15879114

Reynaud, Stéphane; Delpy, Laurent; Fleury, Laurence; Dougier, Hei-Lanne; Sirac, Christophe; Cogné, Michel

2005-05-15

247

IL-10-Producing B Cells Are Induced Early in HIV-1 Infection and Suppress HIV-1-Specific T Cell Responses  

PubMed Central

A rare subset of IL-10-producing B cells, named regulatory B cells (Bregs), suppresses adaptive immune responses and inflammation in mice. In this study, we examined the role of IL-10-producing B cells in HIV-1 infection. Compared to uninfected controls, IL-10-producing B cell frequencies were elevated in both blood and sigmoid colon during the early and chronic phase of untreated HIV-1 infection. Ex vivo IL-10-producing B cell frequency in early HIV-1 infection directly correlated with viral load. IL-10-producing B cells from HIV-1 infected individuals were enriched in CD19+TIM-1+ B cells and were enriched for specificity to trimeric HIV-1 envelope protein. Anti-retroviral therapy was associated with reduced IL-10-producing B cell frequencies. Treatment of B cells from healthy donors with microbial metabolites and Toll-like receptor (TLR) agonists could induce an IL-10 producing phenotype, suggesting that the elevated bacterial translocation characteristic of HIV-1 infection may promote IL-10-producing B cell development. Similar to regulatory B cells found in mice, IL-10-producing B cells from HIV-1-infected individuals suppressed HIV-1-specific T cell responses in vitro, and this suppression is IL-10-dependent. Also, ex vivo IL-10-producing B cell frequency inversely correlated with contemporaneous ex vivo HIV-1-specific T cell responses. Our findings show that IL-10-producing B cells are induced early in HIV-1 infection, can be HIV-1 specific, and are able to inhibit effective anti-HIV-1 T cell responses. HIV-1 may dysregulate B cells toward Bregs as an immune evasion strategy. PMID:24586620

Kim, Connie J.; Clayton, Kiera; Zhao, Hanqi; Lee, Erika; Cao, Jin Chao; Ziegler, Blake; Gregor, Alexander; Yue, Feng Yun; Huibner, Sanja; MacParland, Sonya; Schwartz, Jordan; Song, Hai Han; Benko, Erika; Gyenes, Gabor; Kovacs, Colin; Kaul, Rupert; Ostrowski, Mario

2014-01-01

248

Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice.  

PubMed

The Ataxia Telangiectasia-mutated (ATM) kinase senses DNA double-strand breaks (DSB) and facilitates their repair. In humans, ATM deficiency predisposes to B- and T-cell lymphomas, but in mice it leads only to thymic lymphomas. We tested the hypothesis that increased DSB frequency at a cellular oncogene could promote B-cell lymphoma by generating ATM-deficient mice with a V(D)J recombination target (DJ? cassette) within c-myc intron 1 ("DA" mice). We also generated ATM-deficient mice carrying an E?-Bcl-2 transgene (AB mice) to test whether enhanced cellular survival could promote B-cell lymphomas. About 30% of DA or AB mice and nearly 100% of mice harboring the combined genotypes (DAB mice) developed mature B-cell lymphomas. In all genotypes, B-cell tumors harbored oncogenic c-myc amplification generated by breakage-fusion-bridge (BFB) from dicentric chromosomes formed through fusion of IgH V(D)J recombination-associated DSBs on chromosome 12 to sequences downstream of c-myc on chromosome 15. AB tumors demonstrate that B lineage cells harboring spontaneous DSBs leading to IgH/c-myc dicentrics are blocked from progressing to B-cell lymphomas by cellular apoptotic responses. DA and DAB tumor translocations were strictly linked to the cassette, but occurred downstream, frequently in a 6-kb region adjacent to c-myc that harbors multiple cryptic V(D)J recombination targets, suggesting that bona fide V(D)J target sequences may activate linked cryptic targets. Our findings indicate that ATM deficiency allows IgH V(D)J recombination DSBs in developing B cells to generate dicentric translocations that, via BFB cycles, lead to c-myc-activating oncogenic translocations and amplifications in mature B cells. PMID:24913718

Tepsuporn, Suprawee; Hu, Jiazhi; Gostissa, Monica; Alt, Frederick W

2014-09-01

249

DHA down-regulates phenobarbital-induced cytochrome P450 2B1 gene expression in rat primary hepatocytes by attenuating CAR translocation  

SciTech Connect

The constitutive androstane receptor (CAR) plays an important role in regulating the expression of detoxifying enzymes, including cytochrome P450 2B (CYP 2B). Phenobarbital (PB) induction of human CYP 2B6 and mouse CYP 2b10 has been shown to be mediated by CAR. Our previous study showed that PB-induced CYP 2B1 expression in rat primary hepatocytes is down-regulated by both n-6 and n-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA); however, the mechanism for this down-regulation by DHA was previously unknown. The objective of the present study was to determine whether change in CAR translocation is involved in the down-regulation by n-6 and n-3 PUFAs of PB-induced CYP 2B1 expression in rat primary hepatocytes. We used 100 {mu}M arachidonic acid, linoleic acid, eicosapentaenoic acid, and DHA to test this hypothesis. PB triggered the translocation of CAR from the cytosol into the nucleus in a dose-dependent and time-dependent manner in our hepatocyte system, and the CAR distribution in rat primary hepatocytes was significantly affected by DHA. DHA treatment decreased PB-inducible accumulation of CAR in the nuclear fraction and increased it in the cytosolic fraction in a dose-dependent manner. The down-regulation of CYP 2B1 expression by DHA occurred in a dose-dependent manner, and a similar pattern was found for the nuclear accumulation of CAR. The results of immunoprecipitation showed a CAR/RXR heterodimer bound to nuclear receptor binding site 1 (NR-1) of the PB-responsive enhancer module (PBREM) of the CYP 2B1gene. The EMSA results showed that PB-induced CAR binding to NR-1 was attenuated by DHA. Taken together, these results suggest that attenuation of CAR translocation and decreased subsequent binding to NR-1 are involved in DHA's down-regulation of PB-induced CYP 2B1 expression.

Li, C.-C.; Lii, C.-K.; Liu, K.-L. [Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan (China); Yang, J.-J. [School of Dentistry, Chung Shan Medical University, Taichung, Taiwan (China); Chen, H.-W. [Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan (China)], E-mail: hawwen@csmu.edu.tw

2007-12-15

250

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome.  

PubMed

The Williams-Beuren syndrome (WBS) is a complex developmental disorder with multisystemic manifestations including supravalvular aortic stenosis (SVAS), a so-called elfin face, a hoarse voice, and a specific cognitive phenotype. Most WBS patients have a >1 Mb deletion on one of their chromosomes 7 in q11 but except for elastin, whose haploinsufficiency causes the cardiovascular malformations, it is unknown which genes in the deletion area contribute to the phenotype. We have investigated a family with a cytogenetically balanced translocation t(7;16)(q11.23;q13) in which affected individuals manifested a broad spectrum of clinical phenotypes ranging from a hoarse voice as the only feature to the full WBS phenotype. Molecular cytogenetic and DNA sequence analyses of the translocation breakpoint showed that the cytogenetic rearrangement disrupts the elastin gene locus within intron 5 in the exact same manner in all translocation carriers. The recently described large inversion of the 7q11.23 region was not present in this family. Our data demonstrate that disruption of the elastin gene by a translocation breakpoint may cause classical WBS, atypical WBS, SVAS, or no recognisable phenotype, and provide a clear example for extensive phenotypic variability associated with a position effect in humans. PMID:12080386

Duba, Hans-Christoph; Doll, Andreas; Neyer, Michael; Erdel, Martin; Mann, Christian; Hammerer, Ignaz; Utermann, Gerd; Grzeschik, Karl-Heinz

2002-06-01

251

Regulation of VH Replacement by B Cell Receptor (BCR)-mediated Signaling in Human Immature B Cells  

PubMed Central

VH replacement provides a unique RAG-mediated recombination mechanism to edit non-functional IgH genes or IgH genes encoding self reactive B cell receptors (BCRs) and contributes to the diversification of antibody repertoire in mouse and human. Currently, it is not clear how VH replacement is regulated during early B lineage cell development. Here we show that crosslinking BCRs induces VH replacement in human EU12 ?HC+ cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling-induced VH replacement is dependent on the activation of Syk and Src kinases; but is inhibited by CD19 co-stimulation, presumably through activation of the PI3 kinase pathway. These results show for the first time that VH replacement is regulated by BCR-mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments. PMID:23630348

Liu, Jing; Lange, Miles D.; Hong, Sang Yong; Xie, Wanqin; Xu, Kerui; Huang, Lin; Yu, Yangsheng; Ehrhardt, Gotz R. A.; Zemlin, Michael; Burrows, Peter D.; Su, Kaihong; Carter, Robert H.; Zhang, Zhixin

2013-01-01

252

Immunohistochemical and Molecular Characteristics with Prognostic Significance in Diffuse Large B-Cell Lymphoma  

PubMed Central

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. We analyzed 100 cases of DLBCL to evaluate the prognostic value of immunohistochemical markers derived from the gene expression profiling-defined cell origin signature, including MYC, BCL2, BCL6, and FOXP1 protein expression. We also investigated genetic alterations in BCL2, BCL6, MYC and FOXP1 using fluorescence in situ hybridization and assessed their prognostic significance. BCL6 rearrangements were detected in 29% of cases, and BCL6 gene alteration (rearrangement and/or amplification) was associated with the non-germinal center B subtype (non-GCB). BCL2 translocation was associated with the GCB phenotype, and BCL2 protein expression was associated with the translocation and/or amplification of 18q21. MYC rearrangements were detected in 15% of cases, and MYC protein expression was observed in 29% of cases. FOXP1 expression, mainly of the non-GCB subtype, was demonstrated in 37% of cases. Co-expression of the MYC and BCL2 proteins, with non-GCB subtype predominance, was observed in 21% of cases. We detected an association between high FOXP1 expression and a high proliferation rate as well as a significant positive correlation between MYC overexpression and FOXP1 overexpression. MYC, BCL2 and FOXP1 expression were significant predictors of overall survival. The co-expression of MYC and BCL2 confers a poorer clinical outcome than MYC or BCL2 expression alone, whereas cases negative for both markers had the best outcomes. Our study confirms that DLBCL, characterized by the co-expression of MYC and BCL2 proteins, has a poor prognosis and establishes a significant positive correlation with MYC and FOXP1 over-expression in this entity. PMID:24887414

Bellas, Carmen; Garcia, Diego; Vicente, Yolanda; Kilany, Linah; Abraira, Victor; Navarro, Belen; Provencio, Mariano; Martin, Paloma

2014-01-01

253

The product of the Herpes simplex virus 1 UL7 gene interacts with a mitochondrial protein, adenine nucleotide translocator 2  

Microsoft Academic Search

The herpes simplex virus 1 (HSV-1) UL7 gene is highly conserved among herpesviridae. Since the construction of recombinant HSV-1 with a mutation in the UL7 gene has not been reported, the involvement of HSV-1 UL7 in viral replication has been unclear. In this study, we succeeded in generating a UL7 null HSV-1 mutant virus, MT102, and characterized it. Our results

Michiko Tanaka; Tetsutaro Sata; Yasushi Kawaguchi

2008-01-01

254

Activation of human heat shock genes is accompanied by oligomerization, modification, and rapid translocation of heat shock transcription factor HSF1.  

PubMed Central

Transcriptional activity of heat shock (hsp) genes is controlled by a heat-activated, group-specific transcription factor(s) recognizing arrays of inverted repeats of the element NGAAN. To date genes for two human factors, HSF1 and HSF2, have been isolated. To define their properties as well as the changes they undergo during heat stress activation, we prepared polyclonal antibodies to these factors. Using these tools, we have shown that human HeLa cells constitutively synthesize HSF1, but we were unable to detect HSF2. In unstressed cells HSF1 is present mainly in complexes with an apparent molecular mass of about 200 kDa, unable to bind to DNA. Heat treatment induces a shift in the apparent molecular mass of HSF1 to about 700 kDa, concomitant with the acquisition of DNA-binding ability. Cross-linking experiments suggest that this change in complex size may reflect the trimerization of monomeric HSF1. Human HSF1 expressed in Xenopus oocytes does not bind DNA, but derepression of DNA-binding activity, as well as oligomerization of HSF1, occurs during heat treatment at the same temperature at which hsp gene expression is induced in this organism, suggesting that a conserved Xenopus protein(s) plays a role in this regulation. Inactive HSF1 resides in the cytoplasm of human cells; on activation it rapidly translocates to a soluble nuclear fraction, and shortly thereafter it becomes associated with the nuclear pellet. On heat shock, activatable HSF1, which might already have been posttranslationally modified in the unstressed cell, undergoes further modification. These different process provide multiple points of regulation of hsp gene expression. Images PMID:8455624

Baler, R; Dahl, G; Voellmy, R

1993-01-01

255

A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered L-serine level associated with disruption of PSAT1 gene expression  

PubMed Central

L-Serine is required for the synthesis of glycine and D-serine, both of which are NMDA receptor co-agonists. Although roles for D-serine and glycine have been suggested in schizophrenia, little is known about the role of the L-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of L-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the L-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum L-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions. PMID:20955740

Ozeki, Yuji; Pickard, Benjamin S.; Kano, Shin-ichi; Malloy, Mary P.; Zeledon, Mariela; Sun, Daniel Q.; Fujii, Kumiko; Wakui, Keiko; Shirayama, Yukihiko; Fukushima, Yoshimitsu; Kunugi, Hiroshi; Hashimoto, Kenji; Muir, Walter J.; Blackwood, Douglas H.; Sawa, Akira

2010-01-01

256

Lipid rafts and B-cell activation  

Microsoft Academic Search

The B-cell antigen receptor acts during B-cell activation both to initiate signalling cascades and to transport antigen into the cell for subsequent processing and presentation. Recent evidence indicates that membrane microdomains, termed lipid rafts, have a role in B-cell activation as platforms for B-cell receptor (BCR) signalling and might also act in antigen trafficking. Lipid rafts might facilitate the regulation

Susan K. Pierce

2002-01-01

257

Blimp1 Is Required for the Formation of Immunoglobulin Secreting Plasma Cells and Pre-Plasma Memory B Cells  

Microsoft Academic Search

Blimp-1 is a transcriptional repressor able to drive the terminal differentiation of B cells into Ig-secreting plasma cells. We have created mice with a B cell-specific deletion of prdm1, the gene encoding Blimp-1. B cell development and the number of B cells responding to antigen appear to be normal in these mice. However, in response to either TD or TI

Miriam Shapiro-Shelef; Kuo-I Lin; Louise J McHeyzer-Williams; Jerry Liao; Michael G McHeyzer-Williams; Kathryn Calame

2003-01-01

258

EndoU is a novel regulator of AICD during peripheral B cell selection  

PubMed Central

Balanced transmembrane signals maintain a competent peripheral B cell pool limited in self-reactive B cells that may produce pathogenic autoantibodies. To identify molecules regulating peripheral B cell survival and tolerance to self-antigens (Ags), a gene modifier screen was performed with B cells from CD22-deficient C57BL/6 (CD22?/?[B6]) mice that undergo activation-induced cell death (AICD) and fail to up-regulate c-Myc expression after B cell Ag receptor ligation. Likewise, lysozyme auto-Ag–specific B cells in IgTg hen egg lysozyme (HEL) transgenic mice inhabit the spleen but undergo AICD after auto-Ag encounter. This gene modifier screen identified EndoU, a single-stranded RNA-binding protein of ancient origin, as a major regulator of B cell survival in both models. EndoU gene disruption prevents AICD and normalizes c-Myc expression. These findings reveal that EndoU is a critical regulator of an unexpected and novel RNA-dependent pathway controlling peripheral B cell survival and Ag responsiveness that may contribute to peripheral B cell tolerance. PMID:24344237

Poe, Jonathan C.; Kountikov, Evgueni I.; Lykken, Jacquelyn M.; Natarajan, Abirami; Marchuk, Douglas A.

2014-01-01

259

EndoU is a novel regulator of AICD during peripheral B cell selection.  

PubMed

Balanced transmembrane signals maintain a competent peripheral B cell pool limited in self-reactive B cells that may produce pathogenic autoantibodies. To identify molecules regulating peripheral B cell survival and tolerance to self-antigens (Ags), a gene modifier screen was performed with B cells from CD22-deficient C57BL/6 (CD22(-/-[B6])) mice that undergo activation-induced cell death (AICD) and fail to up-regulate c-Myc expression after B cell Ag receptor ligation. Likewise, lysozyme auto-Ag-specific B cells in Ig(Tg) hen egg lysozyme (HEL) transgenic mice inhabit the spleen but undergo AICD after auto-Ag encounter. This gene modifier screen identified EndoU, a single-stranded RNA-binding protein of ancient origin, as a major regulator of B cell survival in both models. EndoU gene disruption prevents AICD and normalizes c-Myc expression. These findings reveal that EndoU is a critical regulator of an unexpected and novel RNA-dependent pathway controlling peripheral B cell survival and Ag responsiveness that may contribute to peripheral B cell tolerance. PMID:24344237

Poe, Jonathan C; Kountikov, Evgueni I; Lykken, Jacquelyn M; Natarajan, Abirami; Marchuk, Douglas A; Tedder, Thomas F

2014-01-13

260

Treatment of Diffuse Large B Cell Lymphoma  

PubMed Central

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in all countries and all age groups. DLBCL is potentially curable, and the outcome of patients with DLBCL has completely changed with the introduction of therapy involving the monoclonal antibody rituximab in combination with chemotherapy. Nonetheless, relapse is detected after treatment with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone in approximately 30% of patients. It has recently become clear that DLBCL represents a heterogeneous admixture of quite different entities. Gene expression profiling has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses; however, incorporation of this information into treatment algorithms awaits further investigation. Future approaches to DLBCL treatment will use this new genetic information to identify potential biomarkers for prognosis and targets for treatment. PMID:23269875

2012-01-01

261

Contributions of B cells to lupus pathogenesis.  

PubMed

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. This review summarizes first the results obtained in the mouse that have revealed how B cell tolerance is breached in SLE. We then review the B cell subsets, in addition to the autoAb producing cells, which contribute to SLE pathogenesis, focusing on marginal zone B cells, B-1 cells and regulatory B cells. Finally, we review the interactions between B cells and other immune cells that have been implicated in SLE, such as dendritic cells, macrophages, neutrophils and T cells. PMID:24332482

Sang, Allison; Zheng, Ying-Yi; Morel, Laurence

2014-12-01

262

TLR9 expressed on plasma membrane acts as a negative regulator of human B cell response.  

PubMed

Toll-like receptors (TLRs) are positioned at the interface between innate and adaptive immunity. Unlike others, those such as TLR9, that recognize nucleic acids, are confined to the endosomal compartment and are scarce on the cell surface. Here, we present evidence for TLR9 expression on the plasma membrane of B cells. In contrast to endosomal TLR9, cell surface TLR9 does not bind CpG-B oligodeoxynucleotides. After B cell-receptor (BCR) stimulation, TLR9 was translocated into lipid rafts with the BCR, suggesting that it could serve as a co-receptor for BCR. Nevertheless, stimulation of B cells with anti-TLR9 antibodies did not modify the BCR-induced responses despite up-regulation of tyrosine phosphorylation of proteins. However, CpG-B activation of B cells, acting synergistically with BCR signals, was inhibited by anti-TLR9 stimulation. Induction of CD25 expression and proliferation of B cells were thus down-regulated by the engagement of cell surface TLR9. Overall, our results indicate that TLR9 expressed on the plasma membrane of B cells might be a negative regulator of endosomal TLR9, and could provide a novel control by which activation of autoreactive B cells is restrained. PMID:24582318

Guerrier, Thomas; Pochard, Pierre; Lahiri, Ayan; Youinou, Pierre; Pers, Jacques-Olivier; Jamin, Christophe

2014-06-01

263

Molecular programming of B cell memory  

PubMed Central

The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information — resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes — has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming. PMID:22158414

McHeyzer-Williams, Michael; Okitsu, Shinji; Wang, Nathaniel; McHeyzer-Williams, Louise

2014-01-01

264

Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas.  

PubMed

Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target. PMID:18987657

Feldman, A L; Law, M; Remstein, E D; Macon, W R; Erickson, L A; Grogg, K L; Kurtin, P J; Dogan, A

2009-03-01

265

B-cell biology and development.  

PubMed

B cells develop from hematopoietic precursor cells in an ordered maturation and selection process. Extensive studies with many different mouse mutants provided fundamental insights into this process. However, the characterization of genetic defects causing primary immunodeficiencies was essential in understanding human B-cell biology. Defects in pre-B-cell receptor components or in downstream signaling proteins, such as Bruton tyrosine kinase and B-cell linker protein, arrest development at the pre-B-cell stage. Defects in survival-regulating proteins, such as B-cell activator of the TNF-? family receptor (BAFF-R) or caspase recruitment domain-containing protein 11 (CARD11), interrupt maturation and prevent differentiation of transitional B cells into marginal zone and follicular B cells. Mature B-cell subsets, immune responses, and memory B-cell and plasma cell development are disturbed by mutations affecting Toll-like receptor signaling, B-cell antigen receptor coreceptors (eg, CD19), or enzymes responsible for immunoglobulin class-switch recombination. Transgenic mouse models helped to identify key regulatory mechanisms, such as receptor editing and clonal anergy, preventing the activation of B cells expressing antibodies recognizing autoantigens. Nevertheless, the combination of susceptible genetic backgrounds with the rescue of self-reactive B cells by T cells allows the generation of autoreactive clones found in patients with many autoimmune diseases and even in those with primary immunodeficiencies. The rapid progress of functional genomic research is expected to foster the development of new tools that specifically target dysfunctional B lymphocytes to treat autoimmunity, B-cell malignancies, and immunodeficiency. PMID:23465663

Pieper, Kathrin; Grimbacher, Bodo; Eibel, Hermann

2013-04-01

266

A new 17p13.3 microduplication including the PAFAH1B1 and YWHAE genes resulting from an unbalanced X;17 translocation.  

PubMed

Submicroscopic duplications of the genomic interval deleted in Miller-Dieker syndrome (MDS) were recently identified by array-based comparative genomic hybridization (a-CGH) studies, describing new genomic disorders in the MDS locus. These rearrangements of varying size, from 59-88 kb to 4 Mb, were non-recurrent, and appear to result from diverse molecular mechanisms. Only five patients had overlapping 17p13.3 duplications including the entire MDS critical region. We describe here a 13-year-old girl with a novel microduplication of the MDS critical region, involving the PAFAH1B1 and YWHAE genes. She presented with moderate psychomotor retardation, speech delay, behavioral problems, and bilateral cleft lip and palate, a previously unreported manifestation. Initially diagnosed as having an apparently simple terminal Xq26 deletion on standard cytogenetic analysis, she was found to have an associated terminal 4.2 Mb 17p13.3 submicroscopic duplication, identified by subtelomere FISH analysis, further characterized by high-resolution array CGH, resulting from an unbalanced X;17 translocation. Phenotypic comparison with the 5 other patients previously described, revealed common phenotypic features, such as hypotonia, mild to moderate developmental delay/mental retardation, speech abnormalities, behavioral problems, recurrent infections, relatively increase of body weight, discrete facial dysmorphism including downslanting palpebral fissures, broad midface, pointed chin, contributing to further delineate this new 17p13.3 microduplication syndrome. PMID:21195811

Hyon, Capucine; Marlin, Sandrine; Chantot-Bastaraud, Sandra; Mabboux, Philippe; Beaujard, Marie-Paule; Al Ageeli, Essam; Vazquez, Marie-Paule; Picard, Arnaud; Siffroi, Jean-Pierre; Portnoï, Marie-France

2011-01-01

267

Mast Cells Control the Expansion and Differentiation of IL-10-Competent B Cells.  

PubMed

The discovery of B cell subsets with regulatory properties, dependent on IL-10 production, has expanded our view on the mechanisms that control inflammation. Regulatory B cells acquire the ability to produce IL-10 in a stepwise process: first, they become IL-10 competent, a poised state in which B cells are sensitive to trigger signals but do not actually express the Il-10 gene; then, when exposed to appropriate stimuli, they start producing IL-10. Even if the existence of IL-10-competent B cells is now well established, it is not yet known how different immune cell types cross talk with B cells and affect IL-10-competent B cell differentiation and expansion. Mast cells (MCs) contribute to the differentiation and influence the effector functions of various immune cells, including B lymphocytes. In this study, we explored whether MCs could play a role in the expansion of IL-10-competent B cells and addressed the in vivo relevance of MC deficiency on the generation of these cells. We show that MCs can expand IL-10-competent B cells, but they do not directly induce IL-10 production; moreover, the absence of MCs negatively affects IL-10-competent B cell differentiation. Noteworthy, our findings reveal that the CD40L/CD40 axis plays a significant role in MC-driven expansion of IL-10-competent B cells in vitro and highlight the importance of MC CD40L signaling in the colon. PMID:25267976

Mion, Francesca; D'Incà, Federica; Danelli, Luca; Toffoletto, Barbara; Guarnotta, Carla; Frossi, Barbara; Burocchi, Alessia; Rigoni, Alice; Gerdes, Norbert; Lutgens, Esther; Tripodo, Claudio; Colombo, Mario P; Rivera, Juan; Vitale, Gaetano; Pucillo, Carlo E

2014-11-01

268

Stromal Cell-Independent B-Cell Development In Vitro: Generation and Recovery of Autoreactive Clones  

PubMed Central

We describe and characterize a stromal-cell independent culture system that efficiently supports pro-B cell to IgM+ B-cell development with near normal levels of IgH and Ig? diversity. Pro-B cells present in non-adherent bone marrow cells proliferate in the presence of IL-7 and subsequent to the removal of IL-7 and addition of BAFF, differentiate normally into IgM+ B cells. B-cell development in vitro closely follows the patterns of development in vivo with culture derived (CD) B cells demonstrating characteristic patterns of surface antigen expression and gene activation. IgM+ CD B cells respond to TLR stimulation by proliferation and differentiation into antibody-secreting cells. Self-reactive IgM+ B-cell development is blocked in 3H9 IgH knockin mice; however, cultures of 3H9 IgH knockin pro-B cells yields high frequencies of “forbidden”, autoreactive IgM+ B cells. Furthermore, serum IgG autoantibody exceeded that present in autoimmune, C4?/? animals following the reconstitution of RAG1?/? mice with IgM+ CD cells derived from BL/6 mice. PMID:20109461

Holl, T. Matt; Haynes, Barton F.; Kelsoe, Garnett

2013-01-01

269

Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas  

PubMed Central

Background The biologic heterogeneity of soft tissue sarcomas (STS), even within histological subtypes, complicates treatment. In earlier studies, gene expression patterns that distinguish two subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF) were used to separate 73 STS into two or four groups with different probabilities of developing metastatic disease (PrMet). This study was designed to confirm our earlier observations in a larger independent data set. Methods We utilized these gene sets, hierarchical clustering (HC), and Kaplan-Meier analysis, to examine 309 STS, using Affymetrix chip expression profiling. Results HC using the combined AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p = 0.048), and also among the four different clusters defined by the second branch points (p < 0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UPS) (p = 0.0004). HC of both the LipoD and UPS sample sets divided the samples into two groups with different PrMet (p = 0.0128, and 0.0002, respectively). HC of the UPS samples also showed four groups with different PrMet (p = 0.0007). HC found no subgroups of the LMS samples. Conclusions These data confirm our earlier studies, and suggest that this approach may allow the identification of more than two subsets of STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management. PMID:24950699

2014-01-01

270

B Cells Promote Tumor Progression via STAT3 Regulated-Angiogenesis  

PubMed Central

The role of B cells in cancer and the underlying mechanisms remain to be further explored. Here, we show that tumor-associated B cells with activated STAT3 contribute to tumor development by promoting tumor angiogenesis. B cells with or without Stat3 have opposite effects on tumor growth and tumor angiogenesis in both B16 melanoma and Lewis Lung Cancer mouse models. Ex vivo angiogenesis assays show that B cell-mediated tumor angiogenesis is mainly dependent on the induction of pro-angiogenic gene expression, which requires Stat3 signaling in B cells. Furthermore, B cells with activated STAT3 are mainly found in or near tumor vasculature and correlate significantly with overall STAT3 activity in human tumors. Moreover, the density of B cells in human tumor tissues correlates significantly with expression levels of several STAT3-downstream pro-angiogenic genes, as well as the degree of tumor angiogenesis. Together, these findings define a novel role of B cells in promoting tumor progression through angiogenesis and identify STAT3 in B cells as potential therapeutic target for anti-angiogenesis therapy. PMID:23734190

Pal, Sumanta; Jove, Veronica; Deng, Jiehui; Zhang, Wang; Hoon, Dave S. B.; Wakabayashi, Mark; Forman, Stephen; Yu, Hua

2013-01-01

271

Chronic hepatitis C virus infection breaks tolerance and drives polyclonal expansion of autoreactive B cells.  

PubMed

Chronic Hepatitis C virus (HCV) infection has been linked with B cell lymphoproliferative disorders and several autoimmune-related diseases. The mechanisms of how chronic viral infection affects B cell development and predisposes the patients to autoimmune manifestations are poorly understood. In this study, we established an experimental system to probe the B cell responses and characterize the antibodies from chronic-HCV-infected individuals. We identified an unusual polyclonal expansion of the IgM memory B cell subset in some patients. This B cell subset is known to be tightly regulated, and autoreactive cells are eliminated by tolerance mechanisms. Genetic analysis of the immunoglobulin (Ig) heavy chain variable gene (V(H)) sequences of the expanded cell population showed that the levels of somatic hypermutation (SHM) correlate with the extent of cell expansion in the patients and that the V(H) genes exhibit signs of antigen-mediated selection. Functional analysis of the cloned B cell receptors demonstrated autoreactivity in some of the expanded IgM memory B cells in the patients which is not found in healthy donors. In summary, this study demonstrated that, in some patients, chronic HCV infection disrupts the tolerance mechanism that normally deletes autoreactive B cells, therefore increasing the risk of developing autoimmune antibodies. Long-term follow-up of this expanded B cell subset within the infected individuals will help determine whether these cells are predictors of more-serious clinical manifestations. PMID:22623650

Roughan, Jill E; Reardon, Kathryn M; Cogburn, Kristin E; Quendler, Heribert; Pockros, Paul J; Law, Mansun

2012-07-01

272

Cloning and functional expression of a gene encoding a vacuolar-type proton-translocating pyrophosphatase from Trypanosoma cruzi.  

PubMed Central

Acidocalcisomes are acidic Ca(2+)-storage organelles found in trypanosomatids that are similar to organelles known historically as volutin granules. Acidification of these organelles is driven in part by a vacuolar H(+)-pyrophosphatase (V-H(+)-PPase), an enzyme that is also present in plant vacuoles and in some bacteria. Here, we report the cloning and sequencing of a gene encoding the acidocalcisomal V-H(+)-PPase of Trypanosoma cruzi. The protein (T. cruzi pyrophosphatase, TcPPase) predicted from the nucleotide sequence of the gene has 816 amino acids and a molecular mass of 85 kDa. Several sequence motifs found in plant V-H(+)-PPases were present in TcPPase, explaining its sensitivity to N-ethylmaleimide and N,N'-dicyclohexylcarbodi-imide. Heterologous expression of the cDNA encoding TcPPase in the yeast Saccharomyces cerevisiae produced a functional enzyme. Phylogenetic analysis of the available V-H(+)-PPase sequences indicates that TcPPase is nearer to the vascular plant cluster and the branch containing Chara, a precursor to land plants, than to any of the other pyrophosphatase sequences included in the analysis. The apparent lack of such a V-H(+)-PPase in mammalian cells may provide a target for the development of new drugs. PMID:10998372

Hill, J E; Scott, D A; Luo, S; Docampo, R

2000-01-01

273

Regulation of Hepatitis C Virus Replication by Nuclear Translocation of Nonstructural 5A Protein and Transcriptional Activation of Host Genes  

PubMed Central

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is involved in regulating viral replication through its direct interaction with the HCV RNA-dependent RNA polymerase. NS5A also alters infected cell metabolism through complex interactions with numerous host cell proteins. NS5A has furthermore been suggested to act as a transcriptional activator, although the impact on viral replication is unclear. To study this, HCV NS5A variants were amplified from hepatic tissue from an HCV-infected patient, and their abilities to activate gene transcription were analyzed in a single-hybrid yeast (Saccharomyces cerevisiae) model. Different variants isolated from the same patient displayed different transactivational activities. When these variants were inserted into the HCV subgenomic replicon system, they demonstrated various levels of RNA replication, which correlated with their transactivational activities. We showed that the C-terminal fragment of NS5A was localized to the nucleus and that a functional NS5A nuclear localization signal and cellular caspase activity were required for this process. Furthermore, nuclear localization of NS5A was necessary for viral replication. Finally, we demonstrate that nuclear NS5A binds to host cell promoters of several genes previously identified as important for efficient HCV RNA replication, inducing their transcription. Taken together, these results demonstrate a new mechanism by which HCV modulates its cellular environment, thereby enhancing viral replication. PMID:23468497

Maqbool, Muhammad Ahmad; Imache, Mohamed R.; Higgs, Martin R.; Carmouse, Sophie; Pawlotsky, Jean-Michel

2013-01-01

274

Peripheral B cells latently infected with Epstein–Barr virus display molecular hallmarks of classical antigen-selected memory B cells  

PubMed Central

Epstein–Barr virus (EBV) establishes a lifelong persistent infection within peripheral blood B cells with the surface phenotype of memory cells. To date there is no proof that these cells have the genotype of true germinal-center-derived memory B cells. It is critical to understand the relative contribution of viral mimicry versus antigen signaling to the production of these cells because EBV encodes proteins that can affect the surface phenotype of infected cells and provide both T cell help and B cell receptor signals in the absence of cognate antigen. To address these questions we have developed a technique to identify single EBV-infected cells in the peripheral blood and examine their expressed Ig genes. The genes were all isotype-switched and somatically mutated. Furthermore, the mutations do not cause stop codons and display the pattern expected for antigen-selected memory cells based on their frequency, type, and location within the Ig gene. We conclude that latently infected peripheral blood B cells display the molecular hallmarks of classical antigen-selected memory B cells. Therefore, EBV does not disrupt the normal processing of latently infected cells into memory, and deviations from normal B cell biology are not tolerated in the infected cells. This article provides definitive evidence that EBV in the peripheral blood persists in true memory B cells. PMID:16330748

Souza, Tatyana A.; Stollar, B. David; Sullivan, John L.; Luzuriaga, Katherine; Thorley-Lawson, David A.

2005-01-01

275

A gene cluster involved in aerial mycelium formation in Streptomyces griseus encodes proteins similar to the response regulators of two-component regulatory systems and membrane translocators.  

PubMed Central

Mutants of Streptomyces griseus deficient in A-factor production are sporulation negative, since A-factor is an essential hormonal regulator for the induction of morphological and physiological differentiation in this bacterium. A DNA fragment which induced aerial mycelium formation and sporulation in an A-factor-deficient mutant strain, S. griseus HH1, was cloned from this mutant strain. Subcloning experiments and nucleotide sequencing showed that two open reading frames, ORF1 with 656 amino acids and ORF2 with 201 amino acids, were required in order to induce sporulation. The amino acid sequence of ORF1 significantly resembled that of the Escherichia coli HlyB protein, a member of a family of bacterial membrane proteins engaged in ATP-dependent secretion mechanisms. Conserved features of this surface translocator family, such as the transmembrane structure predicted by their hydropathy profiles and the amino acid sequence forming an ATP-binding fold, were also conserved in ORF1. The ORF1 gene appeared to constitute a transcriptional unit with an additional upstream gene encoding ORF3, which was greatly similar to ORF1 in size and amino acid sequence. The other protein, ORF2, showed significant end-to-end homology with the E. coli uhpA product, a regulatory protein for the uptake of sugar phosphates. Like UhpA as a response regulator of a bacterial two-component regulatory system, ORF2 contained a helix-turn-helix DNA-binding domain at its COOH-terminal portion and an Asp residue (Asp-54) probably to be phosphorylated at its NH2-terminal portion. An amino acid replacement from Asp-54 to Asn resulted in the loss of the ability of ORF2 to induce sporulation in strain HH1. Images PMID:8458843

Ueda, K; Miyake, K; Horinouchi, S; Beppu, T

1993-01-01

276

socs7, a target gene of microRNA-145, regulates interferon-? induction through STAT3 nuclear translocation in bladder cancer cells  

PubMed Central

We recently reported that microRNA (miR)-145 is downregulated and induces apoptosis in human bladder cancer cells. Also, it is suggested that the ectopic expression of miR-145 induces apoptosis with the induction of TRAIL expression in several cancer cells. Here, we demonstrated a novel mechanism of apoptosis induction by miR-145 in bladder cancer cells. Exogenous miR-145 in T24 and NKB1 cells markedly increased the expression levels of interferon (IFN)-?, 2?–5?-oligoadenylate synthetase 1, which lies upstream of 2?–5? oligoadenylates/RNase L system, and TRAIL, and induced apparent caspase-dependent apoptosis that was suppressed by cotreatment with a pan-caspase inhibitor; moreover, these expression levels were reduced by cotreatment with an miR-145 inhibitor. The apoptosis did not depend on Toll-like receptor 3 (TLR3) expression, because TLR3-silencing failed to inhibit IFN-? induction by miR-145. Then, we focused on the suppressor of cytokine signaling 7 (socs7), whose expression level was upregulated in bladder cancer cells compared with its level in normal human urothelial cells, as a putative target gene involved in IFN-? induction by miR-145. Expectedly, exogenous miR-145 decreased the expression level of SOCS7, and socs7-silencing enhanced IFN-? induction by transfection with a TLR3 ligand, polyinosinic acid-polycytidylic acid (PIC). The results of a luciferase reporter assay revealed that miR-145 targeted socs7. In addition, socs7-silencing significantly decreased the level of p-Akt and suppressed the growth of T24 cells. Furthermore, exogenous miR-145 or socs7-silencing promoted nuclear translocation of STAT3. In conclusion, the machinery of IFN-? induction through the regulation of SOCS7 by miR-145 was closely associated with the induction of apoptosis. Moreover, exogenous miR-145 promoted IFN-? induction by targeting socs7, which resulted in the nuclear translocation of STAT3. Additionally, our data indicate that SOCS7 functioned as an oncogene, the finding that revealed a novel mechanism of carcinogenesis in bladder cancer cells. PMID:23392170

Noguchi, S; Yamada, N; Kumazaki, M; Yasui, Y; Iwasaki, J; Naito, S; Akao, Y

2013-01-01

277

Several lymphoma-specific genetic events in parallel can be found in mature B-cell neoplasms.  

PubMed

The mature B-cell neoplasms frequently result from translocations involving the IGH gene localized on 14q32. In rare instances, combinations of different IGH rearrangements were described, and even coincidence of three genetic lymphoma-specific events has been rarely reported. We here present eight patients with triple hit lymphoma, and two with four different lymphoma specific events detected by chromosome banding analysis and interphase FISH (seven males, three females, 47-82 years). All showed bone marrow involvement (Burkitt's lymphoma: n = 5, diffuse large B-cell lymphoma: n = 2; features intermediate between BL/DLBCL: n = 1; secondary aggressive B-cell lymphoma: n = 1; follicular lymphoma: n = 1). Eight patients had triple hit lymphoma combining IGH-BCL2/t(14;18)(q32;q21), MYC/8q24, and BCL6/3q27 rearrangements. Two showed an additional IGH-CCND1/t(11;14)(q13;q32) as fourth genetic event (according to research of the Mitelman database, the first reports on four genetic hits in lymphomas). All cases had complex aberrant karyotypes (median, 11 cytogenetic alterations per patient). Interphase FISH revealed a high rate of CDKN2A deletions (five of nine cases investigated; 56%), being homozygous in two of these cases. At the time of study, four of nine patients with follow-up data were alive (44%), one of these in remission. The two patients with four genetic hits died 6 and 9 days from diagnosis. Additional cases of lymphomas with three or four genetic hits should be collected to evaluate whether their clinical course differs from dual hit lymphomas. PMID:20960563

Bacher, Ulrike; Haferlach, Torsten; Alpermann, Tamara; Kern, Wolfgang; Schnittger, Susanne; Haferlach, Claudia

2011-01-01

278

Mechanisms of Gene Duplication and Translocation and Progress towards Understanding Their Relative Contributions to Animal Genome Evolution  

PubMed Central

Duplication of genetic material is clearly a major route to genetic change, with consequences for both evolution and disease. A variety of forms and mechanisms of duplication are recognised, operating across the scales of a few base pairs upto entire genomes. With the ever-increasing amounts of gene and genome sequence data that are becoming available, our understanding of the extent of duplication is greatly improving, both in terms of the scales of duplication events as well as their rates of occurrence. An accurate understanding of these processes is vital if we are to properly understand important events in evolution as well as mechanisms operating at the level of genome organisation. Here we will focus on duplication in animal genomes and how the duplicated sequences are distributed, with the aim of maintaining a focus on principles of evolution and organisation that are most directly applicable to the shaping of our own genome. PMID:22919542

Mendivil Ramos, Olivia; Ferrier, David E. K.

2012-01-01

279

Expression of chloroplast protein genes during the cell cycle of Chlamydomonas reinhardtii: evidence for transcriptional and translocational control  

SciTech Connect

Chlamydomonas reinhardtii cells, growing synchronously under a repeating 12 h light:12 h dark cycle, were used to investigate the synthesis and regulation of chloroplast proteins. The cells accumulate chlorophyll, the major thylakoid membrane proteins, and ribulose-1,5-bisphosphate carboxylase (RuBPCase) during the light (G1) period of the cell cycle. Pulse-labeling in vivo with (/sup 3/H)arginine, and analysis of the protein synthetic capacity of thylakoid-bound polysomes in vitro, shows that these proteins are synthesized de novo during the light. Specific antibody and cloned DNA probes were obtained and used to estimate translatable and/or steady-state mRNA levels for light-harvesting (LHCII) and reaction center (D-1 and D-2) polypeptides of photosystem II, a light-harvesting polypeptide of photosystem I (LHCI), and the large (LS) and small (SS) subunits of RuBPCase. Levels of mRNA for the nuclear-encoded LHCI, LHCII and SS correlated with the synthesis of these polypeptides in vivo; they were higher in the light period and several-folded lower or absent during the dark period. The results suggest that synthesis of nuclear-encoded chloroplast proteins are regulated primarily by the level of mRNA. In contrast, regulation of chloroplast-encoded genes is achieved by controlling the translation of mRNA that is constitutively present, and by transcriptional mechanisms during light induction.

Herrin, D.L.

1986-01-01

280

B-cell maturation in chronic lymphocytic leukaemia. IV. T-cell-dependent activation of leukaemic B cells by staphylococcal enterotoxin 'superantigens'.  

PubMed Central

Staphylococcal enterotoxins (SE) are potent T-lymphocyte activators that stimulate T cells by directly cross-linking HLA-DR molecules on antigen-presenting cells with the V beta gene products of the T-cell receptor. The different SE activate all T cells expressing a given V beta, and, therefore, have been termed 'superantigens'. Here we show that SE are potent activators of leukaemic B cells from patients with chronic lymphocytic leukaemia (CLL). Purified B cells from seven of eight CLL patients with high WBC counts (greater than 80,000/microliters) responded to one or several of the tested SE (SEA, SEB, SEC1, SED, SEE) by proliferation ([3H]TdR incorporation) and/or Ig secretion. In several instances, the response of leukaemic B cells to SE was much stronger than was the response to other known B-cell activators including EBV, pokeweed mitogen (PWM), phorbolester (TPA), and Staphylococcus aureus Cowan I (SAC). The activation of leukaemic B cells by SE was strictly dependent on the addition of irradiated T cells isolated from healthy donors. FACS analysis of cultured cells ensured that the proliferating cells were indeed B cells. Taken together, these results demonstrate that SE are strong T-cell-dependent B-cell activators that, in some cases, can stimulate maturation of leukaemic B cells which are refractory to other activation signals. PMID:1572690

Duan, X; Nerl, C; Janssen, O; Kabelitz, D

1992-01-01

281

B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice  

PubMed Central

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell–intrinsic mechanisms critically contribute to WAS-associated autoimmunity. PMID:22302739

Recher, Mike; Burns, Siobhan O.; de la Fuente, Miguel A.; Volpi, Stefano; Dahlberg, Carin; Walter, Jolan E.; Moffitt, Kristin; Mathew, Divij; Honke, Nadine; Lang, Philipp A.; Patrizi, Laura; Falet, Herve; Keszei, Marton; Mizui, Masayuki; Csizmadia, Eva; Candotti, Fabio; Nadeau, Kari; Bouma, Gerben; Delmonte, Ottavia M.; Frugoni, Francesco; Fomin, Angela B. Ferraz; Buchbinder, David; Lundequist, Emma Maria; Massaad, Michel J.; Tsokos, George C.; Hartwig, John; Manis, John; Terhorst, Cox; Geha, Raif S.; Snapper, Scott; Lang, Karl S.; Malley, Richard; Westerberg, Lisa

2012-01-01

282

Genomes of Ashbya Fungi Isolated from Insects Reveal Four Mating-Type Loci, Numerous Translocations, Lack of Transposons, and Distinct Gene Duplications  

PubMed Central

The filamentous fungus Ashbya gossypii is a cotton pathogen transmitted by insects. It is readily grown and manipulated in the laboratory and is commercially exploited as a natural overproducer of vitamin B2. Our previous genome analysis of A. gossypii isolate ATCC10895, collected in Trinidad nearly 100 years ago, revealed extensive synteny with the Saccharomyces cerevisiae genome, leading us to use it as a model organism to understand the evolution of filamentous growth. To further develop Ashbya as a model system, we have investigated the ecological niche of A. gossypii and isolated additional strains and a sibling species, both useful in comparative analysis. We isolated fungi morphologically similar to A. gossypii from different plant-feeding insects of the suborder Heteroptera, generated a phylogenetic tree based on rDNA-ITS sequences, and performed high coverage short read sequencing with one A. gossypii isolate from Florida, a new species, Ashbya aceri, isolated in North Carolina, and a genetically marked derivative of ATCC10895 intensively used for functional studies. In contrast to S. cerevisiae, all strains carry four not three mating type loci, adding a new puzzle in the evolution of Ashbya species. Another surprise was the genome identity of 99.9% between the Florida strain and ATCC10895, isolated in Trinidad. The A. aceri and A. gossypii genomes show conserved gene orders rearranged by eight translocations, 90% overall sequence identity, and fewer tandem duplications in the A. aceri genome. Both species lack transposable elements. Finally, our work identifies plant-feeding insects of the suborder Heteroptera as the most likely natural reservoir of Ashbya, and that infection of cotton and other plants may be incidental to the growth of the fungus in its insect host. PMID:23749448

Dietrich, Fred S.; Voegeli, Sylvia; Kuo, Sidney; Philippsen, Peter

2013-01-01

283

Carabin deficiency in B cells increases BCR-TLR9 costimulation-induced autoimmunity  

PubMed Central

The mechanisms behind flares of human autoimmune diseases in general, and of systemic lupus in particular, are poorly understood. The present scenario proposes that predisposing gene defects favour clinical flares under the influence of external stimuli. Here, we show that Carabin is low in B cells of (NZB × NZW) F1 mice (murine SLE model) long before the disease onset, and is low in B cells of lupus patients during the inactive phases of the disease. Using knock-out and B-cell-conditional knock-out murine models, we identify Carabin as a new negative regulator of B-cell function, whose deficiency in B cells speeds up early B-cell responses and makes the mice more susceptible to anti-dsDNA production and renal lupus flare after stimulation with a Toll-like Receptor 9 agonist, CpG-DNA. Finally, in vitro analysis of NF?B activation and Erk phosphorylation in TLR9- and B-cell receptor (BCR)-stimulated Carabin-deficient B cells strongly suggests how the internal defect synergizes with the external stimulus and proposes Carabin as a natural inhibitor of the potentially dangerous crosstalk between BCR and TLR9 pathways in self-reactive B cells. PMID:23109291

Schickel, Jean-Nicolas; Pasquali, Jean-Louis; Soley, Anne; Knapp, Anne-Marie; Decossas, Marion; Kern, Aurelie; Fauny, Jean-Daniel; Marcellin, Luc; Korganow, Anne-Sophie; Martin, Thierry; Soulas-Sprauel, Pauline

2012-01-01

284

Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells  

PubMed Central

Regulatory T cells (Tregs) play an essential role in preventing autoimmunity. Mutations in the forkhead box protein 3 (FOXP3) gene, which encodes a transcription factor critical for Treg function, result in a severe autoimmune disorder and the production of various autoantibodies in mice and in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. However, it is unknown whether Tregs normally suppress autoreactive B cells. To investigate a role for Tregs in maintaining human B-cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells isolated from IPEX patients. Characteristics and reactivity of antibodies expressed by new emigrant/transitional B cells from IPEX patients were similar to those from healthy donors, demonstrating that defective Treg function does not impact central B-cell tolerance. In contrast, mature naive B cells from IPEX patients often expressed autoreactive antibodies, suggesting an important role for Tregs in maintaining peripheral B-cell tolerance. T cells displayed an activated phenotype in IPEX patients, including their Treg-like cells, and showed up-regulation of CD40L, PD-1, and inducibl T-cell costimulator (ICOS), which may favor the accumulation of autoreactive mature naive B cells in these patients. Hence, our data demonstrate an essential role for Tregs in the establishment and the maintenance of peripheral B-cell tolerance in humans. PMID:23223361

Kinnunen, Tuure; Chamberlain, Nicolas; Morbach, Henner; Choi, Jinyoung; Kim, Sangtaek; Craft, Joseph; Mayer, Lloyd; Cancrini, Caterina; Passerini, Laura; Bacchetta, Rosa; Ochs, Hans D.; Torgerson, Troy R.

2013-01-01

285

Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells.  

PubMed

Regulatory T cells (Tregs) play an essential role in preventing autoimmunity. Mutations in the forkhead box protein 3 (FOXP3) gene, which encodes a transcription factor critical for Treg function, result in a severe autoimmune disorder and the production of various autoantibodies in mice and in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. However, it is unknown whether Tregs normally suppress autoreactive B cells. To investigate a role for Tregs in maintaining human B-cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells isolated from IPEX patients. Characteristics and reactivity of antibodies expressed by new emigrant/transitional B cells from IPEX patients were similar to those from healthy donors, demonstrating that defective Treg function does not impact central B-cell tolerance. In contrast, mature naive B cells from IPEX patients often expressed autoreactive antibodies, suggesting an important role for Tregs in maintaining peripheral B-cell tolerance. T cells displayed an activated phenotype in IPEX patients, including their Treg-like cells, and showed up-regulation of CD40L, PD-1, and inducibl T-cell costimulator (ICOS), which may favor the accumulation of autoreactive mature naive B cells in these patients. Hence, our data demonstrate an essential role for Tregs in the establishment and the maintenance of peripheral B-cell tolerance in humans. PMID:23223361

Kinnunen, Tuure; Chamberlain, Nicolas; Morbach, Henner; Choi, Jinyoung; Kim, Sangtaek; Craft, Joseph; Mayer, Lloyd; Cancrini, Caterina; Passerini, Laura; Bacchetta, Rosa; Ochs, Hans D; Torgerson, Troy R; Meffre, Eric

2013-02-28

286

14-3-3? regulates B-cell homeostasis through stabilization of FOXO1  

PubMed Central

14-3-3? regulates cytokinesis and cell cycle arrest induced by DNA damage but its role in the immune system is unknown. Using gene-targeted 14-3-3?–deficient (i.e., KO) mice, we studied the role of 14-3-3? in B-cell functions. Total numbers of B cells were reduced by spontaneous apoptosis of peripheral B cells. Upon B-cell antigen receptor engagement in vitro, KO B cells did not proliferate properly or up-regulate CD86. In response to T cell-independent antigens, KO B cells showed poor secretion of antigen-specific IgM. This deficit led to increased lethality of KO mice after vesicular stomatitis virus infection. KO B cells showed elevated total FOXO transcriptional activity but also increased FOXO1 degradation. Coimmunoprecipitation revealed that endogenous 14-3-3? protein formed a complex with FOXO1 protein. Our results suggest that 14-3-3? maintains FOXO1 at a consistent level critical for normal B-cell antigen receptor signaling and B-cell survival. PMID:21205887

Su, Yu-Wen; Hao, Zhenyue; Hirao, Atsushi; Yamamoto, Kazuo; Lin, Wen-Jye; Young, Ashley; Duncan, Gordon S.; Yoshida, Hiroki; Wakeham, Andrew; Lang, Philipp A.; Murakami, Kiichi; Hermeking, Heiko; Vogelstein, Bert; Ohashi, Pamela; Mak, Tak W.

2011-01-01

287

NFATc1 affects mouse splenic B cell function by controlling the calcineurin-NFAT signaling network  

PubMed Central

By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/?A, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell–independent type II antigens, as well as IgG3+ plasmablast formation. Mice bearing NFATc1?/? B cells harbor twofold more interleukin 10–producing B cells. NFATc1?/? B cells suppress the synthesis of interferon-? by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1?/? B cells are caused by decreased BCR-induced Ca2+ flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/?A expression, NFATc1 controls the Ca2+-dependent Cn–NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation. PMID:21464221

Bhattacharyya, Sankar; Deb, Jolly; Patra, Amiya K.; Thuy Pham, Duong Anh; Chen, Wen; Vaeth, Martin; Berberich-Siebelt, Friederike; Klein-Hessling, Stefan; Lamperti, Edward D.; Reifenberg, Kurt; Jellusova, Julia; Schweizer, Astrid; Nitschke, Lars; Leich, Ellen; Rosenwald, Andreas; Brunner, Cornelia; Engelmann, Swen; Bommhardt, Ursula; Avots, Andris; Muller, Martin R.; Kondo, Eisaku

2011-01-01

288

A Novel VHH Antibody Targeting the B Cell-Activating Factor for B-Cell Lymphoma  

PubMed Central

Objective: To construct an immune alpaca phage display library, in order to obtain a single domain anti-BAFF (B cell-activating factor) antibody. Methods: Using phage display technology, we constructed an immune alpaca phage display library, selected anti-BAFF single domain antibodies (sdAbs), cloned three anti-BAFF single-domain antibody genes into expression vector pSJF2, and expressed them efficiently in Escherichia coli. The affinity of different anti-BAFF sdAbs were measured by Bio layer interferometry. The in vitro biological function of three sdAbs was investigated by cell counting kit-8 (CCK-8) assay and a competitive enzyme-linked immunosorbent assay (ELISA). Results: We obtained three anti-BAFF single domain antibodies (anti-BAFF64, anti-BAFF52 and anti-BAFFG3), which were produced in high yield in Escherichia coli and inhibited tumor cell proliferation in vitro. Conclusion: The selected anti-BAFF antibodies could be candidates for B-cell lymphoma therapies. PMID:24879522

Wu, Wen; Li, Shenghua; Zhang, Weijing; Sun, Jian; Ren, Guangda; Dong, Quanchao

2014-01-01

289

Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals  

PubMed Central

Pre-B cell receptor (pre-BCR) signaling and migration from IL-7–rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C? stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Ig? germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7–dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C? and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development. PMID:24297995

Heizmann, Beate

2013-01-01

290

Human regulatory B cells combine phenotypic and genetic hallmarks with a distinct differentiation fate.  

PubMed

Regulatory B cells (B-reg) produce IL-10 and suppress inflammation in both mice and humans, but limited data on the phenotype and function of these cells have precluded detailed assessment of their contribution to host immunity. In this article, we report that human B-reg cannot be defined based on a phenotype composed of conventional B cell markers, and that IL-10 production can be elicited in both the CD27(+) memory population and naive B cell subset after only a brief stimulation in vitro. We therefore sought to obtain a better definition of IL-10-producing human B-regs using a multiparameter analysis of B cell phenotype, function, and gene expression profile. Exposure to CpG and anti-Ig are the most potent stimuli for IL-10 secretion in human B cells, but microarray analysis revealed that human B cells cotreated with these reagents resulted in only ?0.7% of genes being differentially expressed between IL-10(+) and IL-10(-) cells. Instead, connectivity map analysis revealed that IL-10-secreting B cells are those undergoing specific differentiation toward a germinal center fate, and we identified a CD11c(+) B cell subset that was not capable of producing IL-10 even under optimal conditions. Our findings will assist in the identification of a broader range of human pro-B-reg populations that may represent novel targets for immunotherapy. PMID:25080484

Lin, Wenyu; Cerny, Daniela; Chua, Edmond; Duan, Kaibo; Yi, June Tai Jing; Shadan, Nurhidaya Binte; Lum, Josephine; Maho-Vaillant, Maud; Zolezzi, Francesca; Wong, Siew Cheng; Larbi, Anis; Fink, Katja; Musette, Philippe; Poidinger, Michael; Calbo, Sébastien

2014-09-01

291

Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis  

PubMed Central

Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies. PMID:22312109

Du, Likun; Peng, Roujun; Bjorkman, Andrea; Filipe de Miranda, Noel; Rosner, Cornelia; Kotnis, Ashwin; Berglund, Mattias; Liu, Chonghai; Rosenquist, Richard; Enblad, Gunilla; Sundstrom, Christer; Hojjat-Farsangi, Mohammad; Rabbani, Hodjattallah; Teixeira, Manuel R.; Revy, Patrick; Durandy, Anne; Zeng, Yixin; Gennery, Andrew R.; de Villartay, Jean-Pierre

2012-01-01

292

KLF2- A Negative Regulator of Pre-B Cell Clonal Expansion and B Cell Activation  

PubMed Central

Maturation as well as antigen-dependent activation of B cells is accompanied by alternating phases of proliferation and quiescence. We and others have previously shown that Krüppel-like factor 2 (KLF2), a regulator of T cell quiescence and migration, is upregulated in small resting precursor (pre)-B cells after assembly of the immature pre-B cell receptor (pre-BCR) and is downregulated upon antigen-induced proliferation of mature B cells. These findings suggest that KLF2, besides its function in maintaining follicular B cell identity, peripheral B cell homeostasis and homing of antigen-specific plasma cells to the bone marrow, also controls clonal expansion phases in the B cell lineage. Here, we demonstrate that enforced expression of KLF2 in primary pre-B cells results in a severe block of pre-BCR-induced proliferation, upregulation of the cell cycle inhibitors p21 and p27 and downregulation of c-myc. Furthermore, retroviral KLF2 transduction of primary B cells impairs LPS-induced activation, favors apoptosis and results in reduced abundance of factors, such as AID, IRF4 and BLIMP1, that control the antigen-dependent phase of B cell activation and plasma cell differentiation. Hence, we conclude that KLF2 is not only a key player in terminating pre-B cell clonal expansion but also a potent suppressor of B cell activation. PMID:24874925

Winkelmann, Rebecca; Sandrock, Lena; Kirberg, Jorg; Jack, Hans-Martin; Schuh, Wolfgang

2014-01-01

293

KLF2--a negative regulator of pre-B cell clonal expansion and B cell activation.  

PubMed

Maturation as well as antigen-dependent activation of B cells is accompanied by alternating phases of proliferation and quiescence. We and others have previously shown that Krüppel-like factor 2 (KLF2), a regulator of T cell quiescence and migration, is upregulated in small resting precursor (pre)-B cells after assembly of the immature pre-B cell receptor (pre-BCR) and is downregulated upon antigen-induced proliferation of mature B cells. These findings suggest that KLF2, besides its function in maintaining follicular B cell identity, peripheral B cell homeostasis and homing of antigen-specific plasma cells to the bone marrow, also controls clonal expansion phases in the B cell lineage. Here, we demonstrate that enforced expression of KLF2 in primary pre-B cells results in a severe block of pre-BCR-induced proliferation, upregulation of the cell cycle inhibitors p21 and p27 and downregulation of c-myc. Furthermore, retroviral KLF2 transduction of primary B cells impairs LPS-induced activation, favors apoptosis and results in reduced abundance of factors, such as AID, IRF4 and BLIMP1, that control the antigen-dependent phase of B cell activation and plasma cell differentiation. Hence, we conclude that KLF2 is not only a key player in terminating pre-B cell clonal expansion but also a potent suppressor of B cell activation. PMID:24874925

Winkelmann, Rebecca; Sandrock, Lena; Kirberg, Jörg; Jäck, Hans-Martin; Schuh, Wolfgang

2014-01-01

294

Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells.  

PubMed Central

Transcription of the human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest events that occurs after stimulation of B or T cells via their antigen receptors. Antibody directed at surface immunoglobulin (anti-Ig) on B cells has previously been shown to induce a rapid burst of TNF-alpha gene transcription, which can be blocked by the immunosuppressants cyclosporin A (CsA) and FK506. Here, TNF-alpha gene transcription is shown also to be highly and rapidly induced in human B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analogues that block calcineurin phosphatase activity. Endogenous TNF-alpha produced after stimulation was involved in B-cell proliferation since anti-TNF-alpha monoclonal antibody inhibited both anti-Ig- and anti-CD40-induced B-cell proliferative responses. Moreover, addition of TNF-alpha during stimulation resulted in augmentation of B-cell proliferation, which was also inhibited by anti-TNF-alpha monoclonal antibody. Although lymphotoxin alpha (LT-alpha) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-beta mRNA is constitutively expressed in B cells. Thus, TNF-alpha is a necessary autocrine growth factor for human B cells stimulated via two independent CsA-sensitive pathways and plays a role similar to that of interleukin 2 in T-cell proliferation. The autocrine nature of TNF-alpha in activated B cells implies a potential role for this cytokine in infection-related polyclonal B-cell expansion and in B-cell malignancies. Images PMID:7518925

Boussiotis, V A; Nadler, L M; Strominger, J L; Goldfeld, A E

1994-01-01

295

WNT and FGF gene clusters (review).  

PubMed

Mouse mammary tumor virus (MMTV) is a retrovirus, activating Wnt genes (Wnt1/int-1, Wnt3/int-4, Wnt10b), Fgf genes (Fgf3/int-2, Fgf4, Fgf8) and other genes (Notch4/int-3, Eif3s6/int-6) due to proviral integration. Among 19 WNT genes, WNT3 and WNT14B genes are clustered in human chromosome 17q21, WNT3A and WNT14 in human chromosome 1q42, WNT10A and WNT6 in human chromosome 2q35, and WNT10B and WNT1 in human chromosome 12q13. Among 22 FGF genes, FGF19, FGF4 and FGF3 genes are clustered in human chromosome 11q13, while FGF23 and FGF6 in human chromosome 12p13. WNT and FGF gene clusters are conserved between the human genome and the mouse genome. Activation of mouse Wnt or Fgf genes due to proviral integration of MMTV occurs in 5 out of 13 clustered genes, and in 1 out of 28 solitary genes (p=0.0033), which clearly indicates that mouse Wnt or Fgf gene clusters are recombination hot spots associated with carcinogenesis. Recombination results in retroviral integration as well as in chromosomal translocation, gene amplification and deletion during carcinogenesis. The CCND1-FGF19-FGF4-FGF3 gene cluster in human chromosome 11q13 is amplified in breast cancer, squamous cell carcinoma of head and neck, and bladder tumors, and is also translocated in parathyroid tumors and B-cell lymphoma. WNT gene clusters on human chromosome 1q42, 2q35, 12q13, and 17q21 as well as FGF gene cluster on human chromosome 12p13 might be amplified or translocated in human cancer just like FGF gene cluster on human chromosome 11q13. PMID:12429977

Katoh, Masaru

2002-12-01

296

The Epstein-Barr Virus (EBV) BZLF2 Gene Product Associates with the gH and gL Homologs of EBV and Carries an Epitope Critical to Infection of B Cells but Not of Epithelial Cells  

Microsoft Academic Search

Glycoprotein gp85, the product of the BXLF2 open reading frame (ORF), is the gH homolog of Epstein-Barr virus (EBV) and has been implicated in penetration of virus into B cells. Like its counterparts in other herpesviruses, it associates with a gL homolog, gp25, which is the product of the BKRF2 ORF. Unlike the gH homologs of other herpesviruses, however, gp85

QINGXUE LI; SUSAN M. TURK; ANDLINDSEY M. HUTT-FLETCHER

1995-01-01

297

Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.  

PubMed

The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain (IGH) locus or non-IG sequences. The former translocation, t(3;14)(p13;q32), results in dysregulated expression of FOXP1 juxtaposed with strong regulatory elements of IGH. Thus far, molecular consequences of rare non-IG aberrations of FOXP1 remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non-IG rearrangements of FOXP1 are usually acquired during clinical course of various lymphoma subtypes, including diffuse large B cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukemia, and correlate with a poor prognosis. Importantly, these aberrations constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non-IG rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms (FOXP1(NT)), as shown by QRT-PCR and Western blot analysis. In contrast, t(3;14)(p13;q32)/IGH-FOXP1 affects the 5' untranslated region of FOXP1 and results in overexpress the full-length FOXP1 protein (FOXP1(FL)). RNA-sequencing of a few lymphoma cases expressing FOXP1(NT) and FOXP1(FL) detected neither FOXP1-related fusions nor FOXP1 mutations. Further bioinformatic analysis of RNA-sequencing data retrieved a set of genes, which may comprise direct or non-direct targets of FOXP1(NT), potentially implicated in disease progression. In summary, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. We hypothesize that the primary t(3;14)(p13;q32)/IGH-FOXP1 activates expression of the FOXP1(FL) protein with potent oncogenic activity, whereas the secondary non-IG rearrangements of FOXP1 promote expression of the FOXP1(NT) proteins, likely driving progression of disease. PMID:24416450

Rouhigharabaei, Leila; Finalet Ferreiro, Julio; Tousseyn, Thomas; van der Krogt, Jo-Anne; Put, Natalie; Haralambieva, Eugenia; Graux, Carlos; Maes, Brigitte; Vicente, Carmen; Vandenberghe, Peter; Cools, Jan; Wlodarska, Iwona

2014-01-01

298

Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated Isoforms of FOXP1  

PubMed Central

The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain (IGH) locus or non-IG sequences. The former translocation, t(3;14)(p13;q32), results in dysregulated expression of FOXP1 juxtaposed with strong regulatory elements of IGH. Thus far, molecular consequences of rare non-IG aberrations of FOXP1 remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non-IG rearrangements of FOXP1 are usually acquired during clinical course of various lymphoma subtypes, including diffuse large B cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukemia, and correlate with a poor prognosis. Importantly, these aberrations constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non-IG rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms (FOXP1NT), as shown by QRT-PCR and Western blot analysis. In contrast, t(3;14)(p13;q32)/IGH-FOXP1 affects the 5? untranslated region of FOXP1 and results in overexpress the full-length FOXP1 protein (FOXP1FL). RNA-sequencing of a few lymphoma cases expressing FOXP1NT and FOXP1FL detected neither FOXP1-related fusions nor FOXP1 mutations. Further bioinformatic analysis of RNA-sequencing data retrieved a set of genes, which may comprise direct or non-direct targets of FOXP1NT, potentially implicated in disease progression. In summary, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. We hypothesize that the primary t(3;14)(p13;q32)/IGH-FOXP1 activates expression of the FOXP1FL protein with potent oncogenic activity, whereas the secondary non-IG rearrangements of FOXP1 promote expression of the FOXP1NT proteins, likely driving progression of disease. PMID:24416450

Tousseyn, Thomas; van der Krogt, Jo-Anne; Put, Natalie; Haralambieva, Eugenia; Graux, Carlos; Maes, Brigitte; Vicente, Carmen; Vandenberghe, Peter; Cools, Jan; Wlodarska, Iwona

2014-01-01

299

The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas  

PubMed Central

We previously developed a multivariate model based on the RNA expression of 6 genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2) that predicts survival in diffuse large B-cell lymphoma (DLBCL) patients. Since LMO2 emerged as the strongest predictor of superior outcome, we generated a monoclonal anti-LMO2 antibody in order to study its tissue expression pattern. Immunohistologic analysis of over 1200 normal and neoplastic tissue and cell lines showed that LMO2 protein is expressed as a nuclear marker in normal germinal-center (GC) B cells and GC-derived B-cell lines and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors and in megakaryocytes and also in lymphoblastic and acute myeloid leukemias. It was rarely expressed in mature T, natural killer (NK), and plasma cell neoplasms and was absent from nonhematolymphoid tissues except for endothelial cells. Hierarchical cluster analysis of immunohistologic data in DLBCL demonstrated that the expression profile of the LMO2 protein was similar to that of other GC-associated proteins (HGAL, BCL6, and CD10) but different from that of non-GC proteins (MUM1/IRF4 and BCL2). Our results warrant inclusion of LMO2 in multivariate analyses to construct a clinically applicable immunohistologic algorithm for predicting survival in patients with DLBCL. PMID:17038524

Natkunam, Yasodha; Zhao, Shuchun; Mason, David Y.; Chen, Jun; Taidi, Behnaz; Jones, Margaret; Hammer, Anne S.; Hamilton Dutoit, Stephen; Lossos, Izidore S.; Levy, Ronald

2007-01-01

300

Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites.  

E-print Network

Mature B-cell neoplasm t(2;3)(p11;q27) IGK@ FRA2L BCL6 FRA3C Mature B-cell neoplasm, Follicular lymphoma t(2;11)(p11;q13) IGK@ FRA2L CCND1 FRA11A, FRA11H Mature B-cell neoplasm t(2;18)(p11;q21) IGK@ FRA2L FVT1 FRA18B Follicular lymphoma t(3;16)(q27;p12... FRA10G RET FRA10G Papillary thyroid carcinoma t(3;5)(q25;q35) NPM1 FRA5G MLF1 FRA3D Acute myeloid leukemia t(3;6)(q27;p21) PIM1 FRA6H BCL6 FRA3C Diffuse large B-cell lymphoma t(3;6)(q27;p21) SFRS3 FRA6H BCL6 FRA3C Follicular lymphoma t(19;19)(p13;q13...

Burrow, Allison A.; Williams, Laura E.; Pierce, Levi C. T.; Wang, Yuh-Hwa

2009-01-30

301

Stochastic pairing of Ig heavy and light chains frequently generates B cell antigen receptors that are subject to editing in vivo  

Microsoft Academic Search

We examined the generation and selection of the B cell antibody repertoire through crossing of mice bearing distinct Ig heavy (H) and light (L) chain rearranged variable region transgenes. Ig gene knock- in and transgenic mice whose H and L chains pair to form a non-autoreactive, functional B cell antigen receptor (BCR) have significantly reduced pre-B cells in the bone

Tatiana Novobrantseva; Shengli Xu; Joy En-Lin Tan; Mitsuo Maruyama; Stephan Schwers; Roberta Pelanda; Kong-Peng Lam

2005-01-01

302

Immortalization of antigen selected B cells.  

PubMed

This paper reports the generation of monoclonal antibody producing hybridomas from a small number of antigen-specific B cells selected by panning on antigen-coated dishes and rosetting with antigen-coupled paramagnetic beads. Anti-HIV positive B cells from spleen could be recovered by panning with an efficiency of 5% and a purity of 24%. Immunobead selection of anti-HIV positive B cells from the same mice yielded a recovery of 17% and a purity of 7%. Various experimental conditions with respect to the selection of specific B cells were investigated, leading to an optimized protocol for the isolation of a limited subset of B cells. The selected cells retained their property to produce immunoglobulins and could be clonally expanded in the presence of human T cell supernatant and irradiated murine thymoma helper cells to generate sufficient cells for a mini-electrofusion with NS-1 myeloma cells. Up to 78 specific hybridomas could be generated from one anti-HIV positive B cell. An overall efficiency of specific B cell immortalization of up to 10% was obtained. PMID:7687638

Steenbakkers, P G; van Wezenbeek, P M; Olijve, W

1993-07-01

303

Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans?  

PubMed Central

Wiskott–Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott–Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1?, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21low B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients. PMID:24369837

Castiello, Maria Carmina; Bosticardo, Marita; Pala, Francesca; Catucci, Marco; Chamberlain, Nicolas; van Zelm, Menno C.; Driessen, Gertjan J.; Pac, Malgorzata; Bernatowska, Ewa; Scaramuzza, Samantha; Aiuti, Alessandro; Sauer, Aisha V.; Traggiai, Elisabetta; Meffre, Eric; Villa, Anna; van der Burg, Mirjam

2014-01-01

304

Molecular characterization of the early B cell response to pulmonary Cryptococcus neoformans infection  

PubMed Central

The role of B cells in host defense against fungi has been difficult to establish. We quantified and determined the molecular derivation of B-1a, B-1b and B-2 B-cell populations in C57BL/6 mice after pulmonary infection with Cryptococcus neoformans (CN). Total B-1 and B-2 cell numbers increased in lungs and peritoneal cavity (PerC) as early as day one post-infection, but lacked signs of clonal expansion. Labeled capsular (24067) and acapsular (Cap67) CN strains were used to identify CN-binding B-cell subsets by flow-cytometry. PerC B-1a B cells exhibited the most acapsular and capsular CN-binding in CN-infected mice and CN-selected B-1 B cells secreted laminarin- and CN-binding IgM. Single-cell PCR-based sequence analysis of B-1a, B-1b and B-2 cell immunoglobulin heavy chain variable region (VH) genes revealed increased usage of VH11 and VH12, respectively, in acapsular and capsular CN-selected B-1a cells. Germline VH segments were used with capsular CN-selected cells having less junctional diversity than acapsular CN-selected cells. Further studies in B-1 B cell-depleted mice showed that these mice had higher brain and lung fungal burdens and less alveolar macrophage phagocytosis of CN than control and B-1a B cell-reconstituted mice. Together, these results establish a mechanistic role for B-1 B cells in the innate B-cell response to pulmonary infection with CN and reveal that IgM-producing B-1a cells, which express germline VH genes, bind CN and contribute to early fungal clearance. Thus, B-1a B cells provide a first line of defense during pulmonary CN infection in mice. PMID:23175699

Rohatgi, Soma; Pirofski, Liise-anne

2012-01-01

305

Innate B cells: oxymoron or validated concept?  

PubMed Central

B lymphocytes promote the initial innate interferon response to viral pathogens without the need for antigen receptor activation. B cell dependent IFN production requires the cytokine, lymphotoxin-?. The LT? pathway is well known to regulate lymphoid organogenesis and homeostasis by differentiating stromal cells and macrophages. However, in response to viral pathogens these same B cell-regulated populations rapidly produce type 1 interferons. Thus, B cells act as innate effector cells via LT? homeostatic pathways, which serve as innate host barriers to viral pathogens. PMID:24358807

2012-01-01

306

Functionally responsive self-reactive B cells of low affinity express reduced levels of surface IgM.  

PubMed

Somatic gene rearrangement generates a diverse repertoire of B cells, many which have receptors possessing a range of affinities for self-Ag. Newly generated B cells express high and relatively uniform amounts of surface IgM (sIgM), while follicular (FO) B cells express sIgM at widely varying levels. It is plausible, therefore, that downmodulation of sIgM serves as a mechanism to maintain weakly self-reactive B cells in a responsive state by decreasing their avidity for self-Ag. We tested this hypothesis by performing comparative functional tests with FO IgM(hi) and IgM(lo) B cells from the unrestricted repertoire of WT C57BL/6 mice. We found that FO IgM(lo) B cells mobilized Ca(2+) equivalently to IgM(hi) B cells when the same number of sIgM molecules was engaged. In agreement, FO IgM(lo) B cells were functionally competent to produce an antibody response following adoptive transfer. The FO IgM(lo) cell population had elevated levels of Nur77 transcript, and was enriched with nuclear-reactive specificities. Hybridoma sampling revealed that these B-cell receptors were of low affinity. Collectively, these results suggest that sIgM downmodulation by low-affinity, self-reactive B cells preserves their immunocompetence and circumvents classical peripheral tolerance mechanisms that would otherwise reduce diversity within the B cell compartment. PMID:24375379

Kirchenbaum, Greg A; St Clair, James B; Detanico, Thiago; Aviszus, Katja; Wysocki, Lawrence J

2014-04-01

307

Themis2 is not required for B cell development, activation, and antibody responses.  

PubMed

Themis1 is a protein implicated in transducing signals from the TCR. Mice deficient in Themis1 show a strong impairment in T cell selection in the thymus and defective T cell activation. The related Themis2 protein is expressed in B cells where it associates with signaling proteins Grb2 and Vav1, and is tyrosine phosphorylated after BCR stimulation. Thus, it has been proposed that Themis2 may transduce BCR signals, and hence play important roles in B cell development and activation. In this article, we show that Themis2 is expressed in all developing subsets of B cells, in mature follicular and marginal zone B cells, and in activated B cells, including germinal center B cells and plasma cells. In contrast, B lineage cells express no other Themis-family genes. Activation of B cells leads to reduced Themis2 expression, although it remains the only Themis-family protein expressed. To analyze the physiological function of Themis2, we generated a Themis2-deficient mouse strain. Surprisingly, we found that Themis2 is not required for B cell development, for activation, or for Ab responses either to model Ags or to influenza viral infection. PMID:24907343

Hartweger, Harald; Schweighoffer, Edina; Davidson, Sophia; Peirce, Matthew J; Wack, Andreas; Tybulewicz, Victor L J

2014-07-15

308

Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity  

PubMed Central

The B cell–depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti–myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell–depleting therapies for autoimmune diseases. PMID:22426210

Maurer, Michael A.; Rakocevic, Goran; Leung, Carol S.; Quast, Isaak; Lukacisin, Martin; Goebels, Norbert; Munz, Christian; Wardemann, Hedda; Dalakas, Marinos; Lunemann, Jan D.

2012-01-01

309

CVID-associated TACI mutations affect autoreactive B cell selection and activation.  

PubMed

Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6-expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications. PMID:24051380

Romberg, Neil; Chamberlain, Nicolas; Saadoun, David; Gentile, Maurizio; Kinnunen, Tuure; Ng, Yen Shing; Virdee, Manmeet; Menard, Laurence; Cantaert, Tineke; Morbach, Henner; Rachid, Rima; Martinez-Pomar, Natalia; Matamoros, Nuria; Geha, Raif; Grimbacher, Bodo; Cerutti, Andrea; Cunningham-Rundles, Charlotte; Meffre, Eric

2013-10-01

310

A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia  

PubMed Central

We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia. Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25. PTK2 is a well-known non-receptor tyrosine kinase whereas THOC2 encodes a component of the evolutionarily conserved multiprotein THO complex, involved in mRNA export from nucleus. The translocation generated a sterile fusion transcript under the control of the PTK2 promoter, affecting expression of both PTK2 and THOC2 genes. PTK2 is involved in cell adhesion and, in neurons, plays a role in axonal guidance, and neurite growth and attraction. However, PTK2 haploinsufficiency alone is unlikely to be associated with human disease. Therefore, we studied the role of THOC2 in the CNS using three models: 1) THOC2 ortholog knockout in C. elegans which produced functional defects in specific sensory neurons; 2) Thoc2 knockdown in primary rat hippocampal neurons which increased neurite extension; 3) Thoc2 knockdown in neuronal stem cells (LC1) which increased their in vitro growth rate without modifying apoptosis levels. We suggest that THOC2 can play specific roles in neuronal cells and, possibly in combination with PTK2 reduction, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia. PMID:23749989

Di Gregorio, Eleonora; Bianchi, Federico T.; Schiavi, Alfonso; Chiotto, Alessandra M.A.; Rolando, Marco; di Cantogno, Ludovica Verdun; Grosso, Enrico; Cavalieri, Simona; Calcia, Alessandro; Lacerenza, Daniela; Zuffardi, Orsetta; Retta, Saverio Francesco; Stevanin, Giovanni; Marelli, Cecilia; Durr, Alexandra; Forlani, Sylvie; Chelly, Jamel; Montarolo, Francesca; Tempia, Filippo; Beggs, Hilary E.; Reed, Robin; Squadrone, Stefania; Abete, Maria C.; Brussino, Alessandro; Ventura, Natascia; Di Cunto, Ferdinando; Brusco, Alfredo

2014-01-01

311

Comparison of human B cell activation by TLR7 and TLR9 agonists  

PubMed Central

Background Human B cells and plasmacytoid dendritic cells (pDC) are the only cells known to express both TLR7 and TLR9. Plasmacytoid dendritic cells are the primary IFN-? producing cells in response to TLR7 and TLR9 agonists. The direct effects of TLR7 stimulation on human B cells is less understood. The objective of this study was to compare the effects of TLR7 and TLR9 stimulation on human B cell function. Results Gene expression and protein production of cytokines, chemokines, various B cell activation markers, and immunoglobulins were evaluated. Purified human CD19+ B cells (99.9%, containing both naïve and memory populations) from peripheral blood were stimulated with a TLR7-selective agonist (852A), TLR7/8 agonist (3M-003), or TLR9 selective agonist CpG ODN (CpG2006). TLR7 and TLR9 agonists similarly modulated the expression of cytokine and chemokine genes (IL-6, MIP1 alpha, MIP1 beta, TNF alpha and LTA), co-stimulatory molecules (CD80, CD40 and CD58), Fc receptors (CD23, CD32), anti-apoptotic genes (BCL2L1), certain transcription factors (MYC, TCFL5), and genes critical for B cell proliferation and differentiation (CD72, IL21R). Both agonists also induced protein expression of the above cytokines and chemokines. Additionally, TLR7 and TLR9 agonists induced the production of IgM and IgG. A TLR8-selective agonist was comparatively ineffective at stimulating purified human B cells. Conclusion These results demonstrate that despite their molecular differences, the TLR7 and TLR9 agonists induce similar genes and proteins in purified human B cells. PMID:18652679

Hanten, John A; Vasilakos, John P; Riter, Christie L; Neys, Lori; Lipson, Kenneth E; Alkan, Sefik S; Birmachu, Woubalem

2008-01-01

312

B-Cell activation and allosensitization after left ventricular assist device implantation is due to T-Cell activation and CD40 ligand expression  

Microsoft Academic Search

Left ventricular assist device (LVAD) implantation is frequently complicated by B-cell activation and allosensitization, posing a significant risk to successful transplant outcome. This study investigated whether B-cell hyperreactivity and alloantibody production in LVAD recipients involves T-cell dependent pathways. T-cell calcium flux and nuclear translocation of NFATc were used to determine states of T-cell activation. Flow cytometry was used to assess

Michael Schuster; Alfred Kocher; Ranjit John; Marion Hoffman; Jan Ankersmit; Katherine Lietz; Niloo Edwards; Mehmet Oz; Silviu Itescu

2002-01-01

313

The B cell helper side of neutrophils  

PubMed Central

Neutrophils use opsonizing antibodies to enhance the clearance of intruding microbes. Recent studies indicate that splenic neutrophils also induce antibody production by providing helper signals to B cells lodged in the MZ of the spleen. Here, we discuss the B cell helper function of neutrophils in the context of growing evidence indicating that neutrophils function as sophisticated regulators of innate and adaptive immune responses. PMID:23630389

Cerutti, Andrea; Puga, Irene; Magri, Giuliana

2013-01-01

314

B cell memory and idiotype network regulation  

Microsoft Academic Search

This investigation examined the clonal dynamics of B-cell expression and evaluated the role of idiotype network interactions in shaping the expressed secondary B-cell repertoire. Three interrelated experimental approaches were applied. The first approach was designed to distinguish between regulatory influences controlled by the major histocompatibility complex (MHC) and regulatory influences controlled by non-MHC factors including the idiotype network. This approach

Peter George Seferian

1991-01-01

315

Tissue-specific inactivation of HAT cofactor TRRAP reveals its essential role in B cells.  

PubMed

The transformation/transcription domain-associated protein (TRRAP) is a common component of many histone acetyltransferase (HAT) complexes. Targeted-deletion of the Trrap gene led to early embryonic lethality and revealed a critical function of TRRAP in cell proliferation. Here, we investigate the function of TRRAP in murine B cells. To this end, we ablated Trrap gene in a B cell-restricted manner and studied its impact on B-cell development and proliferation, a pre-requisite for class switch recombination (CSR), the process that allows IgM-expressing B lymphocytes to switch to the expression of IgG, IgE, or IgA isotypes. We show that TRRAP deficiency impairs B-cell development but does not directly affect CSR. Instead, cells induced to proliferate undergo apoptosis. Our findings demonstrate a central and general role of TRRAP in cell proliferation. PMID:24675885

Leduc, Claire; Chemin, Guillaume; Puget, Nadine; Sawan, Carla; Moutahir, Mohammed; Herceg, Zdenko; Khamlichi, Ahmed Amine

2014-05-15

316

Human B cells accumulate immunoglobulin V gene somatic mutations in a cell contact-dependent manner in cultures supported by activated T cells but not in cultures supported by CD40 ligand  

PubMed Central

The acquisition of somatic mutations in the rearranged immunoglobulin V regions in B cells occurs within the tightly regulated microenvironment of a germinal centre. The precise mechanism responsible for turning on the mutational process is unknown. To dissect the role of different components of the germinal centre in this mechanism, we have used in vitro cultures of normal human IgD+ peripheral blood B lymphocytes co-cultured with activated CD4+ T cells, or with resting CD4+ T cells, or with CD40 ligand and IL-4. We observed that if the cultures included activated CD4+ T cells, then up to 100% of VH transcripts on day 14 were somatically mutated. Transcripts were found to carry from one to 36 substitutions (median five). In contrast, in the absence of activated T cells, transcripts contained only background levels of somatic mutation irrespective of the presence of resting T cells or CD40 ligand and IL-4. Cell–cell contact was required for mutation because mutations were not detected when B cells were separated from activated T cells by a membrane. PMID:10361232

Huang, S-C; Glas, A M; Pinchuk, G V; Van Montfort, E H N; Rao, S P; Jiang, R; Milner, E C B

1999-01-01

317

Nonrandon X chromosome inactivation in B cells from carriers of X chromosome-linked severe combined immunodeficiency  

SciTech Connect

X chromosome-linked sever combined immunodeficiency (XSCID) is characterized by markedly reduced numbers of T cells, the absence of proliferative responses to mitogens, and hypogammaglobulinemia but normal or elevated number of B cells. To determine if the failure of the B cells to produce immunoglobulin might be due to expression of the XSCID gene defect in B-lineage cells as well as T cells, the authors analyzed patterns of X chromosome inactivation in B cells from nine obligate carriers of this disorder. A series of somatic cell hybrids that selectively retained the active X chromosome was produced from Epstein-Barr virus-stimulated B cells from each woman. To distinguish between the two X chromosome, the hybrids from each woman were analyzed using an X-linked restriction fragment length polymorphism for which the woman in question was heterozygous. In all obligate carriers of XSCID, the B-cell hybrids demonstrated preferential use of a single X chromosome, the nonmutant X, as the active X. To determine if the small number of B-cell hybrids that contained the mutant X were derived from an immature subset of B cells, lymphocytes from three carriers were separated into surface IgM positive and surface IgM negative B cells prior to exposure to Epstein-Barr virus and production of B-cell hybrids. The results demonstrated normal random X chromosome inactivation in B-cell hybrids derived from the less mature surface IgM positive B cells. These results suggest that the XSCID gene product has a direct effect on B cells as well as T cells and is required during B-cell maturation.

Conley, M.E.; Lavoie, A.; Briggs, C.; Brown, P.; Guerra, C.; Puck, J.M.

1988-05-01

318

MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling.  

PubMed

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine-like functions that plays a pivotal role in the pathogenesis of inflammatory diseases by promoting leukocyte recruitment. We showed that MIF promotes the atherogenic recruitment of monocytes and T cells through its receptors CXCR2 and CXCR4. Effects of MIF on B cell recruitment have not been addressed. In this study, we tested the involvement of MIF in B cell chemotaxis and studied the underlying mechanism. We show that MIF promotes primary murine B cell chemotaxis in a dose-dependent manner, comparable to the B cell chemokines CXCL13 and CXCL12. Splenic B cells express CXCR4 and the receptor CD74 but not CXCR2. Inhibition of CXCR4 or CD74 or a genetic deficiency of Cd74 in primary B cells fully abrogated MIF-mediated B cell migration, implying cooperative involvement of both receptors. MIF stimulation of B cells resulted in a rapid increase in intracellular Ca(2+) mobilization and F-actin polymerization. Intriguingly, the tyrosine kinase ZAP-70 was activated upon MIF and CXCL12 treatment in a CXCR4- and CD74-dependent manner. Pharmacological inhibition of ZAP-70 resulted in abrogation of primary B cell migration. Functional involvement of ZAP-70 was confirmed by small interfering RNA-mediated knockdown in Ramos B cell migration. Finally, primary B cells from ZAP-70 gene-deficient mice exhibited ablated transmigration in response to MIF or CXCL12. We conclude that MIF promotes the migration of B cells through a ZAP-70-dependent pathway mediated by cooperative engagement of CXCR4 and CD74. The data also suggest that MIF may contribute to B cell recruitment in vivo (e.g., in B cell-related immune disorders). PMID:24760155

Klasen, Christina; Ohl, Kim; Sternkopf, Marieke; Shachar, Idit; Schmitz, Corinna; Heussen, Nicole; Hobeika, Elias; Levit-Zerdoun, Ella; Tenbrock, Klaus; Reth, Michael; Bernhagen, Jürgen; El Bounkari, Omar

2014-06-01

319

CpG Drives Human Transitional B Cells to Terminal Differentiation and Production of Natural Antibodies  

Microsoft Academic Search

The receptor TLR9, recognizing unmethylated bacterial DNA (CpG), is expressed by B cells and plays a role in the maintenance of serological memory. Little is known about the response of B cells stimulated with CpG alone, without additional cytokines. In this study, we show for the first time the phenotypic modification, changes in gene expression, and functional events downstream to

Federica Capolunghi; Simona Cascioli; Ezio Giorda; Maria Manuela Rosado; Alessandro Plebani; Cinzia Auriti; Giulio Seganti; Roberta Zuntini; Simona Ferrari; Maria Cagliuso; Isabella Quinti; Rita Carsetti

320

Adenosine production by human B cells and B cell-mediated suppression of activated T cells  

PubMed Central

Antibody-independent role of B cells in modulating T-cell responses is incompletely understood. Freshly isolated or cultured B cells isolated from the peripheral blood of 30 normal donors were evaluated for CD39 and CD73 coexpression, the ability to produce adenosine 5?-monophosphate (AMP) and adenosine (ADO) in the presence of exogenous adenosine triphosphate (ATP) as well as A1, A2A, A2B, and A3 adenosine receptor (ADOR) expression. Human circulating B cells coexpress ectonucleotidases CD39 and CD73, hydrolyze exogenous ATP to 5?-AMP and ADO, and express messenger RNA for A1R, A2AR, and A3R. 2-chloroadenosine inhibited B-cell proliferation and cytokine expression, and only A3R selective antagonist restored B-cell functions. This suggested that B cells use the A3R for autocrine signaling and self-regulation. Mediated effects on B-cell growth ± ADOR antagonists or agonists were tested in carboxyfluorescein diacetate succinimidyl ester assays. In cocultures, resting B cells upregulated functions of CD4+ and CD8+ T cells. However, in vitro–activated B cells downregulated CD73 expression, mainly produced 5?-AMP, and inhibited T-cell proliferation and cytokine production. These B cells acquire the ability to restrict potentially harmful effects of activated T cells. Thus, B cells emerge as a key regulatory component of T cell–B cell interactions, and their dual regulatory activity is mediated by the products of ATP hydrolysis, 5?-AMP, and ADO. PMID:23678003

Saze, Zenichiro; Schuler, Patrick J.; Hong, Chang-Sook; Cheng, Dongmei; Jackson, Edwin K.

2013-01-01

321

Identification and characterization of OSTL (RNF217) encoding a RING-IBR-RING protein adjacent to a translocation breakpoint involving ETV6 in childhood ALL.  

PubMed

Genomic aberrations involving ETV6 on band 12p13 are amongst the most common chromosomal abnormalities in human leukemia. The translocation t(6;12)(q23;13) in a childhood B-cell acute lymphoblastic leukemia (ALL) cell line fuses ETV6 with the putative long non-coding RNA gene STL. Linking STL properties to leukemia has so far been difficult. Here, we describe a novel gene, OSTL (annotated as RNF217 in Genbank), which shares the first exon and a CpG island with STL but is transcribed in the opposite direction. Human RNF217 codes for a highly conserved RING finger protein and is mainly expressed in testis and skeletal muscle with different splice variants. RNF217 shows regulated splicing in B cell development, and is expressed in a number of human B cell leukemia cell lines, primary human chronic myeloid leukemia, acute myeloid leukemia with normal karyotype and acute T-ALL samples. Using a yeast two-hybrid screen, we identified the anti-apoptotic protein HAX1 to interact with RNF217. This interaction could be mapped to the C-terminal RING finger motif of RNF217. We propose that some of the recurring aberrations involving 6q might deregulate the expression of RNF217 and result in imbalanced apoptosis signalling via HAX1, promoting leukemia development. PMID:25298122

Fontanari Krause, Luciana M; Japp, Anna Sophia; Krause, Alexandre; Mooster, Jana; Chopra, Martin; Müschen, Markus; Bohlander, Stefan K

2014-01-01

322

Identification and characterization of OSTL (RNF217) encoding a RING-IBR-RING protein adjacent to a translocation breakpoint involving ETV6 in childhood ALL  

PubMed Central

Genomic aberrations involving ETV6 on band 12p13 are amongst the most common chromosomal abnormalities in human leukemia. The translocation t(6;12)(q23;13) in a childhood B-cell acute lymphoblastic leukemia (ALL) cell line fuses ETV6 with the putative long non-coding RNA gene STL. Linking STL properties to leukemia has so far been difficult. Here, we describe a novel gene, OSTL (annotated as RNF217 in Genbank), which shares the first exon and a CpG island with STL but is transcribed in the opposite direction. Human RNF217 codes for a highly conserved RING finger protein and is mainly expressed in testis and skeletal muscle with different splice variants. RNF217 shows regulated splicing in B cell development, and is expressed in a number of human B cell leukemia cell lines, primary human chronic myeloid leukemia, acute myeloid leukemia with normal karyotype and acute T-ALL samples. Using a yeast two-hybrid screen, we identified the anti-apoptotic protein HAX1 to interact with RNF217. This interaction could be mapped to the C-terminal RING finger motif of RNF217. We propose that some of the recurring aberrations involving 6q might deregulate the expression of RNF217 and result in imbalanced apoptosis signalling via HAX1, promoting leukemia development. PMID:25298122

Fontanari Krause, Luciana M.; Japp, Anna Sophia; Krause, Alexandre; Mooster, Jana; Chopra, Martin; Muschen, Markus; Bohlander, Stefan K.

2014-01-01

323

Abnormal B cell response to T cell-independent polyclonal B cell activators in haemophilia A.  

PubMed Central

In addition to T cell abnormalities, patients with haemophilia A show a separate B cell dysfunction. Characteristic are elevated spontaneous IgG (not IgM) levels in the patient's sera and in the culture supernatants of peripheral blood mononuclear cells. It is also observed that these cells fail to show a differentiation response to T cell-independent B cell activators. The B cell dysfunction correlates with the amount of factor VIII concentrates given prophylactically to patients with severe haemophilia. In contrast to the acquired immune deficiency syndrome (AIDS), the proliferation response to B cell mitogens is not affected. PMID:3017621

Kekow, J; Plendl, H; Gross, W L

1986-01-01

324

Repetitive hypoxic preconditioning induces an immunosuppressed B cell phenotype during endogenous protection from stroke  

PubMed Central

Background Repetitive hypoxic preconditioning (RHP) creates an anti-inflammatory phenotype that protects from stroke-induced injury for months after a 2-week treatment. The mechanisms underlying long-term tolerance are unknown, though one exposure to hypoxia significantly increased peripheral B cell representation. For this study, we sought to determine if RHP specifically recruited B cells into the protected ischemic hemisphere, and whether RHP could phenotypically alter B cells prior to stroke onset. Methods Adult, male SW/ND4 mice received RHP (nine exposures over 2 weeks; 8 to 11 % O2; 2 to 4 hours) or identical exposures to 21 % O2 as control. Two weeks following RHP, a 60-minute transient middle cerebral artery occlusion was induced. Standard techniques quantified CXCL13 mRNA and protein expression. Two days after stroke, leukocytes were isolated from brain tissue (70:30 discontinuous Percoll gradient) and profiled on a BD-FACS Aria flow cytometer. In a separate cohort without stroke, sorted splenic CD19+ B cells were isolated 2 weeks after RHP and analyzed on an Illumina MouseWG-6 V2 Bead Chip. Final gene pathways were determined using Ingenuity Pathway Analysis. Student’s t-test or one-way analysis of variance determined significance (P?B cell-specific chemokine, was upregulated in post-stroke cortical vessels of both groups. In the ischemic hemisphere, RHP increased B cell representation by attenuating the diapedesis of monocyte, macrophage, neutrophil and T cells, to quantities indistinguishable from the uninjured, contralateral hemisphere. Pre-stroke splenic B cells isolated from RHP-treated mice had >1,900 genes differentially expressed by microarray analysis. Genes related to B-T cell interactions, including antigen presentation, B cell differentiation and antibody production, were profoundly downregulated. Maturation and activation were arrested in a cohort of B cells from pre-stroke RHP-treated mice while regulatory B cells, a subset implicated in neurovascular protection from stroke, were upregulated. Conclusions Collectively, our data characterize an endogenous neuroprotective phenotype that utilizes adaptive immune mechanisms pre-stroke to protect the brain from injury post-stroke. Future studies to validate the role of B cells in minimizing injury and promoting central nervous system recovery, and to determine whether B cells mediate an adaptive immunity to systemic hypoxia that protects from subsequent stroke, are needed. PMID:24485041

2014-01-01

325

Transitional B cells are the target of negative selection in the B cell compartment  

PubMed Central

B lymphocytes recognize antigen through membrane-bound antigen- receptors, membrane IgM and IgD (mIgM and mIgD). Binding to foreign antigens initiates a cascade of biochemical events that lead to activation and differentiation. In contrast, binding to self-antigens leads to death or to inactivation. It is commonly believed that the B cells acquire the ability to discriminate between self and nonself in the early phases of development. We report here that immature B cells, which have just emerged from the mIgMneg, B220pos pool, are not deleted upon binding of self-antigen. In vivo, developing B cells become sensitive to tolerance induction in a relatively late window of differentiation, when they are in transition from the immature (HSAbright, B220dull) to the mature (HSAdull, B220bright) stage. In the transitional B cells, early markers of differentiation such as Pgp1 (CD44) and ThB reach the highest level of expression, while the expression of CD23 and mIgD, late markers of differentiation, and expression of class II MHC, progressively increases. Most of the transitional B cells, but only few of the mature and of the immature B cells, express the fas antigen, while mature B cells, but not immature and transitional B cells, express bcl-2 protein. mIgM is present in low amounts in immature B cells, reaches the highest level of expression in transitional B cells and is down-regulated in mature resting B cells, where it is coexpressed with mIgD. The high expression of mIgM, the presence of the fas antigen and the absence of bcl-2 protein is compatible with the high sensitivity of transitional B cells to negative selection. In vitro, immature B cells die rapidly by apoptosis after cross-linking of mIgM. This result, combined with the resistance of immature B cells to elimination in vivo, suggests that early in development the stroma cell microenvironment modulates signals transduced through mIgM. The functional and phenotypic division of IgMpos bone marrow B cells in three compartments not only allows to define the target population of physiological processes like negative selection, but will also be a helpful tool for an accurate description of possible developmental blocks in mutant mice. PMID:7760002

1995-01-01

326

Understanding B cell activation: from single molecule tracking, through Tolls, to stalking memory in malaria  

PubMed Central

B lymphocyte activation is initiated by the binding of antigens to the clonally expressed B cell receptors (BCRs) triggering signaling cascades that lead to the transcription of a variety of genes associated with B cell activation. Provided with the appropriate T cell help and the microenvironment of germinal centers antigen drives B cells to proliferate and differentiate into long-lived plasma cells and memory B cells that together constitute immunological memory. Here I describe efforts in my laboratory to gain an understanding of the cellular and molecular mechanisms that underlie three processes central to B cell biology namely, the initiation of BCR signaling, the interactions of the BCR with the innate immune system Toll-like receptors and the generation and maintenance of B cell memory. Such knowledge is likely to aid research efforts in two areas of high public health priority, namely, the development of new therapeutics to control B cell responses in autoimmune disease and the design of effective vaccines to control infectious diseases. PMID:18810335

Pierce, Susan K.

2009-01-01

327

TC-PTP is required for the maintenance of MYC-driven B-cell lymphomas  

PubMed Central

We sought to determine the contributions of protein tyrosine phosphatases (PTPs) to the pathogenesis of B-cell lymphomas. We found that T-cell PTP (TC-PTP) was overexpressed in transformed B cells. We hypothesized that TC-PTP may be a tumor-promoting gene that is regulated by MYC overexpression in B cells. Knockdown of TC-PTP in murine tumors resulted in decreased cell viability in vitro because of an arrest in the G1 phase of the cell cycle. Furthermore, cells with reduced TC-PTP expression were unable to either engraft or expand in vivo. Taken together, these data indicate that TC-PTP is required for B-cell tumor maintenance. Our data also suggested a correlation between TC-PTP expression and MYC overexpression. To investigate this further, we used malignant murine B cells that contain a doxycycline-repressible MYC transgene. We found that repression of MYC overexpression with doxycycline reduced TC-PTP expression. Moreover, enforced expression of TC-PTP showed partial rescue of the expansion of tumor cells after suppression of MYC overexpression. These results suggest that MYC overexpression induces TC-PTP overexpression, which in turn promotes tumor proliferation, implicating TC-PTP as an important effector of the MYC-driven proliferation program in B-cell lymphomas. Thus, TC-PTP may be a suitable molecular target for the treatment of B-cell lymphomas. PMID:19755676

Young, Ryan M.; Polsky, Avital

2009-01-01

328

B-cell-intrinsic STAT6 signaling controls germinal center formation.  

PubMed

Infection with helminths and exposure to antigens induce a strong type 2 immune response resulting in the secretion of the cytokines IL-4 and IL-13 by CD4(+) T cells and several innate cell types. IL-4 and IL-13 promote class switch recombination to IgG1 and IgE while their role for germinal center (GC) formation is poorly understood. We found a dramatic reduction in the numbers of GC B cells when investigating different type 2 immune responses in IL-4/IL-13-deficient mice. IL-4/IL-13 from T cells located outside B-cell follicles was sufficient for GC formation. We further revealed that IL-4/IL-13 acts directly on B cells for the formation of a robust GC response. The frequency of apoptotic GC B cells was not altered in the absence of IL-4/IL-13 and proliferation was even enhanced. However, deficiency of signal transducer and activator of transcription 6 signaling in B cells resulted in failure to downregulate the chemotactic receptor Gpr183 (Ebi2) and downregulation of this receptor has been shown to be essential for proper GC B-cell differentiation. Thus, T-cell-derived extrafollicular IL-4/IL-13 and signal transducer and activator of transcription 6-regulated genes in B cells play a critical role for orchestration of the GC response in type 2 immunity. PMID:24777733

Turqueti-Neves, Adriana; Otte, Manuel; Prazeres da Costa, Olivia; Höpken, Uta E; Lipp, Martin; Buch, Thorsten; Voehringer, David

2014-07-01

329

Visualization of splenic marginal zone B cell shuttling and follicular B cell egress  

PubMed Central

The splenic marginal zone (MZ) is a unique microenvironment where resident immune cells are exposed to the open blood circulation1,2. Despite its importance in responses against blood-borne antigens, lymphocyte migration in the MZ has not been intravitally visualized due to challenges associated with achieving adequate imaging depth in this abdominal organ. Here we develop a 2-photon microscopy procedure to study MZ and follicular (FO) B cell movement in the live spleen. We show that MZ B cells are highly motile and exhibit long membrane extensions. MZ B cells shuttle between MZ and follicles with at least one fifth of the cells exchanging between compartments per hour, a behavior that explains their ability to rapidly deliver antigens from the open blood circulation to the secluded follicles. FO B cells also transit from follicles to MZ but unlike MZ B cells, they fail to undergo integrin-mediated adhesion, become caught in fluid flow and are carried into the red pulp. FO B cell egress via the MZ is sphingosine-1-phosphate receptor-1 (S1PR1)-dependent. This study shows that MZ B cells migrate continually between MZ and follicles and establishes the MZ as a site of S1PR1-dependent B cell exit from follicles. The work also shows how adhesive differences of closely related cells critically influences their behavior in the same microenvironment. PMID:23263181

Arnon, Tal I.; Horton, Robert M.; Grigorova, Irina L.; Cyster, Jason G.

2012-01-01

330

Ibrutinib and indolent B-cell lymphomas.  

PubMed

Most patients with indolent B-cell lymphomas fail to achieve complete remission with current treatment approaches and invariably relapse. During the past decade, innovative immunochemotherapy strategies have substantially improved disease control rates but not survival, thus providing the rationale for development of novel agents targeting dysregulated pathways that are operable in these hematological malignancies. Ibrutinib, a novel first-in-human Bruton's tyrosine kinase (BTK) inhibitor, has progressed into phase III trials after early-phase clinical studies demonstrated effective target inhibition, increased tumor response rates, and significant improvement in survival, particularly in patients with indolent B-cell lymphomas. Recently, the compound was designated a "breakthrough therapy" by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory mantle cell lymphoma and Waldenström macroglobulinemia. This review summarizes recent achievements of ibrutinib, with a focus on its emerging role in the treatment of patients with indolent B-cell lymphoid malignancies. PMID:24445187

Akinleye, Akintunde; Furqan, Muhammad; Adekunle, Oluwaseyi

2014-08-01

331

The complement system in B cell regulation.  

PubMed

Early studies of animals bearing natural deficiencies in complement C3 and C4 and mice transiently deficient in C3 suggested that the complement system played a role in humoral immunity. Identification and characterization of the complement receptors CD21 and CD35 and their expression on B lymphocytes provided evidence for a direct role for complement in "linkage of innate and adaptive immunity". More recent studies of mice bearing targeted deficiencies in complement proteins C3, C4 or the receptors CD21/CD35 has confirmed the importance of complement in B cell responses in vivo and extended our understanding to distinct stages in B cell differentiation in which complement participates in humoral immunity. In this review, a role for complement is described in five distinct stages of B cell differentiation. PMID:15159059

Carroll, Michael C

2004-06-01

332

FOXO1 transcription factor: a critical effector of the PI3K-AKT axis in B-cell development.  

PubMed

B-cell development and differentiation are controlled at multiple levels by the complex interplay of specific receptors and a variety of transcription factors. Several receptors involved in regulating this process, such as IL-7R, pre-B cell receptor (pre-BCR), and BCR, share the ability to trigger the signaling via the phosphoinositide 3-kinase (PI3K)-AKT pathway. FOXO1 transcription factor, a major PI3K-AKT downstream effector, regulates the expression of genes critical for progress through consecutive steps of B-cell differentiation. FOXO1 directs or fine-tunes multiple biological functions that are crucial for differentiating cells, including the cell cycle, apoptosis, oxidative stress response or DNA damage repair. Recent studies have highlighted the key role that FOXO1 plays in the maintenance of the hematopoietic stem cell pool, regulation of progenitor commitment, development of early B-cell precursors, induction of B-cell tolerance, peripheral B-cell homeostasis, and terminal differentiation. FOXO1 deficiency impairs B-cell development, due to decreased expression of its critical target genes, that include early B-cell factor (EBF1), IL-7 receptor, recombination activating genes (RAG1 and 2), activation-induced cytidine deaminase (AID), L-selectin, and BLNK. Taken together, FOXO1 is an important node in a dynamic network of transcription factors that orchestrate B-cell differentiation and specialization. Herein, we review molecular mechanisms of the PI3K-AKT-dependent signal transduction and their impact on early B-cell development, peripheral B-cell homeostasis, and terminal differentiation. PMID:24552152

Szyd?owski, Maciej; Jab?o?ska, Ewa; Juszczy?ski, Przemys?aw

2014-03-01

333

BAFF and selection of autoreactive B cells  

PubMed Central

BAFF is a critical survival factor for transitional and mature B cells and is a promising therapeutic target for SLE. A BAFF inhibitor, belimumab, is the first new drug in 50 years to be approved for the treatment of SLE. However, the mechanism of action of this drug is not entirely clear. In this review we will focus on the role of the BAFF–APRIL signaling pathway in the selection of autoreactive B cells and discuss whether altered selection is the mechanism for the therapeutic efficacy of BAFF inhibition in SLE. PMID:21752714

Liu, Zheng; Davidson, Anne

2011-01-01

334

Regulatory T Cells in B Cell Follicles  

PubMed Central

Understanding germinal center reactions is crucial not only for the design of effective vaccines against infectious agents and malignant cells but also for the development of therapeutic intervention for the treatment of antibody-mediated immune disorders. Recent advances in this field have revealed specialized subsets of T cells necessary for the control of B cell responses in the follicle. These cells include follicular regulatory T cells and Qa-1-restricted cluster of differentiation (CD)8+ regulatory T cells. In this review, we discuss the current knowledge related to the role of regulatory T cells in the B cell follicle.

Chang, Jae-Hoon

2014-01-01

335

Identification of a B cell signature associated with renal transplant tolerance in humans  

PubMed Central

Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients. PMID:20501946

Newell, Kenneth A.; Asare, Adam; Kirk, Allan D.; Gisler, Trang D.; Bourcier, Kasia; Suthanthiran, Manikkam; Burlingham, William J.; Marks, William H.; Sanz, Ignacio; Lechler, Robert I.; Hernandez-Fuentes, Maria P.; Turka, Laurence A.; Seyfert-Margolis, Vicki L.

2010-01-01

336

B-Cell-Intrinsic Hepatitis C Virus Expression Leads to B-Cell-Lymphomagenesis and Induction of NF-?B Signalling  

PubMed Central

Hepatitis C virus (HCV) infection leads to the development of hepatic diseases, as well as extrahepatic disorders such as B-cell non-Hodgkin's lymphoma (B-NHL). To reveal the molecular signalling pathways responsible for HCV-associated B-NHL development, we utilised transgenic (Tg) mice that express the full-length HCV genome specifically in B cells and develop non-Hodgkin type B-cell lymphomas (BCLs). The gene expression profiles in B cells from BCL-developing HCV-Tg mice, from BCL-non-developing HCV-Tg mice, and from BCL-non-developing HCV-negative mice were analysed by genome-wide microarray. In BCLs from HCV-Tg mice, the expression of various genes was modified, and for some genes, expression was influenced by the gender of the animals. Markedly modified genes such as Fos, C3, LT?R, A20, NF-?B and miR-26b in BCLs were further characterised using specific assays. We propose that activation of both canonical and alternative NF-?B signalling pathways and down-regulation of miR-26b contribute to the development of HCV-associated B-NHL. PMID:24651473

Kasama, Yuri; Mizukami, Takuo; Kusunoki, Hideki; Peveling-Oberhag, Jan; Nishito, Yasumasa; Ozawa, Makoto; Kohara, Michinori; Mizuochi, Toshiaki; Tsukiyama-Kohara, Kyoko

2014-01-01

337

Anomalous Dynamics of Translocation  

E-print Network

We study the dynamics of the passage of a polymer through a membrane pore (translocation), focusing on the scaling properties with the number of monomers $N$. The natural coordinate for translocation is the number of monomers on one side of the hole at a given time. Commonly used models which assume Brownian dynamics for this variable predict a mean (unforced) passage time $\\tau$ that scales as $N^2$, even in the presence of an entropic barrier. However, the time it takes for a free polymer to diffuse a distance of the order of its radius by Rouse dynamics scales with an exponent larger than 2, and this should provide a lower bound to the translocation time. To resolve this discrepancy, we perform numerical simulations with Rouse dynamics for both phantom (in space dimensions $d=1$ and 2), and self-avoiding (in $d=2$) chains. The results indicate that for large $N$, translocation times scale in the same manner as diffusion times, but with a larger prefactor that depends on the size of the hole. Such scaling implies anomalous dynamics for the translocation process. In particular, the fluctuations in the monomer number at the hole are predicted to be non-diffusive at short times, while the average pulling velocity of the polymer in the presence of a chemical potential difference is predicted to depend on $N$.

Jeffrey Chuang; Yacov Kantor; Mehran Kardar

2001-08-17

338

N-WASP Is Essential for the Negative Regulation of B Cell Receptor Signaling  

PubMed Central

Negative regulation of receptor signaling is essential for controlling cell activation and differentiation. In B-lymphocytes, the down-regulation of B-cell antigen receptor (BCR) signaling is critical for suppressing the activation of self-reactive B cells; however, the mechanism underlying the negative regulation of signaling remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we demonstrate that neuronal Wiskott–Aldrich syndrome protein (N-WASP), which is coexpressed with WASP in all immune cells, is a critical negative regulator of B-cell signaling. B-cell–specific N-WASP gene deletion causes enhanced and prolonged BCR signaling and elevated levels of autoantibodies in the mouse serum. The increased signaling in N-WASP knockout B cells is concurrent with increased accumulation of F-actin at the B-cell surface, enhanced B-cell spreading on the antigen-presenting membrane, delayed B-cell contraction, inhibition in the merger of signaling active BCR microclusters into signaling inactive central clusters, and a blockage of BCR internalization. Upon BCR activation, WASP is activated first, followed by N-WASP in mouse and human primary B cells. The activation of N-WASP is suppressed by Bruton's tyrosine kinase-induced WASP activation, and is restored by the activation of SH2 domain-containing inositol 5-phosphatase that inhibits WASP activation. Our results reveal a new mechanism for the negative regulation of BCR signaling and broadly suggest an actin-mediated mechanism for signaling down-regulation. PMID:24223520

Liu, Chaohong; Bai, Xiaoming; Wu, Junfeng; Sharma, Shruti; Upadhyaya, Arpita; Dahlberg, Carin I. M.; Westerberg, Lisa S.; Snapper, Scott B.; Zhao, Xiaodong; Song, Wenxia

2013-01-01

339

Genetic Immunization Converts the Trypanosoma cruzi B-Cell Mitogen Proline Racemase to an Effective Immunogen? †  

PubMed Central

Trypanosoma cruzi is the etiologic agent of Chagas' disease. Acute T. cruzi infection results in polyclonal B-cell activation and delayed specific humoral immunity. T. cruzi proline racemase (TcPRAC), a T. cruzi B-cell mitogen, may contribute to this dysfunctional humoral response. Stimulation of murine splenocytes with recombinant protein (rTcPRAC) induced B-cell proliferation, antibody secretion, interleukin-10 (IL-10) production, and upregulation of CD69 and CD86 on B cells. Marginal zone (MZ) B cells are more responsive to T-cell-independent (TI) rTcPRAC stimulation than are follicular mature (FM) B cells in terms of proliferation, antibody secretion, and IL-10 production. During experimental T. cruzi infection, TcPRAC-specific IgG remained undetectable when responses to other T. cruzi antigens developed. Conversely, intradermal genetic immunization via gene gun (GG) delivered TcPRAC as an immunogen, generating high-titer TcPRAC-specific IgG without B-cell dysfunction. TcPRAC GG immunization led to antigen-specific splenic memory B-cell and bone marrow plasma cell formation. TcPRAC-specific IgG bound mitogenic rTcPRAC, decreasing subsequent B-cell activation. GG immunization with rTcPRAC DNA was nonmitogenic and did not affect the generation of specific IgG to another T. cruzi antigen, complement regulatory protein (CRP). These data demonstrate the utility of genetic immunization for the conversion of a protein mitogen to an effective antigen. Furthermore, coimmunization of TcPRAC with another T. cruzi antigen indicates the usefulness of this approach for multivalent vaccine development. PMID:19917711

Bryan, Marianne A.; Norris, Karen A.

2010-01-01

340

Mechanism of the t(14; 18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners  

SciTech Connect

To elucidate the mechanism of the t(14;18)(q32;q21) chromosomal translocation found in follicular lymphoma, the authors examined the structure of both derivative (der) chromosomal breakpoints as well as their germ-line predecessors. They noted that chromosome segment 18q21 was juxtaposed with immunoglobulin heavy (H) chain gene diversity (D/sub H/) regions on all five der(18) chromosomes they examined, and they confirmed the juncture with immunoglobulin H-chain gene joining (J/sub H/) regions on the der(14) chromosome. However, the t(14;18) was not fully reciprocal in that chromosome 14 DNA between the D/sub H/ and J/sub H/ regions was deleted. Furthermore, extra nucleotides, reminiscent of N segments, were present at the der(14) and possibly der(18) junctions. This indicates that despite the mature B-cell phenotype of follicular lymphoma, the t(14;18) occurs during attempted D/sub H/-J/sub H/ joining, the earliest event in immunoglobulin rearrangement in a pre-B-cell. The detailed analysis of the germ-line 18q21 region indicated that most breakpoints clustered within a 150-base-pair major breakpoint region. A direct repeat duplication of chromosome 18 sequences was discovered at both chromosomal junctures, typical of the repair of a naturally occurring staggered double-stranded DNA break. These results prompt a translocation model with illegitimate pairing of a staggered double-stranded DNA break at 18q21 and an immunoglobulin endonuclease-mediated break at 14q32 and with N-segment addition, repair, and ligation to generate der(14) and der(18) chromosomes.

Bakhshi, A.; Wright, J.J.; Graninger, W.; Seto, M.; Owens, J.; Cossman, J.; Jensen, J.P.; Goldman, P.; Korsmeyer, S.J.

1987-04-01

341

miR-181b negatively regulates activation-induced cytidine deaminase in B cells.  

PubMed

Activated B cells reshape their primary antibody repertoire after antigen encounter by two molecular mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM and CSR are initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues on the immunoglobulin loci, which leads to the generation of DNA mutations or double-strand break intermediates. As a bystander effect, endogenous AID levels can also promote the generation of chromosome translocations, suggesting that the fine tuning of AID expression may be critical to restrict B cell lymphomagenesis. To determine whether microRNAs (miRNAs) play a role in the regulation of AID expression, we performed a functional screening of an miRNA library and identified miRNAs that regulate CSR. One such miRNA, miR-181b, impairs CSR when expressed in activated B cells, and results in the down-regulation of AID mRNA and protein levels. We found that the AID 3' untranslated region contains multiple putative binding sequences for miR-181b and that these sequences can be directly targeted by miR-181b. Overall, our results provide evidence for a new regulatory mechanism that restricts AID activity and can therefore be relevant to prevent B cell malignant transformation. PMID:18762567

de Yébenes, Virginia G; Belver, Laura; Pisano, David G; González, Susana; Villasante, Aranzazu; Croce, Carlo; He, Lin; Ramiro, Almudena R

2008-09-29

342

Reciprocal t(9;22) ABL/BCR Fusion Proteins: Leukemogenic Potential and Effects on B Cell Commitment  

PubMed Central

Background t(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph+) determine formation of different fusion genes that are associated with either Ph+ acute lymphatic leukemia (Ph+ ALL) or chronic myeloid leukemia (CML). The “minor” breakpoint in Ph+ ALL encodes p185BCR/ABL from der22 and p96ABL/BCR from der9. The “major” breakpoint in CML encodes p210BCR/ABL and p40ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96ABL/BCR and p40ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL. Methodology All t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR. Principal Findings Both p96ABL/BCR and p40ABL/BCR increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96ABL/BCR and to a minor extent p40ABL/BCR forced the B-cell commitment of SL-cells and UCBC. Conclusions/Significance Our here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22) in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their influence on the lineage commitment. PMID:19876398

Zheng, Xiaomin; Oancea, Claudia; Henschler, Reinhard; Moore, Malcolm A. S.; Ruthardt, Martin

2009-01-01

343

Distinct cytokines balance the development of regulatory T cells and interleukin-10-producing regulatory B cells.  

PubMed

Regulatory T cells have been well described and the factors regulating their development and function have been identified. Recently, a growing body of evidence has documented the existence of interleukin-10 (IL-10) -producing B cells, which are called regulatory B10 cells. These cells attenuate autoimmune, inflammatory and transplantation reactions, and the main mechanism of their inhibitory action is the production of IL-10. We show that the production of IL-10 by lipopolysaccharide-stimulated B cells is significantly enhanced by IL-12 and interferon-? and negatively regulated by IL-21 and transforming growth factor-?. In addition, exogenous IL-10 also inhibits B-cell proliferation and the expression of the IL-10 gene in lipopolysaccharide-stimulated B cells. The negative autoregulation of IL-10 production is supported by the observation that the inclusion of anti-IL-10 receptor monoclonal antibody enhances IL-10 production and the proliferation of activated B cells. The effects of cytokines on IL-10 production by B10 cells did not correlate with their effects on B-cell proliferation or on IL-10 production by T cells or macrophages. The cytokine-induced changes in IL-10 production occurred on the level of IL-10 gene expression, as confirmed by increased or decreased IL-10 mRNA expression in the presence of a particular cytokine. The regulatory cytokines modulate the number of IL-10-producing cells rather than augmenting or decreasing the secretion of IL-10 on a single-cell level. Altogether these data show that the production of IL-10 by B cells is under the strict regulatory control of cytokines and that individual cytokines differentially regulate the development and activity of regulatory T cells and IL-10-producing regulatory B cells. PMID:24256319

Holan, Vladimir; Zajicova, Alena; Javorkova, Eliska; Trosan, Peter; Chudickova, Milada; Pavlikova, Michaela; Krulova, Magdalena

2014-04-01

344

The effects of preB-cell colonyenhancing factor on the human fetal membranes by microarray analysis  

E-print Network

, Hawaii OBJECTIVE: Our purpose was to show the effects of pre­B-cell colony­enhancing factor on the genes membrane rupture, which are achieved in our species through autocrine/paracrine events at the maternal

Bryant-Greenwood, Gillian D.

345

Aberrant B cell selection and activation in systemic lupus erythematosus.  

PubMed

The detrimental role of B lymphocytes in systemic lupus erythematosus (SLE) is evident from the high levels of pathogenic antinuclear autoantibodies (ANAs) found in SLE patients. Affirming this causative role, additional antibody-independent roles of B cells in SLE were appreciated. In recent years, many defects in B cell selection and activation have been identified in murine lupus models and SLE patients that explain the increased emergence and persistence of autoreactive B cells and their lowered activation threshold. Therefore, clinical trials with B cell depletion regimens in SLE patients were initiated but disappointingly the efficacy of B cell depleting agents proved to be limited. Remarkably however, a major breakthrough in SLE therapy was accomplished by blocking B cell survival factors rather then eliminating B cells. This surprising finding indicates that although SLE is a B cell-driven disease, the amplifying crosstalk between B cells and other cells of the immune system likely evokes the observed tolerance breakdown in B cells. Moreover, this implies that intelligent interception of pro-inflammatory loops rather then selectively silencing B cells will be key to the development of new SLE therapies. In this review, we will not only highlight the intrinsic B cell defects that facilitate the persistence of autoreactive B cells and their activation, but in addition we will focus on B cell extrinsic signals derived from T cells and innate immune cells that lower the activation threshold for B cells. PMID:23768157

Kil, Laurens P; Hendriks, Rudi W

2013-08-01

346

Problem-elephant translocation: translocating the problem and the elephant?  

PubMed

Human-elephant conflict (HEC) threatens the survival of endangered Asian elephants (Elephas maximus). Translocating "problem-elephants" is an important HEC mitigation and elephant conservation strategy across elephant range, with hundreds translocated annually. In the first comprehensive assessment of elephant translocation, we monitored 16 translocations in Sri Lanka with GPS collars. All translocated elephants were released into national parks. Two were