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1

B?cell translocation gene 1 serves as a novel prognostic indicator of hepatocellular carcinoma.  

PubMed

Although the B?cell translocation gene 1 (BTG1) plays an important role in apoptosis and negatively regulates cell proliferation, BTG1 expression in hepatocellular carcinoma (HCC) has not been evaluated. In this study expression analysis of BTG1 was conducted to clarify the role of BTG1 in the initiation of HCC carcinogenesis and progression. BTG1 mRNA expression levels were determined for HCC cell lines and 151 surgical specimen pairs using quantitative real?time reverse transcription polymerase chain reaction (RT?qPCR) assay. The mutational and methylation status of HCC cell lines were analyzed via high resolution melting (HRM) analysis and direct sequencing analysis to elucidate the regulatory mechanisms of BTG1 expression. The expression and distribution of the BTG1 protein in liver tissues were evaluated using immunohistochemistry (IHC). Decreased expression of BTG1 mRNA was confirmed in the majority of HCC cell lines (89%) and clinical HCC tissues (85%) compared with non?cancerous liver tissues. Mutations or promoter hypermethylation were not identified in HCC cell lines. BTG1 mRNA expression levels were not influenced by background liver status. The pattern of BTG1 protein expression was consistent with that of BTG1 mRNA. Downregulation of BTG1 mRNA in HCC was significantly associated with shorter disease?specific and recurrence?free survival rates. Multivariate analysis of disease?specific survival rates identified BTG1 mRNA downregulation as an independent prognostic factor for HCC (hazard ratio 2.12, 95% confidence interval 1.12?4.04, P=0.022). Our results indicate that altered BTG1 expression might affect hepatocarcinogenesis and may represent a novel biomarker for HCC carcinogenesis and progression. PMID:25405901

Kanda, Mitsuro; Sugimoto, Hiroyuki; Nomoto, Shuji; Oya, Hisaharu; Hibino, Soki; Shimizu, Dai; Takami, Hideki; Hashimoto, Ryoji; Okamura, Yukiyasu; Yamada, Suguru; Fujii, Tsutomu; Nakayama, Goro; Koike, Masahiko; Fujiwara, Michitaka; Kodera, Yasuhiro

2015-02-01

2

Topoisomerase Inhibitors Modulate Gene Expression of B-Cell Translocation Gene 2 and Prostate Specific Antigen in Prostate Carcinoma Cells  

PubMed Central

Camptothecin (CPT) and doxorubicin (DOX) have been demonstrated to have potent anti-tumor activity. The B-cell translocation gene 2 (BTG2) is involved in the regulation of cell cycle progression. We evaluated the molecular mechanisms of CPT and DOX on cell proliferation and the expressions of BTG2 and prostate specific antigen (PSA) in prostate carcinoma cells. Our results indicated that CPT or DOX treatments induced Go/G1 cell cycle arrest in LNCaP cells and apoptosis at higher dosage. Immunoblot and transient gene expression assay indicated that CPT or DOX treatments induced p53 and BTG2 gene expression, with the later effect dependent on the p53 response element within BTG2 promoter area since mutation of the p53 response element from GGGAAAGTCC to GGAGTCC or from GGCAGAGCCC to GGCACC by site-directed mutagenesis abolished the stimulation of CPT or DOX on the BTG2 promoter activity, which is also supported by our results that cotreatments of pifithrin-?, an inhibitor of p53 dependent transcriptional activation, blocked the induction of CPT or DOX on BTG2 gene expression. CPT or DOX also downregulated the protein expressions of androgen receptor (AR) and PSA. Transient gene expression assays suggested that CPT or DOX’s attenuation of PSA promoter activity is dependent on both the androgen and p53 response elements within of the PSA promoter. Our results indicated that CPT and DOX attenuate cell proliferation via upregulation of BTG2 gene expression through the p53-dependent pathway. The CPT and DOX block the PSA gene expression by upregulation of p53 activity and downregulation of androgen receptor activity. PMID:24586533

Chung, Li-Chuan; Yeh, Chun-Nan; Chang, Phei-Lang; Chen, Wen-Tsung; Juang, Horng-Heng

2014-01-01

3

Detection of 14q32 translocations in B-cell malignancies by in situ hybridization with yeast artificial chromosome clones containing the human IgH gene locus.  

PubMed

Partner sites of 14q32 translocations found in B-cell malignancies were detected by fluorescence in situ hybridization (FISH) using yeast artificial chromosome (YAC) clones, Y20 and Y6, containing the human Ig heavy chain (IgH) gene locus. Y20 spans a 160-kb upstream and 40-kb downstream region of the JH segments on chromosome band 14q32.33. Y6 is 300-kb upstream of Y20, and spans a further 320-kb telomeric region. The human DNA sequences amplified by Alu polymerase chain reaction of the YAC clones were used as probes for FISH to study six patients with non-Hodgkin's lymphoma (NHL), one patient with acute lymphoblastic leukemia, and one cell line FR4 established from a plasmacytoma. Three telomeric YAC clones each specific for 3q, 8q, and 18q were also used to further characterize 14q32 translocations. The IgH YACs were successfully applied to detect cytogenetically invisible subtelomeric translocation of the IgH gene locus to each partner site in t(14;18), t(8;14), and t(14;19), and to identify t(3;14) (q27;q32.33) in three patients with 14q32 translocation of unknown origin. Furthermore, complex translocations involving more than three chromosomes were detected in an NHL patient with t(8;14), and t(3;12), and in the FR4 with der(14)t(8;14), der(8)dic(1;8), and del(1)(q21). The technique would be a useful tool in elucidating the mechanisms of a 14q32 translocation in B-cell malignancies. PMID:8180392

Taniwaki, M; Matsuda, F; Jauch, A; Nishida, K; Takashima, T; Tagawa, S; Sugiyama, H; Misawa, S; Abe, T; Kashima, K

1994-05-15

4

Translocation (3;16)(q27;p11) in a Patient with Diffuse Large B-Cell Lymphoma Associated with the BCL6 Gene Rearrangement  

Microsoft Academic Search

A patient with B-cell lineage diffuse large-cell lymphoma carrying the t(3;16)(q27;p11) and BCL-6 rearrangement is described. Cytogenetic studies showed 46,XY,t(3;16)(q27;p11.2)[11]\\/46,idem,add(18)(q21)[7]\\/46,XY[2]. The chromosomal translocation involving the 3q27 locus was associated with the BCL-6 gene rearrangement identified by Southern blot analysis. This case involved systemic lymph nodes, as large as 3 cm in diameter, bilaterally in neck, axilla, and inguinal regions. The

Ryo Ichinohasama; Ikuo Miura; Tomoaki Shishido; Keisuke Matsumoto; Yoshinaka Shimizu; Tohru Miki; John F DeCoteau; Marshall E Kadin; Kiyoshi Ooya

1998-01-01

5

MRD detection in B-cell non-Hodgkin lymphomas using Ig gene rearrangements and chromosomal translocations as targets for real-time quantitative PCR.  

PubMed

Minimal residual disease (MRD) diagnostics is of high clinical relevance in patients with indolent B-cell Non-Hodgkin lymphomas (B-NHL) and serves as a surrogate parameter to evaluate treatment effectiveness and long-term prognosis. MRD diagnostics performed by real-time quantitative PCR (RQ-PCR) is the gold-standard and currently the most sensitive and the most broadly applied method in follicular lymphoma (FL) and mantle cell lymphoma (MCL). RQ-PCR analysis of the junctional regions of the rearranged immunoglobulin heavy-chain gene (IgH) serves as the most broadly applicable MRD target in B-NHL (?80%). Chromosomal translocations as t(14;18) translocation in FL and t(11;14) translocation in MCL can be used in selected lymphoma subtypes. In patients with B-cell chronic lymphocytic leukemia, both flow-cytometry as well as RQ-PCR are equally suitable for MRD assessment as long as a sensitivity of ?10(-4) shall be achieved.MRD diagnostics targeting the IgH gene is complex and requires extensive knowledge and experience because the junctional regions of each lymphoma have to be identified before the patient-specific RQ-PCR assays can be designed for MRD monitoring. Furthermore, somatic mutations of the IgH region occurring during B-cell development of germinal center and post-germinal center lymphomas may hamper appropriate primer binding leading to false negative results. The translocations mentioned above have the advantage that consensus forward primers and probes, both placed in the breakpoint regions of chromosome 18 in FL and chromosome 11 in MCL, can be used in combination with a reverse primer placed in the IgH joining region of chromosome 14. RQ-PCR-based methods can reach a good sensitivity (?10(-4)). This chapter provides all relevant background information and technical aspects for the complete laboratory process from detection of the clonal IgH gene rearrangement and the chromosomal translocations at diagnosis to the actual MRD measurements in clinical follow-up samples of B-NHL. However, it should be noted that MRD diagnostics for clinical treatment protocols has to be accompanied by regular international quality control rounds to ensure the reproducibility and reliability of the MRD results. PMID:23296964

Pott, Christiane; Brüggemann, Monika; Ritgen, Matthias; van der Velden, Vincent H J; van Dongen, Jacques J M; Kneba, Michael

2013-01-01

6

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

7

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

PubMed

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

8

B cell translocation gene 1 reduces the biological outcome of kidney cancer through induction of cell proliferation, cell cycle arrest, cell apoptosis and cell metastasis.  

PubMed

The aim of the present study was to determine the expression and function of B cell translocation gene 1 (BTG1) in kidney carcinoma. Kidney samples were obtained from cancer lesions (n=85) and the adjacent normal tissue (n=40) in kidney cancer patients immediately following endoscopic biopsy. The effect of BTG1 overexpression was examined in vitro utilizing a human kidney cancer cell line, ACHN, stably transfected with a recombinant lentivirus (LeBTG1 cells) and compared to empty vector?transfected controls (LeEmpty). BTG1 protein expression was significantly lower in kidney cancer tissue biopsies compared to normal tissue, as measured by immunohistochemistry (34.1 vs. 77.8% of tissues; P<0.05) and western blotting (0.481±0.051 vs. 0.857±0.081; P<0.05). In vitro analyses revealed that LeBTG1 cells had a reduced survival fraction compared to control LeEmpty cells, with higher rates of apoptosis (16.6±2.5 vs. 6.1±0.7%; P<0.05). The proportion of LeBTG1 cells in G0/G1 stage and S phase was also significantly different from LeEmpty cells (66.8±5.3 and 22.2±1.5% vs. 44.4±3.1 and 34.5±2.3%, respectively; P<0.05), and the migration and invasion of LeBTG1 cells was significantly impaired with respect to LeEmpty cells (74.0±9.0 and 53.0±7.0 vs. 118.0±15.0 and 103.0±13.0, respectively; P<0.05). These effects were accompanied by decreased protein expression of cyclin D1, B?cell lymphoma 2 and matrix metalloproteinase 9 in LeBTG1 cells (0.118±0.018, 0.169±0.015 and 0.207±0.027, respectively) compared to control LeEmpty cells (0.632±0.061, 0.651±0.063 and 0.443±0.042, respectively; P<0.05). Reduced BTG1 expression is associated with increased disease severity, suggesting it is a negative regulator of kidney cancer and can serve as a prognostic indicator. The results of the present study show that BTG1 protein levels were significantly reduced in kidney cancer biopsy specimens and were associated with disease progression and prognosis. PMID:25571854

Sun, Guogui; Liu, Qing; Cheng, Yunjie; Hu, Wanning

2015-03-01

9

Clinicopathologic Features of CDK6 Translocation-Associated B-Cell Lymphoproliferative Disorders  

PubMed Central

Cyclin-dependent protein kinase 6 (CDK6), in cooperation with cyclin Ds, drives cell cycle progression from G1 to S phase through phosphorylation and subsequent inactivation of Retinoblastoma 1 protein (Rb). Alteration of this pathway results in both non-hematologic and hematologic malignancies, which include a small subset of B-cell lymphoproliferative disorders (BLPDs). We identified 5 cases of BLPD that carried CDK6 chromosomal translocations and characterized their clinical, pathologic, immunophenotypic, and genetic features. Common clinical characteristics included marked neoplastic lymphocytosis, systemic lymphadenopathy, splenomegaly, and bone marrow involvement. Three patients were diagnosed with low-grade B-cell lymphoma and had an indolent clinical course, and 2 patients (one who transformed to large B-cell lymphoma and another who was initially diagnosed with a high-grade B-cell lymphoma) had an aggressive clinical course. Immunophenotypically, the neoplastic B-cells expressed CD5, CDK6, and cytoplasmic Rb in all cases, expressed phospho-RB, p27kip1, and cyclin D2 in most cases, and uniformly lacked expression of all other cyclins. In four cases, the CDK6 translocation partner was kappa immunoglobulin light-chain gene (IGK); and in the fifth case, the CDK6 translocation partner was unknown. These distinct clinicopathologic and cytogenetic features distinguish the CDK6 translocation-associated BLPDs (CDK6-BLPDs) from other mature B-cell lymphomas. PMID:19145199

Chen, Dong; Law, Mark E.; Theis, Jason D.; Gamez, Jeffrey D.; Caron, Lynn B.; Vrana, Julie A.; Dogan, Ahmet; Remstein, Ellen D.

2009-01-01

10

Cell of origin associated classification of B-cell malignancies by gene signatures of the normal B-cell hierarchy.  

PubMed

Recent findings have suggested biological classification of B-cell malignancies as exemplified by the "activated B-cell-like" (ABC), the "germinal-center B-cell-like" (GCB) and primary mediastinal B-cell lymphoma (PMBL) subtypes of diffuse large B-cell lymphoma and "recurrent translocation and cyclin D" (TC) classification of multiple myeloma. Biological classification of B-cell derived cancers may be refined by a direct and systematic strategy where identification and characterization of normal B-cell differentiation subsets are used to define the cancer cell of origin phenotype. Here we propose a strategy combining multiparametric flow cytometry, global gene expression profiling and biostatistical modeling to generate B-cell subset specific gene signatures from sorted normal human immature, naive, germinal centrocytes and centroblasts, post-germinal memory B-cells, plasmablasts and plasma cells from available lymphoid tissues including lymph nodes, tonsils, thymus, peripheral blood and bone marrow. This strategy will provide an accurate image of the stage of differentiation, which prospectively can be used to classify any B-cell malignancy and eventually purify tumor cells. This report briefly describes the current models of the normal B-cell subset differentiation in multiple tissues and the pathogenesis of malignancies originating from the normal germinal B-cell hierarchy. PMID:23998255

Johnsen, Hans Erik; Bergkvist, Kim Steve; Schmitz, Alexander; Kjeldsen, Malene Krag; Hansen, Steen Møller; Gaihede, Michael; Nørgaard, Martin Agge; Bæch, John; Grønholdt, Marie-Louise; Jensen, Frank Svendsen; Johansen, Preben; Bødker, Julie Støve; Bøgsted, Martin; Dybkær, Karen

2014-06-01

11

A novel recurrent translocation t(11;14)(p11;q32) in splenic marginal zone B cell lymphoma  

Microsoft Academic Search

A novel recurrent translocation t(11;14)(p11;q32) was found in three patients with splenic marginal zone B cell lymphoma (MZBCL). Fluorescence in situ hybridization (FISH) studies with IgH probes revealed in all cases involvement of the IgH locus, with breakpoint downstream of the IGVH sequences. Partner genes at 11p11 were not identified. The translocation defined the stem line in two patients, who

A Cuneo; A Bardi; I Wlodarska; D Selleslag; MG Roberti; R Bigoni; F Cavazzini; C De Angeli; E Tammiso; L del Senno; P Cavazzini; A Hagemeijer; G Castoldi

2001-01-01

12

Insulin Phosphorylates Tyrosine Residue 464 of Tub and Translocates Tubby into the Nucleus in HIRcB Cells  

PubMed Central

Background The tubby protein has a motif that might be relevant for its action in the insulin signaling pathway. Previous studies have indicated that tubby undergoes phosphorylation on tyrosine residues in response to several stimuli and is known to localize in the nucleus as well as in the plasma membrane. However, the relationship between phosphorylation and nuclear translocation is not well understood. Here, we report that insulin directly phosphorylates tubby, which translocates into the nucleus. Methods The effects of insulin on Tubby were performed with Western blot. The immunoprecipitation and confocal microscopy were performed to prove phosphorylation and nuclear translocation. Results Mutation study reveals that tyrosine residue 464 of tubby gene (Tub) is a phosphorylation site activated by insulin. In addition, major portions of tubby protein in the plasma membrane are translocated into the nucleus after insulin treatment. Tyrosine kinase inhibitor pretreatment blocked insulin-induced tubby translocation, suggesting that phosphorylation is important for nuclear translocation. Moreover, mutant tyrosine residue 464 did not translocate into the nucleus in respond to insulin. These findings demonstrate that insulin phosphorylates tyrosine residue 464 of Tub, and this event is important for insulin-induced tubby nuclear translocation. Conclusion Insulin phosphorylates tyrosine residue 464 of Tub and translocates tubby into the nuclei of HIRcB cells. PMID:25031889

Kim, Jin Wook; Kim, Hyeon Soo; Kim, Sang Dae

2014-01-01

13

MALT1is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma  

Microsoft Academic Search

The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expres- sion may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification. First, 2 cases, one case of

Dolors Sanchez-Izquierdo; Gerard Buchonnet; Reiner Siebert; Randy D. Gascoyne; Joan Climent; Loraine Karran; Miguel Marin; David Blesa; Douglas Horsman; Andreas Rosenwald; Louis M. Staudt; Donna G. Albertson; Ming-Qing Du; Hongtao Ye; Peter Marynen; Javier Garcia-Conde; Daniel Pinkel; Martin J. S. Dyer; Jose Angel; Martinez-Climent

2003-01-01

14

Human Immunoglobulin Heavy Chain Genes Map to a Region of Translocations in Malignant B Lymphocytes  

Microsoft Academic Search

A human immunoglobulin heavy chain (gamma 4) gene is mapped by chromosome hybridization in situ. This gene is located at band 14q32, a site commonly involved in a chromosomal translocation characteristic of malignant B cells.

Ilan R. Kirsch; Cynthia C. Morton; Kenneth Nakahara; Philip Leder

1982-01-01

15

IGH@ translocations co-exist with other primary rearrangements in B-cell precursor acute lymphoblastic leukemia  

PubMed Central

Primary established genetic abnormalities in B-cell precursor acute lymphoblastic leukemia include high hyperdiploidy (51–65 chromosomes), the translocations t(12;21)(p13;q22)/ETV6-RUNX1 fusion and t(9;22)(q34;q11)/BCR-ABL1 fusion, MLL rearrangements and intrachromosomal amplification of chromosome 21. These rearrangements are of prognostic and therapeutic relevance and are usually mutually exclusive. We identified 28 patients at diagnosis with both a primary genetic rearrangement and an immunoglobulin heavy chain locus translocation using chromosomal analysis and fluorescence in situ hybridization. Among these patients, the immunoglobulin heavy chain locus translocation partner gene was identified in six (CRLF2, CEBPA, CEBPB, TRA/D@, IGF2BP1 and IGK@). Clonal architecture was investigated in 17 patients using multiple color interphase fluorescence in situ hybridization analysis, which showed that the translocation was acquired as a secondary abnormality in ten patients, in four patients the etiology was undetermined and in three patients it was observed in a separate clone from the primary chromosomal rearrangement. These findings demonstrate the co-existence of immunoglobulin heavy chain locus translocations with other primary chromosomal rearrangements either in the same or separate clones, which may have prognostic significance in B-cell precursor acute lymphoblastic leukemia. Clinical trials: UKALLXII: Study ID n. ISRCTN77346223 and ALL2003: Study ID n. ISRCTN07355119 PMID:24816234

Jeffries, Sally J.; Jones, Lisa; Harrison, Christine J.; Russell, Lisa J.

2014-01-01

16

Diffuse Large B-cell Lymphomas of Immunoblastic Type Are a Major Reservoir for MYC-IGH Translocations.  

PubMed

The immunoblastic variant of diffuse large B-cell lymphoma (IB-DLBCL) has recently been recognized as an aggressive lymphoma type with inferior prognosis as compared with other DLBCL variants. At the same time, the presence of MYC rearrangements in DLBCL has been shown to indicate shorter survival in R-CHOP-treated patients. In this study, we investigated the occurrence of MYC gene rearrangements in IB-DLBCL versus non-IB-DLBCL in a large series. Using fluorescence in situ hybridization with an MYC break-apart and MYC-IGH fusion probe, we found that 13/39 evaluable IB-DLBCLs (33%) harbor translocations involving MYC, in contrast with only 5/68 (7%) in the non-IB-DLBCL group (P<0.01). The immunoglobulin heavy chain gene (IGH) was the translocation partner in all rearrangements (100%) involving MYC in IB-DLBCL, which is in contrast to what has been reported for DLBCL in the literature (50% to 70%). Moreover, MYC rearrangements occurred as the sole translocation in the majority of cases (77%), whereas across all DLBCLs the majority of MYC-rearranged cases carry additional rearrangements of either BCL2 and/or BCL6 genes (between 58% and 83% of cases). Finally, MYC-rearranged IB-DLBCLs were CD10 positive in 62% (8/13), whereas this was an uncommon feature in MYC germline IB-DLBCLs (15%). In conclusion, IB-DLBCLs are genetically characterized by frequent MYC-IGH translocations that often occur without additional BCL2 and/or BCL6 translocations. The activation of MYC, therefore, may be an important pathogenetic feature in IB-DLBCL. PMID:25229766

Horn, Heike; Staiger, Annette M; Vöhringer, Matthias; Hay, Ulrich; Campo, Elias; Rosenwald, Andreas; Ott, German; Ott, M Michaela

2015-01-01

17

Expression of T cell receptor genes in human B cells  

PubMed Central

We analyzed the transcription and rearrangement of the T cell antigen receptor (Ti) genes Ti alpha and Ti beta in human B cell, T cell, and myeloid cell lines, as well as in purified tonsillar B and T cells. All four B cell lines examined, as well as one of two myeloid cell lines, expressed low levels of truncated Ti beta transcripts, as did freshly purified tonsillar B cells. Two of the B cell lines and one of the myeloid lines also expressed truncated Ti alpha transcripts, while tonsillar B cells did not. Sequence analysis of cDNA clones from a B cell line demonstrated that these truncated Ti alpha and Ti beta transcripts were composed of unrearranged J and C gene segments. Comparison of cDNA clones from T and B cells suggests that D alpha genes or N regions contribute to the formation of Ti alpha transcripts in T cells but not in B cells. None of the B cell or myeloid cell lines in this study showed evidence of Ti beta gene rearrangements by Southern blotting. Our data, and other studies of gene rearrangements in human tumors, demonstrate that the level of Ti beta transcriptional activity and the frequency of Ti beta gene rearrangements are correlated in all cell types examined. Thus, our data support the accessibility model of antigen receptor gene rearrangement, whereby the susceptibility of gene segments to recombination enzymes is correlated with their transcriptional activity. PMID:2431093

1986-01-01

18

Detection of 14q32.33 translocation and t(11;14) in interphase nuclei of chronic B-cell leukemia/lymphomas by in situ hybridization.  

PubMed

Abnormalities of chromosome 14 involving band q32.33 are among the most commonly observed cytogenetic alterations in B-cell malignancies. To assess the incidence and pathogenetic implications of 14q32.33 translocation in chronic B-cell leukemia/lymphomas, we performed fluorescence in situ hybridization (FISH) analysis with variable region (V(H)) and gamma constant region (Cgamma) gene probes in 37 patients with these disorders. Chromosome 14q32.33 translocation was detected in 2 of 18 patients with chronic lymphocytic leukemia (CLL), 1 of 2 with CLL of mixed cell types (CLL/PL), 1 of 2 with pro-lymphocytic leukemia (PLL), 5 of 6 with leukemic mantle-cell lymphoma (MCL), 2 of 7 with splenic B-cell leukemia/lymphoma of possible marginal zone origin (SBLL) and 2 with leukemic follicular lymphoma (FL). To further characterize 14q32.33 translocations in these patients, we developed a new procedure using double-color FISH with PRAD1, BCL2, V(H) and Cgamma gene probes. Chromosome t(11;14) was detected in 1 patient with CLL/PL, 1 with PLL and 5 with MCL. Chromosome t(14;18) was detected in 2 patients with FL. In a PLL patient with t(11;14), the cosmid CPP29 containing the PRAD1 gene and its 5'-flanking region split and co-localized with both Cgamma and V(H) gene probes, thus spanning the breakpoint. In CLL and SBLL patients, donor chromosomes were other than chromosomes 2, 11, 18 and 19, suggesting the involvement of a novel oncogene(s) in the pathogenesis of these diseases. Interphase FISH rapidly detected 14q32.33 translocation, t(11;14) and t(14;18) in B-cell malignancies with low mitotic activity at the single-cell level, facilitating the correlation of the molecular features of these translocations with clinical characteristics. PMID:9212219

Takashima, T; Itoh, M; Ueda, Y; Nishida, K; Tamaki, T; Misawa, S; Abe, T; Seto, M; Machii, T; Taniwaki, M

1997-07-01

19

Chromosomal translocations involving the IGH@ locus in B-cell precursor acute lymphoblastic leukemia: 29 new cases and a review of the literature.  

PubMed

Chromosomal translocations involving the immunoglobulin heavy chain locus (IGH@) are recurrent but rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and various partner genes have been described. Here, we report a new series of 29 cases of BCP-ALL with IGH@ translocations. The partner gene was identified by fluorescence in situ hybridization and/or molecular cloning in 20 patients. Members of the CEBP gene family (n = 11), BCL2 (n = 3), ID4 (n = 3), EPOR (n = 2), and TRA/D@ (n = 1) were identified and demonstrated by quantitative real-time reverse transcriptase-polymerase chain reaction to be markedly up-regulated. The present cases, added to those already reported, confirm the diversity of the partner genes, which, apart from BCL2, are specific to BCP-ALL. Collectively, patients with IGH@ translocations may represent a novel sub-group of BCP-ALL occurring in adolescents and young adults. PMID:23827691

Chapiro, Elise; Radford-Weiss, Isabelle; Cung, Hong-Anh; Dastugue, Nicole; Nadal, Nathalie; Taviaux, Sylvie; Barin, Carole; Struski, Stephanie; Talmant, Pascaline; Vandenberghe, Peter; Mozziconacci, Marie-Joelle; Tigaud, Isabelle; Lefebvre, Christine; Penther, Dominique; Bastard, Christian; Lippert, Eric; Mugneret, Francine; Romana, Serge; Bernard, Olivier A; Harrison, Christine J; Russell, Lisa J; Nguyen-Khac, Florence

2013-05-01

20

Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells.  

PubMed

Whereas chromosomal translocations are common pathogenetic events in cancer, mechanisms that promote them are poorly understood. To elucidate translocation mechanisms in mammalian cells, we developed high-throughput, genome-wide translocation sequencing (HTGTS). We employed HTGTS to identify tens of thousands of independent translocation junctions involving fixed I-SceI meganuclease-generated DNA double-strand breaks (DSBs) within the c-myc oncogene or IgH locus of B lymphocytes induced for activation-induced cytidine deaminase (AID)-dependent IgH class switching. DSBs translocated widely across the genome but were preferentially targeted to transcribed chromosomal regions. Additionally, numerous AID-dependent and AID-independent hot spots were targeted, with the latter comprising mainly cryptic I-SceI targets. Comparison of translocation junctions with genome-wide nuclear run-ons revealed a marked association between transcription start sites and translocation targeting. The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics. PMID:21962511

Chiarle, Roberto; Zhang, Yu; Frock, Richard L; Lewis, Susanna M; Molinie, Benoit; Ho, Yu-Jui; Myers, Darienne R; Choi, Vivian W; Compagno, Mara; Malkin, Daniel J; Neuberg, Donna; Monti, Stefano; Giallourakis, Cosmas C; Gostissa, Monica; Alt, Frederick W

2011-09-30

21

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; Sörqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R.; Rosenquist, Richard; Sundström, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David

2013-01-01

22

Microdeletion syndromes, balanced translocations, and gene mapping.  

PubMed Central

High resolution prometaphase chromosome banding has allowed the detection of discrete chromosome aberrations which escaped earlier metaphase examinations. Consistent tiny deletions have been detected in some well established malformation syndromes: an interstitial deletion in 15q11/12 in the majority of patients with the Prader-Willi syndrome and in a minority of patients with the Angelman (happy puppet) syndrome; a terminal deletion of 17p13.3 in most patients examined with the Miller-Dieker syndrome; an interstitial deletion of 8q23.3/24.1 in a large majority of patients with the Giedion-Langer syndrome; an interstitial deletion of 11p13 in virtually all patients with the WAGR (Wilms' tumour-aniridia-gonadoblastoma-retardation) syndrome; and an interstitial deletion in 22q11 in about one third of patients with the DiGeorge sequence. In addition, a combination of chromosome prometaphase banding and DNA marker studies has allowed the localisation of the genes for retinoblastoma and for Wilms' tumour and the clarification of both the autosomal recessive nature of the mutation and the possible somatic mutations by which the normal allele can be lost in retina and kidney cells. After a number of X linked genes had been mapped, discrete deletions in the X chromosome were detected by prometaphase banding with specific attention paid to the sites of the gene(s) in males who had from one to up to four different X linked disorders plus mental retardation. Furthermore, the detection of balanced translocations in probands with disorders caused by autosomal dominant or X linked genes has allowed a better insight into the localisation of these genes. In some females with X linked disorders, balanced X; autosomal translocations have allowed the localisation of X linked genes at the breakpoint on the X chromosome. Balanced autosome; autosome translocations segregating with autosomal dominant conditions have provided some clues to the gene location of these conditions. In two conditions, Greig cephalopolysyndactyly and dominant aniridia, two translocation families with one common breakpoint have allowed quite a confident location of the genes at the common breakpoint at 7p13 and 11p13, respectively. PMID:3050093

Schinzel, A

1988-01-01

23

Plasmablastic transformation of low-grade CD5+ B-cell lymphoproliferative disorder with MYC gene rearrangements.  

PubMed

Plasmablastic transformation of low-grade B-cell lymphoproliferative disorders is rarely reported, particularly in cases with clonal evolution. Moreover, the relationship of these 2 morphologically and immunophenotypically distinctive neoplasms remains elusive. Here, we report 2 exceptional cases of plasmablastic transformation with apparently direct transformation from their preceding low-grade B-cell lymphoproliferative disorder. In both cases, the plasmablastic transformation and low-grade lymphoproliferative disorder shared the same immunoglobulin heavy chain gene rearrangements and an identical chromosomal translocation. Notably, both plasmablastic transformation cases also carried MYC gene rearrangements on chromosome 8q24, which have been frequently identified in de novo plasmablastic lymphoma. Therefore, our data suggest that dysregulation of MYC gene may play a critical role in the pathogenesis of plasmablastic transformation. PMID:23791008

Pan, Zenggang; Xie, Qingmei; Repertinger, Susan; Richendollar, Bill G; Chan, Wing C; Huang, Qin

2013-10-01

24

Concurrent activation of MYC and BCL2 in B cell non-Hodgkin lymphoma cell lines by translocation of both oncogenes to the same immunoglobulin heavy chain locus.  

PubMed

Concurrent activation of BCL2 and MYC usually occurs in B cell non-Hodgkin lymphoma (B-NHL) by translocation of both oncogenes to both immunoglobulin heavy chain (IGH) alleles: this abrogates immunoglobulin synthesis. We have studied three B-NHL cell lines (DoHH2, VAL and ROS 50) and show that concurrent activation of BCL2 and MYC may follow translocation of both oncogenes to the same IGH allele. Conventional cytogenetics of DoHH2 suggested the presence of a t(14;18)(q32;q21) translocation. However, fluorescent in situ hybridization (FISH) studies using whole chromosome paints, alpha satellite probes and flow-sorted chromosomes as probes revealed an unexpected complexity of rearrangements involving chromosomes 8, 14 and 18, namely t(8;14;18)(q24;q32;q21). DNA blot and previous PCR analysis confirmed the juxtaposition of BCL2 major breakpoint region (mbr) with IGJH6, but also demonstrated a rearrangement within the first exon of MYC. The centromeric (5') MYC rearranged fragment comigrated with the BCL2-JH6 rearranged fragment in BamHI, EcoRI and Bg/II restriction digests. The der(8)t(8;14;18) therefore comprised 5' MYC (exon I)-Sgamma4-JH6-BCL2 mbr. Similar rearrangements were observed in both ROS 50 and VAL cell lines which contained two and three copies of the der(8)t(8;14;18) respectively. Quantitative flow cytometry for BCL2 and MYC expression showed abundant expression of both proteins in all three lines. These data indicate the der(14)t(14;18)(q32;q21) may itself be the target for any second translocation. The presence of the intact BCL2-JH fusion gene on the der(8)t(8;14;18) allowed concurrent activation of both BCL2 and MYC with no loss of immunoglobulin expression. PMID:8684002

Dyer, M J; Lillington, D M; Bastard, C; Tilly, H; Lens, D; Heward, J M; Stranks, G; Morilla, R; Monrad, S; Guglielmi, P; Kluin-Nelemans, J C; Hagemeijer, A; Young, B D; Catovsky, D

1996-07-01

25

Induction of B-cell tolerance by retroviral gene therapy.  

PubMed

The primary immunologic barrier to overcome before clinical xenotransplantation can be successful is rejection mediated by preformed natural antibodies in the host, directed toward a single carbohydrate epitope Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal) present on porcine tissue, encoded for by the enzyme glucosyltransferase UDP galactose:beta-D-galactosyl-1, 4-N-acetyl-D-glucosaminide alpha(1-3)galactosyltransferase (EC 2.4.1. 151) or simply alphaGT. Although we have shown previously that a gene therapy approach could be used to prevent production of natural antibodies specific for alphaGal, the ability to induce and maintain tolerance after rigorous antigen challenge would be required if similar approaches are to be used clinically. Here, we demonstrate in alphaGT knockout mice (GT(0) mice), which, like humans, contain in their serum antibodies that bind alphaGal, that the efficient transduction and expression of a retrovirally transduced alphaGT gene in bone marrow-derived cells induces stable long-term tolerance to the alphaGal epitope. GT(0) mice reconstituted with alphaGT-transduced bone marrow cells were unable to produce antibodies that bind alphaGal after extensive immunization with pig cells. Furthermore, using ELISPOT assays, we were unable to detect the presence of B cells that produce alphaGal reactive antibodies after immunization, suggesting that such B cells were eliminated from the immunologic repertoire after gene therapy. Interestingly, after tolerance to alphaGal is induced by gene therapy, the antiporcine non-alphaGal humoral response changes from a predominantly IgM to an IgG response. This suggests that once the natural antibody barrier is eliminated by the induction of tolerance, the antipig response changes to a typical T-cell-dependent response involving isotype switching. Thus, gene therapy approaches may be used to overcome immunologic responses leading to xenograft rejection, and similar gene therapy approaches could be used to overcome autoimmunity. PMID:11049978

Bracy, J L; Iacomini, J

2000-11-01

26

Molecular Cloning of the Chromosomal Breakpoint of B-Cell Lymphomas and Leukemias with the t(11;14) Chromosome Translocation  

Microsoft Academic Search

The chromosomal breakpoint of chronic lymphocytic leukemia (CLL) cells of the B-cell type carrying the translocated long arms of chromosomes 11 and 14 [t(11;14) (q13;q32)] was cloned. The breakpoint was found to be within the joining segment of the human heavy chain locus on the translocated long arm of chromosome 14. A probe that is specific for chromosome 11 and

Yoshihide Tsujimoto; Jorge Yunis; Louise Onorato-Showe; Jan Erikson; Peter C. Nowell; Carlo M. Croce

1984-01-01

27

The 'zinc knuckle' motif of Early B cell Factor is required for transcriptional activation of B cell-specific genes  

PubMed Central

Early B cell factor (EBF) is a critical regulator of B lymphocyte-specific gene transcription. EBF functions, in part, by binding to regulatory sites of genes required for the pre-B- and mature B cell receptors. These DNA targets include the promoters of the mb-1 and Vpreb1 genes that encode Ig-? and one of the components of surrogate light chain, respectively. The biochemical basis of DNA binding and gene activation by EBF is poorly understood. The DNA-binding domain (DBD) of EBF includes a putative zinc-binding motif (HX3CX2CX5C), which we have designated the 'Zn-knuckle'. The Zn-knuckle is required for binding of the mb-1 promoter site in EMSA, but it has not been demonstrated to be important for functional activities of EBF in B cells. Therefore, we expressed EBF with mutations in the Zn-knuckle motif or flanking sequences in plasmacytoma cells in which activation of endogenous mb-1 and Vpreb1 genes is dependent on EBF. EBF with mutations that prevent zinc coordination by the Zn-knuckle did not activate transcription of either target gene. Other mutations affected the sequence preference of DNA binding and differentially inhibited activation of these genes. Our results demonstrate the importance of the Zn-knuckle motif in EBF. These experiments also confirm that EBF can re-activate multiple genes of the early B cell program in plasmacytoma cells, which provide a useful cell-based assay for dissecting mechanisms involving EBF. PMID:18606452

Fields, Scott; Ternyak, Kristina; Gao, Hua; Ostraat, Rachel; Akerlund, Janie; Hagman, James

2008-01-01

28

Regulation of B cell fate commitment and immunoglobulin VH gene rearrangements by Ikaros  

PubMed Central

The transcription factor Ikaros is essential for B cell development. However, its molecular functions in B cell fate specification and commitment have remained elusive. We showed that the transcription factor EBF rescued the generation of CD19+ pro-B cells from Ikzf1-/- hematopoietic progenitors. Intriguingly, these pro-B cells, in spite of expressing normal amounts of EBF and Pax5, were not committed to the B cell fate. They also failed to selectively undergo VH to DJH recombination at the immunoglobulin heavy-chain (Igh) locus. Ikaros induced VH gene rearrangements by activating Rag gene expression as well as by controlling VH gene accessibility and compaction of the Igh locus. Thus Ikaros is an obligate component of a network that regulates B cell fate commitment and Igh recombination. PMID:18568028

Reynaud, Damien; Demarco, Ignacio; Reddy, Karen; Schjerven, Hilde; Bertolino, Eric; Chen, Zhengshan; Smale, Stephen T.; Winandy, Susan; Singh, Harinder

2009-01-01

29

Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression.  

PubMed

Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation of Cd79a (mb-1) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences of Ebf1 haploinsufficiency together with haploinsufficiency of Runx1 genes in mice. Although numbers of "committed" pro-B cells were maintained in Ebf1(+/-)Runx1(+/-) (ER(het)) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, kappa0 sterile transcripts, CD2 and CD25 were reduced and delayed in ER(het) pro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells in ER(het) mice. Late pre-B and immature and mature B cells were decreased in the bone marrow of Ebf1(+/-) (E(het)) mice and were nearly absent in ER(het) mice. Although we did not observe significant effects of haploinsuficiencies on IgH or Igkappa rearrangements, a relative lack of Iglambda rearrangements was detected in E(het) and ER(het) pre-B cells. Together, these observations suggest that B cell lineage progression is impaired at multiple stages in the bone marrow of E(het) and ER(het) mice. Furthermore, enforced expression of EBF1 and RUNX1 in terminally differentiated plasmacytoma cells activated multiple early B cell-specific genes synergistically. Collectively, these studies illuminate the effects of reduced Ebf1 dosage and the compounding effects of reduced Runx1 dosage. Our data confirm and extend the importance of EBF1 in regulating target genes and Ig gene rearrangements necessary for B cell lineage specification, developmental progression, and homeostasis. PMID:20385820

Lukin, Kara; Fields, Scott; Lopez, Desiree; Cherrier, Marie; Ternyak, Kristina; Ramírez, Julita; Feeney, Ann J; Hagman, James

2010-04-27

30

B-cell biomarkers in transplantation - from genes to therapy.  

PubMed

An increased understanding of the mechanisms by which the immune system mounts a response to transplanted organs has allowed the development of immunosuppressive regimens that limit acute T-cell-mediated rejection (TCMR). However, the treatment of acute and chronic antibody-mediated rejection (ABMR) in kidney transplants remains sub-optimal. The occurrence and severity of antibody-mediated graft pathology are variable, and genetic polymorphisms that affect the magnitude and nature of the B-cell response, as well as effector functions of antibody, are likely to contribute to such phenotypic variation. Here we review current efforts to understand and quantify the contribution of B cells to renal transplant pathology by studying variation in DNA, mRNA and proteins. Large genetic studies with information on B-cell-specific genetic variants are scarce. At a transcriptomic level, there is evidence that B cells are essential contributors to transplant tolerance and may protect against TCMR and ABMR. In contrast, at the protein level, the detection of donor-specific human leukocyte antigen (HLA) antibodies and an assessment of their capacity to bind complement allow patients of high immunological risk to be identified. Other biomarkers, such as serum B-cell-activating factor (BAFF) or interleukin (IL)-10-producing B cells, may allow this risk stratification to be refined. An increased understanding of the significance of these biomarkers should allow a more accurate assessment of how an individual patient's B cells will impact allograft responses and thereby allow clinicians to adjust therapeutic strategies appropriately. PMID:25626600

Banham, G D; Clatworthy, M R

2015-02-01

31

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

Microsoft Academic Search

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malig- nancy 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

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

2001-01-01

32

Diagnostic value of immunoglobulin ? light chain gene rearrangement analysis in B-cell lymphomas  

PubMed Central

Analysis of the immunoglobulin ? light chain (IGK) gene is an alternative method for B-cell clonality assessment in the diagnosis of mature B-cell proliferations in which the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements fails. The aim of the present study was to evaluate the added value of standardized BIOMED-2 assay for the detection of clonal IGK gene rearrangements in the diagnostic setting of suspected B-cell lymphomas. With this purpose, 92 specimens from 80 patients with the final diagnosis of mature B-cell lymphoma (37 specimens), mature T-cell lymphoma (26 specimens) and reactive lymphoid proliferation (29 specimens) were analyzed for B-cell clonality. B-cell clonality analysis was performed using the BIOMED-2 IGH and IGK gene clonality assays. The determined sensitivity of the IGK assay was 67.6%, while the determined sensitivity of the IGH assay was 75.7%. The sensitivity of combined IGH+IGK assay was 81.1%. The determined specificity of the IGK assay was 96.2% in the group of T-cell lymphomas and 96.6% in the group of reactive lesions. The determined specificity of the IGH assay was 84.6% in the group of lymphomas and 86.2% in the group of reactive lesions. The comparison of GeneScan (GS) and heteroduplex pretreatment-polyacrylamide gel electrophoresis (HD-PAGE) methods for the analysis of IGK gene rearrangements showed a higher efficacy of GS analysis in a series of 27 B-cell lymphomas analyzed by both methods. In the present study, we demonstrated that by applying the combined IGH+IGK clonality assay the overall detection rate of B-cell clonality was increased by 5.4%. Thus, we confirmed the added value of the standardized BIOMED-2 IGK assay for assessment of B-cell clonality in suspected B-cell lymphomas with inconclusive clinical and cyto/histological diagnosis. PMID:25501347

KOKOVIC, IRA; NOVAKOVIC, BARBARA JEZERSEK; NOVAKOVIC, SRDJAN

2015-01-01

33

Diagnostic value of immunoglobulin ? light chain gene rearrangement analysis in B-cell lymphomas.  

PubMed

Analysis of the immunoglobulin ? light chain (IGK) gene is an alternative method for B-cell clonality assessment in the diagnosis of mature B-cell proliferations in which the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements fails. The aim of the present study was to evaluate the added value of standardized BIOMED-2 assay for the detection of clonal IGK gene rearrangements in the diagnostic setting of suspected B-cell lymphomas. With this purpose, 92 specimens from 80 patients with the final diagnosis of mature B-cell lymphoma (37 specimens), mature T-cell lymphoma (26 specimens) and reactive lymphoid proliferation (29 specimens) were analyzed for B-cell clonality. B-cell clonality analysis was performed using the BIOMED-2 IGH and IGK gene clonality assays. The determined sensitivity of the IGK assay was 67.6%, while the determined sensitivity of the IGH assay was 75.7%. The sensitivity of combined IGH+IGK assay was 81.1%. The determined specificity of the IGK assay was 96.2% in the group of T-cell lymphomas and 96.6% in the group of reactive lesions. The determined specificity of the IGH assay was 84.6% in the group of lymphomas and 86.2% in the group of reactive lesions. The comparison of GeneScan (GS) and heteroduplex pretreatment-polyacrylamide gel electrophoresis (HD-PAGE) methods for the analysis of IGK gene rearrangements showed a higher efficacy of GS analysis in a series of 27 B-cell lymphomas analyzed by both methods. In the present study, we demonstrated that by applying the combined IGH+IGK clonality assay the overall detection rate of B-cell clonality was increased by 5.4%. Thus, we confirmed the added value of the standardized BIOMED-2 IGK assay for assessment of B-cell clonality in suspected B-cell lymphomas with inconclusive clinical and cyto/histological diagnosis. PMID:25501347

Kokovic, Ira; Jezersek Novakovic, Barbara; Novakovic, Srdjan

2015-03-01

34

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas.  

PubMed

Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n=14) or more aggressive chemotherapy regimens (n=17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P=0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P=0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (P<0.01), less frequently expressed CD10 (P<0.01), and patients less often had an elevated serum lactate dehydrogenase level (P=0.01). In aggregate, these results support expanding the category of MYC/BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations. PMID:25103070

Li, Shaoying; Seegmiller, Adam C; Lin, Pei; Wang, Xuan J; Miranda, Roberto N; Bhagavathi, Sharathkumar; Medeiros, L Jeffrey

2015-02-01

35

Induction of Ig Light Chain Gene Rearrangement in Heavy Chain-Deficient B Cells by Activated Ras  

Microsoft Academic Search

During B cell development, rearrangement and expression of Ig heavy chain (HC) genes promote development and expansion of pre-B cells accompanied by the onset of Ig light chain (LC) variable region gene assembly. To elucidate the signaling pathways that control these events, we have tested the ability of activated Ras expression to promote B cell differentiation to the stage of

Albert C. Shaw; Wojciech Swat; Laurie Davidson; Frederick W. Alt

1999-01-01

36

Gene flow and endangered species translocations: a topic revisited  

Microsoft Academic Search

Understanding the evolutionary role of gene flow is pivotal to the conservation of endangered populations. Gene flow can be enhanced through population translocations that are conducted to maintain genetic variation and combat the negative consequences of inbreeding depression (two of the major concerns in the conservation of subdivided or isolated populations). While researchers have given extensive consideration to the idea

Andrew Storfer

1999-01-01

37

Insights into Gene Expression Changes Impacting B-Cell Transformation: Cross-Species Microarray Analysis of Bovine Leukemia Virus Tax-Responsive Genes in Ovine B Cells  

PubMed Central

Large-animal models for leukemia have the potential to aid in the understanding of networks that contribute to oncogenesis. Infection of cattle and sheep with bovine leukemia virus (BLV), a complex retrovirus related to human T-cell leukemia virus type 1 (HTLV-1), is associated with the development of B-cell leukemia. Whereas the natural disease in cattle is characterized by a low tumor incidence, experimental infection of sheep leads to overt leukemia in the majority of infected animals, providing a model for studying the pathogenesis associated with BLV and HTLV-1. TaxBLV, the major oncoprotein, initiates a cascade of events leading toward malignancy, although the basis of transformation is not fully understood. We have taken a cross-species ovine-to-human microarray approach to identify TaxBLV-responsive transcriptional changes in two sets of cultured ovine B cells following retroviral vector-mediated delivery of TaxBLV. Using cDNA-spotted microarrays comprising 10,336 human genes/expressed sequence tags, we identified a cohort of differentially expressed genes, including genes related to apoptosis, DNA transcription, and repair; proto-oncogenes; cell cycle regulators; transcription factors; small Rho GTPases/GTPase-binding proteins; and previously reported TaxHTLV-1-responsive genes. Interestingly, genes known to be associated with human neoplasia, especially B-cell malignancies, were extensively represented. Others were novel or unexpected. The results suggest that TaxBLV deregulates a broad network of interrelated pathways rather than a single B-lineage-specific regulatory process. Although cross-species approaches do not permit a comprehensive analysis of gene expression patterns, they can provide initial clues for the functional roles of genes that participate in B-cell transformation and pinpoint molecular targets not identified using other methods in animal models. PMID:16439548

Klener, Pavel; Szynal, Maud; Cleuter, Yvette; Merimi, Makram; Duvillier, Hugues; Lallemand, Françoise; Bagnis, Claude; Griebel, Philip; Sotiriou, Christos; Burny, Arsène; Martiat, Philippe; Van den Broeke, Anne

2006-01-01

38

The molecular biology of B-cell lymphoma: Clinicopathologic implications  

Microsoft Academic Search

Summary Nonrandom chromosomal translocations like the t(14;18), t(8;14), and t(11;14) are found in distinct types of B-cell malignancies. Recent molecular studies concerning their structure and origin showed that many translocations occur in early precursor B cells and may be interpreted as aberrant immunoglobulin gene rearrangements. The available data from in vitro experiments, transgenic mice, and normal human individuals indicate that

P. M. Kluin

1991-01-01

39

A novel gene product associated with mu chains in immature B cells.  

PubMed Central

A previously unreported B cell specific gene, which we have named 8HS-20, was isolated from the cDNA library of a pre-B cell clone by subtraction and differential hybridization. This gene is selectively expressed as a 0.75 kb transcript in pre-B and bone marrow-derived B cell lines; a transcript of the same size is also found in bone marrow and, albeit at low levels, in spleen. The deduced amino acid sequence of the 8HS-20 cDNA displayed homology to a B cell specific gene, VpreB-1, and to members of the immunoglobulin supergene family including V lambda, V kappa, VH, TCRV alpha, V beta and CD8. Biochemical analysis using purified antiserum against 8HS-20 oligopeptides indicates that the gene encodes proteins with mol. wts of 13.5, 14, 15.5 and 16 kDa, which associate with mu chains in pre-B cell lines, and that these molecules are expressed concomitantly with VpreB-1 and lambda 5 gene products in the same cell lines. Images PMID:8491176

Shirasawa, T; Ohnishi, K; Hagiwara, S; Shigemoto, K; Takebe, Y; Rajewsky, K; Takemori, T

1993-01-01

40

Identification of co-expressed gene signatures in mouse B1, marginal zone and B2 B-cell populations  

PubMed Central

In mice, three major B-cell subsets have been identified with distinct functionalities: B1 B cells, marginal zone B cells and follicular B2 B cells. Here, we used the growing body of publicly available transcriptomics data to create an expression atlas of 84 gene expression microarray data sets of distinct mouse B-cell subsets. These data were subjected to network-based cluster analysis using BioLayout Express3D. Using this analysis tool, genes with related functions clustered together in discrete regions of the network graph and enabled the identification of transcriptional networks that underpinned the functional activity of distinct cell populations. Some gene clusters were expressed highly by most of the cell populations included in this analysis (such as those with activity related to house-keeping functions). Others contained genes with expression patterns specific to distinct B-cell subsets. While these clusters contained many genes typically associated with the activity of the cells they were specifically expressed in, many novel B-cell-subset-specific candidate genes were identified. A large number of uncharacterized genes were also represented in these B-cell lineage-specific clusters. Further analysis of the activities of these uncharacterized candidate genes will lead to the identification of novel B-cell lineage-specific transcription factors and regulators of B-cell function. We also analysed 36 microarray data sets from distinct human B-cell populations. These data showed that mouse and human germinal centre B cells shared similar transcriptional features, whereas mouse B1 B cells were distinct from proposed human B1 B cells. PMID:24032749

Mabbott, Neil A; Gray, David

2014-01-01

41

Clinical, morphologic, phenotypic, and genetic evidence of cyclin D1-positive diffuse large B-cell lymphomas with CYCLIN D1 gene rearrangements.  

PubMed

Overexpression of cyclin D1 in diffuse large B-cell lymphomas (DLBCLs) is observable in about 5% of cases and is linked to gains of additional CYCLIN D1 gene copies or deregulation at the mRNA level. All cyclin D1-positive DLBCL cases reported so far lack the canonical t(11;14)(q13;q32) translocation that is a genetic hallmark and the primary cause of cyclin D1 overexpression in mantle cell lymphoma (MCL). Using standard histologic and genetic techniques, complemented with genome-wide aberration analysis by array comparative genomic hybridization, we characterized 2 exceptional cases of blastoid B-cell lymphomas with cyclin D1 overexpression, both bearing genetic rearrangements in the CYCLIN D1 gene locus. One of them had a t(11;14)(q13;q32) translocation and featured morphology, immunophenotype, and genetic copy number aberrations typical of DLBCL. The second case had a complex t(4;11;14) translocation, but the other features were intermediate between DLBCL and MCL and did not allow unambiguous classification in any of the current diagnostic lymphoma categories. On the basis of these findings, we conclude that detection of t(11;14) should not preclude a diagnosis of cyclin D1-positive DLBCL when all other parameters are in agreement with such a diagnosis. Moreover, a yet unacknowledged diagnostic "gray zone" may exist between DLBCL and MCL. PMID:24722063

Juskevicius, Darius; Ruiz, Christian; Dirnhofer, Stephan; Tzankov, Alexandar

2014-05-01

42

Developmental hierarchy of immunoglobulin gene rearrangements in human leukemic pre-B-cells.  

PubMed Central

We have used a special class of human acute lymphocytic leukemias, the common "non-T/non-B" cell type, to define a hierarchy of genetic rearrangements that occur during the earliest stages of B-cell maturation. This has allowed us to identify intermediate cells predicted by a hierarchial model in which immunoglobulin heavy chain variable region gene formation precedes that of light chain and in which kappa light chain gene formation precedes that of lambda. The model emphasizes the flexible nature of immunoglobulin gene recombination that not infrequently produces aberrant or null genes that are phenotypically excluded from expression. Remaining alleles or isotypic genes can then be utilized as "spares" undergoing recombination until a valid gene is formed. Significantly, the excluded allele or isotype is frequently deleted from the genome. In addition to defining a pathway of genetic maturation, this analysis provides a powerful means to further classify cases of non-T/non-B-cell acute lymphocytic leukemia, most of which seem to reside at early stages along the B-cell pathway of differentiation. Images PMID:6273911

Korsmeyer, S J; Hieter, P A; Ravetch, J V; Poplack, D G; Waldmann, T A; Leder, P

1981-01-01

43

Aberrant B cell receptor signaling from B29 (Ig, CD79b) gene mutations of chronic lymphocytic leukemia B cells  

Microsoft Academic Search

Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low or undetectable surface B cell receptor (BCR) and diminished responses to BCR-mediated signaling. These features suggest that CLL cells may have sustained mutations affecting one or more of the BCR proteins required for receptor surface assembly and signal transduction. Loss of expression and mutations in the critical BCR protein B29 (Ig,

Melinda S. Gordon; Roberta M. Kato; Frederick Lansigan; Alexis A. Thompson; Randolph Wall; David J. Rawlings

2000-01-01

44

A Critical Role of the Thy28-MYH9 Axis in B Cell-Specific Expression of the Pax5 Gene in Chicken B Cells  

PubMed Central

Accumulating evidence suggests that Pax5 plays essential roles in B cell lineage commitment. However, molecular mechanisms of B cell-specific expression of Pax5 are not fully understood. Here, we applied insertional chromatin immunoprecipitation (iChIP) combined with stable isotope labeling using amino acids in cell culture (SILAC) (iChIP-SILAC) to direct identification of proteins interacting with the promoter region of the endogenous single-copy chicken Pax5 gene. By comparing B cells with macrophage-like cells trans-differentiated by ectopic expression of C/EBP?, iChIP-SILAC detected B cell-specific interaction of a nuclear protein, Thy28/Thyn1, with the Pax5 1A promoter. Trans-differentiation of B cells into macrophage-like cells caused down-regulation of Thy28 expression. Loss-of-function of Thy28 induced decrease in Pax5 expression and recruitment of myosin-9 (MYH9), one of Thy28-interacting proteins, to the Pax5 1A promoter. Loss-of-function of MYH9 also induced decrease in Pax5 expression. Thus, our analysis revealed that Thy28 is functionally required for B cell-specific expression of Pax5 via recruitment of MYH9 to the Pax5 locus in chicken B cells. PMID:25607658

Fujita, Toshitsugu; Kitaura, Fusako; Fujii, Hodaka

2015-01-01

45

Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch  

PubMed Central

Two transcription factors, Pax5 and Blimp-1, form a gene regulatory network (GRN) with a double-negative loop, which defines either B-cell (Pax5 high) or plasma cell (Blimp-1 high) status as a binary switch. However, it is unclear how this B-cell GRN registers class switch DNA recombination (CSR), an event that takes place before the terminal differentiation to plasma cells. In the absence of Bach2 encoding a transcription factor required for CSR, mouse splenic B cells more frequently and rapidly expressed Blimp-1 and differentiated to IgM plasma cells as compared with wild-type cells. Genetic loss of Blimp-1 in Bach2?/? B cells was sufficient to restore CSR. These data with mathematical modelling of the GRN indicate that Bach2 achieves a time delay in Blimp-1 induction, which inhibits plasma cell differentiation and promotes CSR (Delay-Driven Diversity model for CSR). Reduction in mature B-cell numbers in Bach2?/? mice was not rescued by Blimp-1 ablation, indicating that Bach2 regulates B-cell differentiation and function through Blimp-1-dependent and -independent GRNs. PMID:20953163

Muto, Akihiko; Ochiai, Kyoko; Kimura, Yoshitaka; Itoh-Nakadai, Ari; Calame, Kathryn L; Ikebe, Dai; Tashiro, Satoshi; Igarashi, Kazuhiko

2010-01-01

46

Molecular requirements for the mu-induced light chain gene rearrangement in pre-B cells.  

PubMed Central

During B cell differentiation rearrangement of immunoglobulin (Ig) genes is partially regulated by the Ig proteins. Rearrangement of heavy (H) chain genes is inhibited, whilst that of light (L) chain genes is induced by the membrane form of the mu H chain. In order to analyse additional structural requirements of mu induced L chain gene rearrangement we transfected wild-type mu and mutant mu constructs lacking functional exons encoding the first or second constant domains into Abelson murine leukemia virus (AMuLV) transformed pre-B cells. All mu chains are expressed on the surface of the pre-B cell and all associate with omega and iota, two proteins forming a surrogate light chain, necessary for mu membrane expression. Nevertheless, only wild-type mu and not the mutant mu proteins promote L gene rearrangement. A heterodimer of proteins with Mr of 33 kd and 36 kd was found associated with wild-type but not with the mutant mu proteins. Continuous presence of mu is required for L chain gene recombination since loss of mu stopped and readdition of mu started L gene rearrangement. We propose that the protein complex composed of mu and the 33 kd/36 kd protein heterodimer is responsible for the activation of the L chain gene locus and its rearrangement. Images PMID:1712291

Iglesias, A; Kopf, M; Williams, G S; Bühler, B; Köhler, G

1991-01-01

47

Human Immunoglobulin (Ig)M 1 IgD 1 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  

Microsoft Academic Search

Summary Immunoglobulin (Ig)M 1 IgD 1 B cells are generally assumed to represent antigen-inexperi- enced, naive B cells expressing variable (V) region genes without somatic mutations. We report here that human IgM 1 IgD 1 peripheral blood (PB) B cells expressing the CD27 cell surface antigen carry mutated V genes, in contrast to CD27-negative IgM 1 IgD 1 B cells.

Ulf Klein; Klaus Rajewsky; Ralf Küppers

48

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

49

A conserved transcriptional enhancer regulates RAG gene expression in developing B cells.  

PubMed

Although expression of the RAG1 and RAG2 genes is essential for lymphocyte development, the mechanisms responsible for the lymphoid- and developmental stage-specific regulation of these genes are poorly understood. We have identified a novel, evolutionarily conserved transcriptional enhancer in the RAG locus, called Erag, which was essential for the expression of a chromosomal reporter gene driven by either RAG promoter. Targeted deletion of Erag in the mouse germline results in a partial block in B cell development associated with deficient V(D)J recombination, whereas T cell development appears unaffected. We found that E2A transcription factors bind to Erag in vivo and can transactivate Erag-dependent reporter constructs in cotransfected cell lines. These findings lead us to conclude that RAG transcription is regulated by distinct elements in developing B and T cells and that Erag is required for optimal levels of RAG expression in early B cell precursors but not in T cells. PMID:12871643

Hsu, Lih-Yun; Lauring, Josh; Liang, Hong-Erh; Greenbaum, Stephen; Cado, Dragana; Zhuang, Yuan; Schlissel, Mark S

2003-07-01

50

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

51

Aberrant B cell receptor signaling from B29 (Ig?, CD79b) gene mutations of chronic lymphocytic leukemia B cells  

PubMed Central

Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low or undetectable surface B cell receptor (BCR) and diminished responses to BCR-mediated signaling. These features suggest that CLL cells may have sustained mutations affecting one or more of the BCR proteins required for receptor surface assembly and signal transduction. Loss of expression and mutations in the critical BCR protein B29 (Ig?, CD79b), are prevalent in CLL and could produce the hallmark features of these leukemic B cells. Because patient CLL cells are intractable to manipulation, we developed a model system to analyze B29 mutations. Jurkat T cells stably expressing ?, ?, and mb1 efficiently assembled a functional BCR when infected with recombinant vaccinia virus bearing wild-type B29. In contrast, a B29 CLL mutant protein truncated in the transmembrane domain did not associate with ? or mb1 at the cell surface. Another B29 CLL mutant lacking the C-terminal immunoreceptor tyrosine activation motif tyrosine and distal residues brought the receptor to the surface as well as wild-type B29 but showed significant impairment in anti-IgM-stimulated signaling events including mitogen-activated protein kinase activation. These findings demonstrate that B29 mutations previously identified in CLL patients can affect BCR-dependent signaling and may contribute to the unresponsive B cell phenotype in CLL. Finally, the features of the B29 mutations in CLL predict that they may be generated by somatic hypermutation. PMID:10792036

Gordon, Melinda S.; Kato, Roberta M.; Lansigan, Frederick; Thompson, Alexis A.; Wall, Randolph; Rawlings, David J.

2000-01-01

52

Vaccinia Virus Inhibits NF-?B-Dependent Gene Expression Downstream of p65 Translocation  

PubMed Central

The transcription factor nuclear factor kappa light-chain enhancer of activated B cells (NF-?B) plays a critical role in host defense against viral infection by inducing the production of proinflammatory mediators and type I interferon. Consequently, viruses have evolved many mechanisms to block its activation. The poxvirus vaccinia virus (VACV) encodes numerous inhibitors of NF-?B activation that target multiple points in the signaling pathway. A derivative of VACV strain Copenhagen, called vv811, lacking 55 open reading frames in the left and right terminal regions of the genome was reported to still inhibit NF-?B activation downstream of tumor necrosis factor alpha (TNF-?) and interleukin-1? (IL-1?), suggesting the presence of one or more additional inhibitors. In this study, we constructed a recombinant vv811 lacking the recently described NF-?B inhibitor A49 (vv811?A49), yielding a virus that lacked all currently described inhibitors downstream of TNF-? and IL-1?. Unlike vv811, vv811?A49 no longer inhibited degradation of the phosphorylated inhibitor of ?B? and p65 translocated into the nucleus. However, despite this translocation, vv811?A49 still inhibited TNF-?- and IL-1?-induced NF-?B-dependent reporter gene expression and the transcription and production of cytokines induced by these agonists. This inhibition did not require late viral gene expression. These findings indicate the presence of another inhibitor of NF-?B that is expressed early during infection and acts by a novel mechanism downstream of p65 translocation into the nucleus. PMID:24371075

Sumner, Rebecca P.; Maluquer de Motes, Carlos; Veyer, David L.

2014-01-01

53

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

54

Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells  

Microsoft Academic Search

B cell-derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that ? 50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more fa- vorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of

Ulf Klein; Yuhai Tu; Gustavo A. Stolovitzky; Michela Mattioli; Giorgio Cattoretti; Hervé Husson; Arnold Freedman; Giorgio Inghirami; Lilla Cro; Luca Baldini; Antonino Neri; Andrea Califano; Riccardo Dalla-Favera

55

B-cell control region at the 5' end of a major histocompatibility complex class II gene: sequences and factors.  

PubMed Central

Transcription of major histocompatibility complex class II genes is elaborately regulated. Mouse class II genes are transcribed primarily in B cells, peripheral macrophages and interdigitating cells, and thymic cortical and medullary cells. In this study, we began to identify the DNA sequences and protein factors that control expression of a class II gene in B cells, addressing in particular how closely they resemble those that regulate immunoglobulin gene expression. We describe a region upstream of the E alpha gene that is crucial for its transcription in the B cells of transgenic mice but is less important in cultured B-cell lines. The sequence of this region reveals several familiar motifs, including a second X-Y pair reminiscent of that residing in the promoter-proximal region of all class II genes, a B motif strikingly homologous to that associated with the immunoglobulin kappa gene enhancer, several Ephrussi motifs, and a Pu box-like sequence very similar to that implicated in simian virus 40 and lymphotrophic papovavirus expression in B cells. Careful study of the proteins that bind specifically to these different motifs prompts us to suggest that major histocompatibility complex class II and immunoglobulin genes rely on quite different factors to achieve B-cell-specific expression. Images PMID:3141781

Dorn, A; Fehling, H J; Koch, W; Le Meur, M; Gerlinger, P; Benoist, C; Mathis, D

1988-01-01

56

Type I Interferons-Induced Follicular Translocation Of Lymphotoxin-Expressing Marginal Zone B Cells Initiates Lupus.  

E-print Network

??Systemic lupus erythematosus (SLE) is characterized by elevation of type I interferon (IFN) signature genes and production of autoantibodies against apoptotic self-antigens. The complex nature… (more)

Li, Hao

2014-01-01

57

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; Trøen, Gunhild; Liestøl, Knut; Holte, Harald; Delabie, Jan; Lind, Guro E.; Smeland, Erlend B.

2014-01-01

58

Gene targeting using the human Nalm-6 pre-B cell line.  

PubMed

Gene targeting by homologous recombination is a powerful tool to precisely manipulate the genome in order to study the function of a gene of interest (GOI). Indeed, it has become a routine methodology in yeasts, murine embryonic stem cells, and a chicken DT40 cell line. However, gene targeting has not been used often in human somatic cells to date since the relative efficiency of gene targeting (the ratio of homologous integrations to random integrations) is remarkably low. In this review, we introduce a fundamental strategy and a protocol to generate a null allele and/or 'tetracycline-inducible conditional gene knochout' for the GOI by gene targeting in the human Nalm-6 pre-B cell line. The Nalm-6 is a rare cell line in which gene targeting by homologous recombination takes place efficiently, and it carries a stable near-diploid karyotype with a doubling time of around 20 h. In addition, the tetracycline-regulated gene depletion (Tet-Off) system is steadily applicable to this cell line. Therefore, gene targeting systems using the Nalm-6 cell are used increasingly and offer promise in the study of human gene functions. This review should prove useful to researchers in a wide rage of fields. PMID:20103924

Adachi, Noritaka; Nishijima, Hitoshi; Shibahara, Kei-ichi

2008-10-01

59

Expression of B-cell-associated genes in peripheral blood mononuclear cells of patients with symptomatic pulmonary embolism.  

PubMed

The aim of the present study was to identify differentially expressed B?cell?associated genes in peripheral blood mononuclear cells and investigate the gene expression characteristics of the different stages of B?cell activation. A total of 20 patients with pulmonary embolisms (PE) and 20 age? and gender?matched controls were enrolled in the present study. Human complementary DNA microarray analysis was used in order to detect the differential expression of B?cell?associated genes between the PE and control groups. Messenger (m)RNA expression was detected for 82 genes involved in B?cell activation. The results showed that PE patients exhibited significantly increased expression levels of the B?cell receptor genes LYN, CD22, SYK, BTK, PTPRC and NFAM1, whereas expression levels of FYN, FCRL4 and LAX1 were significantly decreased compared to those of the control group. Expression levels of T?cell?dependent B?cell?activation genes, including EMR2, TNFSF9, CD86, ICOSLG, CD37 and CD97, were significantly upregulated in PE patients, whereas SPN mRNA expression was significantly downregulated compared with those of the control group. LILRA1 and TLR9 T cell?independent B?cell activation mRNAs were significantly upregulated in PE patients compared with those of the control group. In addition, the expression levels of B?cell?activation regulator genes, including CR1, LILRB4 and VAV1, were significantly increased, whereas SLAMF7 expression levels were significantly decreased in PE patients compared with those of the control group. Furthermore, the expression levels of B?cell?activation?associated cytokine genes demonstrated a significant upregulation of LTA and IL10 and downregulation of L1A, IFNA5, IFNA6, IFNA8, IFNA14, IL2, IL13 and IFNG in PE patients compared to those of the control group. In conclusion, the differential gene expression at different stages of B?cell activation between healthy controls and PE patients indicated that B?cell function was reduced or disorganized in patients with symptomatic PE. PMID:25411767

Lv, Wei; Duan, Qianglin; Wang, Lemin; Gong, Zhu; Yang, Fan; Song, Yanli

2015-03-01

60

MicroRNA and gene networks in human diffuse large B-cell lymphoma.  

PubMed

Molecular biologists have collected considerable data regarding the involvement of genes and microRNAs (miRNAs) in cancer. However the underlying mechanisms of cancer with regard to genes and miRNAs remain unclear. The aim of the present study was to evaluate diffuse large B-cell lymphoma (DLBCL) and construct regulatory networks of genes and miRNAs to gradually reveal the underlying mechanisms of DLBCL development. The first differential expression network that is presented is an experimentally validated network of miRNAs and genes. This network presents known biological regulatory associations among miRNAs and genes in the human body. The second network is a DLBCL differential expression network. Differentially expressed gene and miRNA data regarding DLBCL were collected and, based on the first network and the differentially expressed data, the second network was inferred, which demonstrates the irregular regulatory associations that may lead to the occurrence of DLBCL. The third network is a DLBCL-associated network. This network is comprised of non-differentially expressed genes and miRNAs that contribute to numerous DLBCL processes. The similarities and differences among the three networks were extracted and compared to distinguish key regulatory associations; furthermore, important signaling pathways in DLBCL were identified. The present study partially clarified the pathogenesis of DLBCL and provided an improved understanding of the underlying molecular mechanisms, as well as a potential treatment for DLBCL. PMID:25289101

Wang, Kunhao; Xu, Zhiwen; Wang, Ning; Xu, Ting; Zhu, Minghui

2014-11-01

61

Biased immunoglobulin genes rearrangement in mantle cell lymphoma: Hints to identify the normal B-cell counterpart  

Microsoft Academic Search

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma, originating from naïve B-cells. The blastoid MCL tumors\\u000a often show complex cytogenetic aberrations. In this review, we summarized the data available on immunoglobulin heavy-chain\\u000a (IgH) genes rearrangement for their importance in suggesting the MCL normal counterpart B-cell. Some new data suggesting an\\u000a antigen selection process were also presented in this review.

Hui-lai Zhang; Hua-qing Wang; Xi-shan Hao; Daniela Capello; Sergio B. Cogliatti; Francesco Bertoni; Franco Cavalli

2011-01-01

62

Jun-regulated genes promote interaction of diffuse large B-cell lymphoma with the microenvironment.  

PubMed

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with a high proliferation rate. However, the molecular and genetic features that drive the aggressive clinical behavior of DLBCL are not fully defined. Here, we have demonstrated that activated Jun signaling is a frequent event in DLBCL that promotes dissemination of malignant cells. Downregulation of Jun dramatically reduces lymphoma cell adhesion to extracellular matrix proteins, subcutaneous tumor size in nude mice, and invasive behavior, including bone marrow infiltration and interaction with bone marrow stromal cells. Furthermore, using a combination of RNA interference and gene expression profiling, we identified Jun target genes that are associated with disseminated lymphoma. Among them, ITGAV, FoxC1, and CX3CR1 are significantly enriched in patients with 2 or more extranodal sites. Our results point to activated Jun signaling as a major driver of the aggressive phenotype of DLBCL. PMID:25533033

Blonska, Marzenna; Zhu, Yifan; Chuang, Hubert H; You, M James; Kunkalla, Kranthi; Vega, Francisco; Lin, Xin

2015-02-01

63

GCN5 is involved in regulation of immunoglobulin heavy chain gene expression in immature B cells.  

PubMed

GCN5 is involved in the acetylation of core histones, which is an important epigenetic event for transcriptional regulation through alterations in the chromatin structure in eukaryotes. To investigate physiological roles of GCN5, we have systematically analyzed phenotypes of homozygous GCN5-deficient DT40 mutants. Here, we report participation of GCN5 in regulation of IgM heavy chain (H-chain) gene expression. GCN5-deficiency down-regulates gene expressions of IgM H-chain (as whole, membrane-bound and secreted forms of its mRNA) but not light chain (L-chain), causing decreases in membrane-bound and secreted forms of IgM proteins. Chromatin immnoprecipitation assay revealed that GCN5 binds to the chicken IgM H-chain gene around its constant region but not L-chain gene, and acetylate Lys-9 residues of histone H3 within chromatin surrounding the constant region. These results suggest that GCN5 takes part in transcriptional regulation of the IgM H-chain gene via histone acetylation resulting in formation of relaxed chromatin arrangement around its coding region and plays a key role in epigenetic regulation of B cell functions. PMID:24746634

Kikuchi, Hidehiko; Nakayama, Masami; Kuribayashi, Futoshi; Imajoh-Ohmi, Shinobu; Nishitoh, Hideki; Takami, Yasunari; Nakayama, Tatsuo

2014-07-01

64

Chlamydia psittaci-negative ocular adnexal marginal zone B-cell lymphomas have biased VH4-34 immunoglobulin gene expression and proliferate in a distinct inflammatory environment.  

PubMed

Ocular adnexal marginal zone B-cell lymphomas (OAMZLs) arise in the connective tissues of the orbit or in the mucosa-associated lymphoid tissue of the conjunctiva. Here, we present the immunological and genetic analyses of 20 primary Chlamydia psittaci (Cp)-negative OAMZLs. Analysis of the immunoglobulin variable heavy chain (IgV(H)) gene usage demonstrated a significant preference for V(H)4-34. A combined analysis across all previously published OAMZLs confirmed that this is a general feature of OAMZL, in particular of the Cp-negative group. Our series of OAMZLs did not express the characteristic rheumatoid factor V(H)DJ(H) rearrangements that were previously found in salivary gland- and gastric-marginal zone B-cell lymphomas (MZBCLs). We did not detect the MZBCL-specific chromosomal translocations, t(11;18) API2-MALT1 (mucosa-associated lymphoid tissue1) and t(14;18) IgH/MALT1. Two cases contained a premature stop codon in the A20 gene (TNFAIP3) and one case harbored the activating MYD88 hotspot mutation L265P. Variable nuclear expression of BCL10, NF?B1 (p50) and NF?B2 (p52) suggests that other additional genetic abnormalities affecting the NF?B pathway exist within this group of lymphomas. OAMZL showed variable expression of the chemokine receptor CXCR3 and integrin ?4?7 by the tumor B cells, and low interferon-? and interlukin-4 mRNA levels in the tissue, indicative of an inflammatory environment with features in between those previously found in cutaneous and other extranodal MZBCL. The strongly biased usage of V(H)4-34 in Cp-negative OAMZLs suggests involvement of a particular stimulatory (auto-) antigen in their development. PMID:22382892

van Maldegem, F; Wormhoudt, T A M; Mulder, M M S; Oud, M E C M; Schilder-Tol, E; Musler, A R; Aten, J; Saeed, P; Kersten, M J; Pals, S T; van Noesel, C J M; Bende, R J

2012-07-01

65

GCN5 is essential for IRF-4 gene expression followed by transcriptional activation of Blimp-1 in immature B cells.  

PubMed

During B-cell differentiation, the gene expression of B-cell differentiation-related transcription factors must be strictly controlled by epigenetic mechanisms including histone acetylation and deacetylation, to complete the differentiation pathway. GCN5, one of the most important histone acetyltransferases, is involved in epigenetic events for transcriptional regulation through alterations in the chromatin structure. In this study, by analyzing the homozygous DT40 mutants GCN5(-/-), generated with gene targeting techniques, we found that GCN5 was necessary for transcriptional activation of IRF-4, an essential transcription factor for plasma cell differentiation. GCN5 deficiency caused drastic decreases in both the mRNA and the protein levels of Blimp-1 and IRF-4. The ectopic expression of Blimp-1 and IRF-4 suggests that IRF-4, but not Blimp-1, is the target gene of GCN5 in immature B cells. Moreover, a chromatin immunoprecipitation assay showed that GCN5 bound to the IRF-4 gene around its 5'-flanking region and acetylated H3K9 residues within chromatin surrounding the region in vivo, suggesting that gene expression of IRF-4 is certainly regulated by GCN5. These results reveal that GCN5 is essential for IRF-4 gene expression, followed by transcriptional activation of Blimp-1, and plays a key role in epigenetic regulation of B-cell differentiation. PMID:24072880

Kikuchi, Hidehiko; Nakayama, Masami; Kuribayashi, Futoshi; Imajoh-Ohmi, Shinobu; Nishitoh, Hideki; Takami, Yasunari; Nakayama, Tatsuo

2014-03-01

66

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

67

DNA repair gene polymorphisms in B cell non-Hodgkin's lymphoma.  

PubMed

Cancer is a group of diseases characterized by DNA injury, and genetic and environmental factors are important in the etiology of the cancers. It is well known that there are association variabilities in DNA repairment and sensitivity against the cancer. The aim of this study is to look for some important gene polymorphisms associated with DNA repair in cases with B cell non-Hodgkin's lymphoma (B-NHL). Ninety-four cases with NHL and 96 healthy controls were included in this study. ERCC2 (Lys751Gln), XPC (Gln939Lys), ERCC5 (Asp1104His), and XRCC3 (Thr241Met) gene polymorphisms were studied by using Tm Shift Real-Time PCR Technology. ERCC5 Asp1104His polymorphism showed a protective effect against the B-NHL in individuals carrying this mutant allele (p?=?0.009), and differences were more prominent in males (p?=?0.001). When the patient and control groups were divided according to their smoking habit, the mutant allele of the XPC gene showed a protective effect in the nonsmoker group (p?=?0.040). The mutant allele G of ERCC5 (CG) polymorphism was found to be protective against lymphoma (p?=?0.010). There were no differences among cases with B-NHL and controls for ERCC2 codon 751, XPC codon 939, and XRCC3 codon 241 gene polymorphisms. DNA repair gene polymorphisms can affect the risk of lymphoma, and it will be useful to detect the DNA repair gene polymorphisms in cases with lymphoma in studies covering a higher number of cases. PMID:25400036

Bahceci, Aykut; Paydas, Semra; Tanriverdi, Kahraman; Ergin, Melek; Seydaoglu, Gulsah; Ucar, Gulsum

2014-11-18

68

Gene structure and characterization of the murine homologue of the B cell-specific transcriptional coactivator OBF-1.  

PubMed Central

The B cell-specific activity of immunoglobulin (Ig) gene promoters is to a large extent mediated by the conserved octamer motif ATTTGCAT. This requires the DNA binding octamer factors Oct-1 and/or Oct-2, as well as an additional B cell-restricted non-DNA binding cofactor. We recently cloned such a coactivator specific for Oct-1 or Oct-2 from human B cells and called it OBF-1. Here we report the isolation and characterization of the murine homologue. Full-length cDNA clones as well as genomic clones were isolated and the gene structure was determined. The deduced protein sequence shows that the mouse protein has an identical length, is likewise proline rich and shows 89% overall identity to the human protein. The OBF-1 gene is expressed in a very highly B cell-specific manner and is transcribed in cells representative of all stages of B cell differentiation, including the earliest ones. We show that OBF-1 interacts in the absence of DNA with the POU domain of Oct-1 or Oct-2 and also with the general transcription factors TBP and TFIIB. Furthermore, we demonstrate that although OBF-1 efficiently activates promoter octamer sites, it does not activate enhancer octamer sites. PMID:8657574

Schubart, D B; Sauter, P; Massa, S; Friedl, E M; Schwarzenbach, H; Matthias, P

1996-01-01

69

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

70

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

71

RNA analysis of B cell lines arrested at defined stages of differentiation allows for an approximation of gene  

E-print Network

expression analysis of a set of mouse B lineage cell lines rep- resenting defined stages of B cell-activating genes Rag-1 and Rag-2 and initiation of Ig recombination events [7]. This generates a functional Ig with the defined stages of differentiation, makes it a useful system for investigations of complex molecular events

Lunds Universitet,

72

Impact of female cigarette smoking on circulating B cells in vivo: the suppressed ICOSLG , TCF3 , and VCAM1 gene functional network may inhibit normal cell function  

Microsoft Academic Search

As pivotal immune guardians, B cells were found to be directly associated with the onset and development of many smoking-induced\\u000a diseases. However, the in vivo molecular response of B cells underlying the female cigarette smoking remains unknown. Using\\u000a the genome-wide Affymetrix HG-133A GeneChip® microarray, we firstly compared the gene expression profiles of peripheral circulating\\u000a B cells between 39 smoking and

Feng Pan; Tie-Lin Yang; Xiang-Ding Chen; Yuan Chen; Ge Gao; Yao-Zhong Liu; Yu-Fang Pei; Bao-Yong Sha; Yan Jiang; Chao Xu; Robert R. Recker; Hong-Wen Deng

2010-01-01

73

Concurrent epigenetic silencing of wnt/?-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia  

PubMed Central

Background The Wnt/?-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/?-catenin pathway inhibitor genes – CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 – in the cell lines EHEB and MEC-1 as well as patient samples. Methods Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and ?-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models. Results For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2´-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/?-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2´-deoxycytidine caused accumulation of ?-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with ?-catenin and thus demonstrating its epigenetically regulated inhibition effect. Conclusions The results suggest an epigenetic silencing mechanism of the Wnt/?-catenin pathway inhibitor genes in CLL. Hypermethylation and silencing of functionally related genes may not be completely stochastic but result from the tumour epigenome reprogramming orchestrated by Polycomb-group repressive complexes. The data are of interest in the context of epigenetic-based therapy. PMID:22672427

2012-01-01

74

A new non-Hodgkin's B-cell line (DoHH2) with a chromosomal translocation t(14;18)(q32;q21).  

PubMed

A spontaneously growing EBV-negative B-cell line (DoHH2) was established from the pleural fluid cells of a 60-year-old man with centroblastic/centrocytic non-Hodgkin's lymphoma, that had transformed into an immunoblastic lymphoma. The pleural fluid cells and the DoHH2 cells expressed IgG lambda, were reactive with CD10 and CD19 monoclonal antibodies, and showed by cytogenetic analysis 48,XY, +7, +del(12)(q24), t(14;18)(q32;q21). Southern blot analysis of mini-satellite DNA patterns, and of rearrangements of the immunoglobulin genes and bcl-2, confirmed that the cell line was derived from the patient's clonal lymphoma cells. Direct nucleotide sequence analysis on polymerase chain reaction (PCR) products of the t(14;18) junction revealed an identical sequence for the JH-bcl-2 junction at JH6 and in the major breakpoint region of bcl-2 in both the original tumor cells and the DoHH2 cell line. The cell line was valuable as a standard quantification control for PCR analysis of the t(14;18) breakpoint. Titration experiments demonstrated the detection of up to one tumor cell in 10(5) normal blood lymphocytes. PMID:1849602

Kluin-Nelemans, H C; Limpens, J; Meerabux, J; Beverstock, G C; Jansen, J H; de Jong, D; Kluin, P M

1991-03-01

75

Mechanisms of B-cell lymphoma pathogenesis  

Microsoft Academic Search

Chromosomal translocations involving the immunoglobulin loci are a hallmark of many types of B-cell lymphoma. Other factors, however, also have important roles in the pathogenesis of B-cell malignancies. Most B-cell lymphomas depend on the expression of a B-cell receptor (BCR) for survival, and in several B-cell malignancies antigen activation of lymphoma cells through BCR signalling seems to be an important

Ralf Küppers

2005-01-01

76

Protein kinase C? gene expression is oppositely regulated by GCN5 and EBF1 in immature B cells.  

PubMed

In this study, we revealed that GCN5 and early B cell factor 1 (EBF1) participate in regulation of protein kinase C? (PKC?) gene expression in an opposite manner in immature B cells. GCN5-deficiency in DT40 caused drastic down-regulation of transcription of PKC?. In contrast, EBF1-deficiency brought about remarkable up-regulation of that of PKC?, and re-expression of EBF1 dramatically suppressed transcription of PKC?. Chromatin immunoprecipitation assay revealed that GCN5 binds to the 5'-flanking region of the chicken PKC? gene and acetylates histone H3, and EBF1 binds to the 5'-flanking region of the gene surrounding putative EBF1 binding motifs. PMID:24657615

Kikuchi, Hidehiko; Nakayama, Masami; Kuribayashi, Futoshi; Imajoh-Ohmi, Shinobu; Nishitoh, Hideki; Takami, Yasunari; Nakayama, Tatsuo

2014-05-01

77

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

PubMed Central

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.

2014-01-01

78

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

79

Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes.  

PubMed

Immunoglobulin genotyping of Epstein-Barr virus (EBV)-positive posttransplantation lymphoproliferative disease has suggested that such lesions often arise from atypical post-germinal center B cells, in some cases carrying functionally inactivated immunoglobulin genes. To investigate whether EBV can rescue cells that are failed products of the somatic hypermutation process occurring in germinal centers (GCs), we isolated GC cells from tonsillar cell suspensions and exposed them to EBV in vitro. Screening more than 100 EBV-transformed cell lines of GC origin identified 6 lines lacking surface immunoglobulin, a phenotype never seen among lines derived from circulating naive or memory B cells. Furthermore, 3 of the 6 surface immunoglobulin-negative GC lines carried inactivating mutations in the immunoglobulin H (IgH) variable gene sequence. The ability of EBV to rescue aberrant products of the germinal center reaction in vitro strengthens the probability that a parallel activity contributes to EBV's lymphomagenic potential in vivo. PMID:16123211

Chaganti, Sridhar; Bell, Andrew I; Pastor, Noelia Begue; Milner, Anne E; Drayson, Mark; Gordon, John; Rickinson, Alan B

2005-12-15

80

Human gene mapping using an X\\/autosome translocation  

Microsoft Academic Search

Human fibroblasts containing a translocation between the X chromosome and chromosome 15 were fused with the 6-thioguanine-resistant mouse cell line, IR. Resulting hybrids, selected in HAT medium, retained the X\\/15 chromosome. Hybrids which were counterselected in 6-thioguanine lost this chromosome. The X-linked markers glucose-6-phosphate dehydrogenase (G6PD), phosphoglycerate kinase (PGK), and hypoxanthine phosphoribosyl transferase (HPRT), and the non-X-linked markers pyruvate kinase

E. Solomon; M. Bobrow; P. N. Goodfellow; W. F. Bodmer; D. M. Swallow; S. Povey; B. Noël

1976-01-01

81

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; Péron, Sophie; Sirac, Christophe; Moreau, Jeanne; Cogné, Michel

2014-01-01

82

Transient B Cell Depletion or Improved Transgene Expression by Codon Optimization Promote Tolerance to Factor VIII in Gene Therapy  

PubMed Central

The major complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against factor VIII (FVIII). The current method for eradicating inhibitors, termed immune tolerance induction (ITI), is costly and protracted. Clinical protocols that prevent rather than treat inhibitors are not yet established. Liver-directed gene therapy hopes to achieve long-term correction of the disease while also inducing immune tolerance. We sought to investigate the use of adeno-associated viral (serotype 8) gene transfer to induce tolerance to human B domain deleted FVIII in hemophilia A mice. We administered an AAV8 vector with either human B domain deleted FVIII or a codon-optimized transgene, both under a liver-specific promoter to two strains of hemophilia A mice. Protein therapy or gene therapy was given either alone or in conjunction with anti-CD20 antibody-mediated B cell depletion. Gene therapy with a low-expressing vector resulted in sustained near-therapeutic expression. However, supplementary protein therapy revealed that gene transfer had sensitized mice to hFVIII in a high-responder strain but not in mice of a low-responding strain. This heightened response was ameliorated when gene therapy was delivered with anti-murine CD20 treatment. Transient B cell depletion prevented inhibitor formation in protein therapy, but failed to achieve a sustained hypo-responsiveness. Importantly, use of a codon-optimized hFVIII transgene resulted in sustained therapeutic expression and tolerance without a need for B cell depletion. Therefore, anti-CD20 may be beneficial in preventing vector-induced immune priming to FVIII, but higher levels of liver-restricted expression are preferred for tolerance. PMID:22655063

Sack, Brandon K.; Merchant, Sherin; Markusic, David M.; Nathwani, Amit C.; Davidoff, Andrew M.; Byrne, Barry J.; Herzog, Roland W.

2012-01-01

83

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

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

An antibody VH gene that promotes marginal zone B cell development and heavy chain allelic inclusion  

Microsoft Academic Search

The Ig heavy (H) chain plays a pivotal role in the regulation of primary B cell development through its association with a variety of other proteins including Iga and Igb, the surrogate light chain components and bona fide L chains, to form transmembrane signaling complexes. Little is known about how alterations in the structure of the H chain variable region

Lynn Heltemes-Harris; Xiaohe Liu; Tim Manser

2005-01-01

86

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

87

M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice  

PubMed Central

In T-cell–dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell–like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell–dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive. PMID:16493007

Schenten, Dominik; Egert, Angela; Pasparakis, Manolis; Rajewsky, Klaus

2006-01-01

88

Sucking genes into pores: Insight into driven translocation  

NASA Astrophysics Data System (ADS)

Flexible polymers such as long DNA, RNA molecules, and proteins, can pass through a narrow pore whose size is comparable to their molecular thickness. We highlight the richness and complexity involved in the dynamics of this unique mode of molecular transport, called translocation, actively driven by external forces. In particular, the process takes place in the condition far from equilibrium accompanying of large conformational distortion in line with the propagation of the tensile force along the chain backbone. A general framework is proposed, which captures such essential features, whereby can account for reported various experimental data from a unified viewpoint.

Sakaue, Takahiro

2010-04-01

89

Somatic hypermutation of the B cell receptor genes B29 (Ig?, CD79b) and mb1 (Ig?, CD79a)  

PubMed Central

Somatic hypermutation (SHM), coupled to selection by antigen, generates high-affinity antibodies during germinal center (GC) B cell maturation. SHM is known to affect Bcl6, four additional oncogenes in diffuse large B cell lymphoma, and the CD95/Fas gene and is regarded as a major mechanism of B cell tumorigenesis. We find that mutations in the genes encoding the B cell receptor (BCR) accessory proteins B29 (Ig?, CD79b) and mb1 (Ig?, CD79a) occur as often as Ig genes in a broad spectrum of GC- and post-GC-derived malignant B cell lines, as well as in normal peripheral B cells. These B29 and mb1 mutations are typical SHM consisting largely of single nucleotide substitutions targeted to hotspots. The B29 and mb1 mutations appear at frequencies similar to those of other non-Ig genes but lower than Ig genes. The distribution of mb1 mutations followed the characteristic pattern found in Ig and most non-Ig genes. In contrast, B29 mutations displayed a bimodal distribution resembling the CD95/Fas gene, in which promoter distal mutations conferred resistance to apoptosis. Distal B29 mutations in the cytoplasmic domain may contribute to B cell survival by limiting BCR signaling. B29 and mb1 are mutated in a much broader spectrum of GC-derived B cells than any other known somatically hypermutated non-Ig gene. This may be caused by the common cis-acting regulatory sequences that control the requisite coexpression of the B29, mb1, and Ig chains in the BCR. PMID:12651942

Gordon, Melinda S.; Kanegai, Cindy M.; Doerr, Jeanette R.; Wall, Randolph

2003-01-01

90

Myelomatous plasma cells display an aberrant gene expression pattern similar to that observed in normal memory B cells  

PubMed Central

Memory B cells (MBCs) remain in a quiescent state for years, expressing pro-survival and anti-apoptotic factors while repressing cell proliferation and activation genes. During their differentiation into plasma cells (PCs), their expression pattern is reversed, with a higher expression of genes related to cell proliferation and activation, and a lower expression of pro-survival genes. To determine whether myelomatous PCs (mPCs) share characteristics with normal PCs and MBCs and to identify genes involved in the pathophysiology of multiple myeloma (MM), we compared gene expression patterns in these three cell sub-types. We observed that mPCs had features intermediate between those of MBCs and normal PCs, and identified 3455 genes differentially expressed in mPCs relative to normal PCs but with a similar expression pattern to that in MBCs. Most of these genes are involved in cell death and survival, cell growth and proliferation and protein synthesis. According to our findings, mPCs have a gene expression pattern closer to a MBC than a PC with a high expression of genes involved in cell survival. These genes should be physiologically inactivated in the transit from MBC to PC, but remain overexpressed in mPCs and thus may play a role in the pathophysiology of the disease.

Báez, Alicia; Piruat, José I; Caballero-Velázquez, Teresa; Sánchez-Abarca, Luís I; Álvarez-Laderas, Isabel; Barbado, M Victoria; García-Guerrero, Estefanía; Millán-Uclés, África; Martín-Sánchez, Jesús; Medrano, Mayte; Pérez-Simón, José Antonio

2015-01-01

91

PU.1 Opposes IL-7-Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase.  

PubMed

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-Cre?PB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-Cre?PB mice. Enriched pro-B cells from CD19-Cre?PB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-Cre?PB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-Cre?PB cells compared with controls. Induction of PU.1 expression in cultured CD19-Cre?PB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells. PMID:25505273

Christie, Darah A; Xu, Li S; Turkistany, Shereen A; Solomon, Lauren A; Li, Stephen K H; Yim, Edmund; Welch, Ian; Bell, Gillian I; Hess, David A; DeKoter, Rodney P

2015-01-15

92

A Novel, Non-canonical Splice Variant of the Ikaros Gene Is Aberrantly Expressed in B-cell Lymphoproliferative Disorders  

PubMed Central

The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders. PMID:23874502

Mancarelli, Maria Michela; Verzella, Daniela; Fischietti, Mariafausta; Di Tommaso, Ambra; Maccarone, Rita; Plebani, Sara; Di Ianni, Mauro; Gulino, Alberto; Alesse, Edoardo

2013-01-01

93

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

94

Restricted immunoglobulin variable region gene usage by normal Ly-1 (CD5+) B cells that recognize phosphatidyl choline  

PubMed Central

5-15% of lymphocytes in the peritoneums of normal adult B10.H-2aH- 4bp/Wts (2a4b) mice are CD5+ (Ly-1) B cells that recognize phosphatidyl choline (PtC), a phospholipid component of all mammalian cells. We produced a set of IgM-secreting hybridomas from the peritoneal cells of normal, adult 2a4b mice. We found that this set of hybridomas shows a similarly high frequency of antibodies specific for PtC (21 of 86) that also react with bromelain-treated mouse erythrocytes. Restriction fragment analysis of Ig gene rearrangements and analysis of expressed Ig idiotypes reveal that these cells use a restricted set of variable region genes to generate the PtC-specific antibodies. The Ig genes used by the PtC-specific hybridomas appear to be the same as those found in the PtC-specific Ly-1 B cell lymphomas, CH27 and CH34. PMID:2499651

1989-01-01

95

Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma.  

PubMed

Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active. Such activation could also lead to lineage-inappropriate activation of oncogenes, as one study described in Hodgkin lymphoma. However, little further evidence for this mechanism in other cancers has been reported. Here, we reanalyzed whole transcriptome data from a large cohort of patients with diffuse large B-cell lymphoma (DLBCL) compared with normal B-cell centroblasts to detect genes ectopically expressed through activation of TE promoters. We have identified 98 such TE-gene chimeric transcripts that were exclusively expressed in primary DLBCL cases and confirmed several in DLBCL-derived cell lines. We further characterized a TE-gene chimeric transcript involving a fatty acid-binding protein gene (LTR2-FABP7), normally expressed in brain, that was ectopically expressed in a subset of DLBCL patients through the use of an endogenous retroviral LTR promoter of the LTR2 family. The LTR2-FABP7 chimeric transcript encodes a novel chimeric isoform of the protein with characteristics distinct from native FABP7. In vitro studies reveal a dependency for DLBCL cell line proliferation and growth on LTR2-FABP7 chimeric protein expression. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in cancer and suggest that LTR2-FABP7 may contribute to the pathogenesis of DLBCL in a subgroup of patients. PMID:25114248

Lock, Frances E; Rebollo, Rita; Miceli-Royer, Katharine; Gagnier, Liane; Kuah, Sabrina; Babaian, Artem; Sistiaga-Poveda, Maialen; Lai, C Benjamin; Nemirovsky, Oksana; Serrano, Isabel; Steidl, Christian; Karimi, Mohammad M; Mager, Dixie L

2014-08-26

96

B-cell deficiency does not abrogate development of cutaneous hyperplasia in mice inheriting the defective fibrillin-1 gene.  

PubMed

Tight-skin (TSK) mouse, the experimental model for scleroderma, develops cutaneous hyperplasia, cardiac hypertrophy, pulmonary emphysema and autoimmunity against scleroderma target autoantigens. The cutaneous hyperplasia is associated with the accumulation of microfibrils and elastic fibers in the middle and deep dermis. Fibrillin-1 (Fbn-1) is a major component of the 10-12 nm microfibrils found in the extracellular matrix. In this study we report the identification of a genetic marker in the Fbn-1 gene that can distinguish the mutant phenotype. TSK mice exhibit an unique polymorphism in the Fbn-1 gene. RNA analysis, PCR analysis and sequence determination of the mutant gene showed that the Fbn-1 gene polymorphism is due to intragenic duplication of a segment of the gene coding for 3.0 Kb of mRNA sequence (10 Kb of the genome). Histological analysis of skin samples from F1 progeny obtained by crossing TSK mice with JH-/-, RAG2-/- or vit/vit showed a significant correlation between the inheritance of the defective Fbn-1 gene and the development of cutaneous hyperplasia. Further, our results also show that in mice deficient in mature B cells inheriting the defective Fbn-1 gene, development of cutaneous hyperplasia is not abrogated. Thus, production of autoantibodies or the presence of mature B lymphocytes do not play an integral role in the pathogenesis of cutaneous hyperplasia. PMID:9451590

Kasturi, K N; Hatakeyama, A; Murai, C; Gordon, R; Phelps, R G; Bona, C A

1997-12-01

97

Involvement of a human endogenous retroviral sequence (THE-7) in a t(7;14)(q21;q32) chromosomal translocation associated with a B cell chronic lymphocytic leukemia.  

PubMed

B cell chronic lymphocytic leukemias (B-CLL) like other blood cell malignancies are characterized by chromosomal anomalies directly involved in tumor pathogenesis. We report here the molecular characterization of a t(7;14)(q21;q32) chromosomal translocation observed during the course of a B-CLL. We show that this translocation led to the juxtaposition of the immunoglobulin heavy chain locus on chromosome 14 to an endogenous retroviral sequence belonging to the THE family (transposable-like human element) on chromosome 7q21. RT-PCR analysis demonstrated that this sequence is transcribed in most of the tumoral and normal tissue analyzed and in the B-CLL described here. These data raise the question of the role of transposable elements in the pathogeny of some leukemias or at least, in the occurrence of chromosomal rearrangements. Structural rearrangements of the 7q21-22 region are frequently encountered in myeloid disorders, and the work presented here could help in their characterization. PMID:9264372

Wahbi, K; Hayette, S; Callanan, M; Gadoux, M; Charrin, C; Magaud, J P; Rimokh, R

1997-08-01

98

Translocations and amplification of the BCL2 gene are detected in interphase nuclei of non-Hodgkin's lymphoma by in situ hybridization with yeast artificial chromosome clones.  

PubMed

Translocation of the BCL2 gene in B-cell malignancies carrying t(14;18) and amplification of the BCL2 gene in a cell line (HBL-2) derived from a non-Hodgkin's lymphoma (NHL) were detected specifically in both metaphase spreads and interphase nuclei by fluorescence in situ hybridization (FISH) using yeast artificial chromosomes (YACs). A YAC clone containing the BCL2 gene yA153A6, a 360-kb clone spanning from approximately 60 kb upstream of BCL2 exon 1 to approximately 60 kb 3' of the minor breakpoint cluster region, was used for single-color FISH analysis. Seven patients with NHL and one patient with acute lymphoblastic leukemia were analyzed for BCL2 translocations. Interphase nuclei of NHL patients showed three signals when hybridized with the yA153A6 probe. This was expected because the YAC clone spans the BCL2 breakpoint regions on 18q21.3. In a patient with acute lymphoblastic leukemia, a positive signal for BCL2 was detected on der(14) at band 14q32.33 by single-color FISH with the yA153A6 probe, whereas no signals were detected on der(18). The amplification of BCL2 in the HBL-2 cell line was observed on a characteristic abnormal chromosome 18, add(18)(q23); the periodic pattern of the fluorescent signal of this region was suggestive of an amplicon. Using double-color FISH with YAC clones containing the more centromeric 18q21.3 gene gastrin-releasing peptide (y302F10) and the 14q32.33 gene (IgH; Y6), we detected t(14;18) by showing the juxtaposition of the 18q21.3 and 14q32.33 bands on the derivative chromosome 18. Interphase FISH with these YAC clones provided a rapid procedure for the diagnosis of B-cell malignancies carrying t(14;18). In addition, we showed that translocations and amplification of the BCL2 gene can be detected at the single-cell level. PMID:7632955

Taniwaki, M; Sliverman, G A; Nishida, K; Horiike, S; Misawa, S; Shimazaki, C; Miura, I; Nagai, M; Abe, M; Fukuhara, S

1995-08-15

99

Chromosomal translocations fusing the BCL6 gene to different partner loci are recurrent in primary central nervous system lymphoma and may be associated with aberrant somatic hypermutation or defective class switch recombination.  

PubMed

Primary central nervous system lymphomas (PCNSLs) are diffuse large B cell lymphomas confined to the brain. Only minimal data exist on chromosomal aberrations underlying PCNSLs. We studied 41 PCNSLs by fluorescence in situ hybridization for breakpoints affecting the BCL6 locus in chromosomal band 3q27. Of 37 cases evaluable, 14 (38%) carried a breakpoint in the BCL6 locus. Two of these showed juxtaposition of BCL6 to the IGH locus. In 4 cases, the BCL6 breakpoints were cloned using long-distance inverse polymerase chain reaction. All breakpoints were located within the BCL6 major translocation cluster. The translocation partners were the IGH gene in 14q32.33, the IGL gene in 22q11.22, and the histone 1 H4I gene in 6p22.1. In the fourth case, a deletion in 3q leads to loss of an 837-kb fragment extending from the first intron of BCL6 to the third intron of the lipoma-preferred partner (LPP) gene. This deletion may bring the BCL6 gene under the control of regulatory elements of the LPP gene or the miRNA-28 gene located in intron 4 of LPP. DNA sequence analysis of the junctional sequences provided evidence that aberrant class switch recombination or somatic hypermutation may be involved in the generation of BCL6 translocations. PMID:16896311

Schwindt, Heinrich; Akasaka, Takashi; Zühlke-Jenisch, Reina; Hans, Volkmar; Schaller, Carlo; Klapper, Wolfram; Dyer, Martin J S; Siebert, Reiner; Deckert, Martina

2006-08-01

100

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

101

Application of HSVtk suicide gene to X-SCID gene therapy: Ganciclovir treatment offsets gene corrected X-SCID B cells  

SciTech Connect

Recently, a serious adverse effect of uncontrolled clonal T cell proliferation due to insertional mutagenesis of retroviral vector was reported in X-SCID gene therapy clinical trial. To offset the side effect, we have incorporated a suicide gene into therapeutic retroviral vector for selective elimination of transduced cells. In this study, B-cell lines from two X-SCID patients were transduced with bicistronic retroviral vector carrying human {gamma}c chain cDNA and Herpes simplex virus thymidine kinase gene. After confirmation of functional reconstitution of the {gamma}c chain, the cells were treated with ganciclovir (GCV). The {gamma}c chain positive cells were eliminated under low concentration without cytotoxicity on untransduced cells and have not reappeared at least for 5 months. Furthermore, the {gamma}c chain transduced cells were still sensitive to GCV after five months. These results demonstrated the efficacy of the suicide gene therapy although further in vivo studies are required to assess feasibility of this approach in clinical trial.

Uchiyama, Toru [Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575 (Japan); Kumaki, Satoru [Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575 (Japan)]. E-mail: kumakis@idac.tohoku.ac.jp; Ishikawa, Yoshinori [Department of Microbiology and Immunity, Graduate School of Medicine, Tohoku University, Seiryo-machi 2-1, Aoba-ku, Sendai 980-8575 (Japan); Onodera, Masafumi [Major of Medical Sciences, Graduate School of Comprehensive Human Sciences, Tsukuba University, Tennodai 1-1-1, Tsukuba 305-8575 (Japan); Sato, Miki [Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575 (Japan); Du, Wei [Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575 (Japan); Sasahara, Yoji [Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575 (Japan); Tanaka, Nobuyuki [Department of Microbiology and Immunity, Graduate School of Medicine, Tohoku University, Seiryo-machi 2-1, Aoba-ku, Sendai 980-8575 (Japan); Sugamura, Kazuo [Department of Microbiology and Immunity, Graduate School of Medicine, Tohoku University, Seiryo-machi 2-1, Aoba-ku, Sendai 980-8575 (Japan); Tsuchiya, Shigeru [Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575 (Japan)

2006-03-10

102

Nucleotide sequence of tobacco chloroplast gene for the alpha subunit of proton-translocating ATPase.  

PubMed Central

The tobacco chloroplast gene for the alpha subunit of proton-translocating ATPase has been cloned and sequenced. The coding region contains 1521 bp (507 codons). The nucleotide sequence and the deduced amino acid sequence show 55% and 54% homologies with those of the E. coli alpha subunit, respectively. The deduced amino acid composition is quite similar to that estimated for the spinach alpha subunit. PMID:6300797

Deno, H; Shinozaki, K; Sugiura, M

1983-01-01

103

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

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

2013-01-01

104

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

105

IRTA1+ monocytoid B cells in reactive lymphadenitis show a unique topographic distribution and immunophenotype and a peculiar usage and mutational pattern of IgVH genes.  

PubMed

The origin and function of monocytoid B cells (MBCs) are poorly understood. Taking advantage of their strong expression of IRTA1 (a receptor that is also associated with MALT marginal zone B cells), we have comprehensively analysed MBCs in 25 cases of lymphadenitis of different aetiologies, shedding new light on the topographical distribution, immunophenotype and IgV(H) gene usage and mutational profile of this B cell subset. IRTA1(+) MBCs, although predominantly located in the subcapsular and intermediary sinuses, were also observed scattered within germinal centres (GCs) in all lymphadenitis cases examined. The molecular characterization of IgV(H) genes revealed that IRTA1(+) MBCs residing in different areas of the lymph node (subcapsular sinus, intermediary sinuses and GCs) can be clonally related (with intraclonal variation), and that those located in GCs are consistently more mutated and selected for expression of a functional antigen receptor than those located in the sinuses. Moreover, by contrast, IRTA1(+) MBCs in GCs express the memory B cell marker CD27. Finally, in toxoplasmic lymphadenitis, the IRTA1(+) MBC population shows a highly preferential usage of the V(H) genes 3-7 and 3-30 (without any obvious peculiarity in their CDR3s), possibly suggesting that a superantigen expressed by Toxoplasma gondii may be involved in the early activation of this B cell subset. PMID:16508918

Lazzi, S; Bellan, C; Tiacci, E; Palummo, N; Vatti, R; Oggioni, M; Amato, T; Schuerfeld, K; Tonini, T; Tosi, P; Falini, B; Leoncini, L

2006-05-01

106

The v gene repertoires of classical and atypical memory B cells in malaria-susceptible west african children.  

PubMed

Immunity to Plasmodium falciparum malaria is naturally acquired in individuals living in malaria-endemic areas of Africa. Abs play a key role in mediating this immunity; however, the acquisition of the components of Ab immunity, long-lived plasma cells and memory B cells (MBCs), is remarkably inefficient, requiring years of malaria exposure. Although long-lived classical MBCs (CD19(+)/CD20(+)/CD21(+)/CD27(+)/CD10(-)) are gradually acquired in response to natural infection, exposure to P. falciparum also results in a large expansion of what we have termed atypical MBCs (CD19(+)/CD20(+)/CD21(-)/CD27(-)/CD10(-)). At present, the function of atypical MBCs in malaria is not known, nor are the factors that drive their differentiation. To gain insight into the relationship between classical and atypical IgG(+) MBCs, we compared the Ab H and L chain V gene repertoires of children living in a malaria-endemic region in Mali. We found that these repertoires were remarkably similar by a variety of criteria, including V gene usage, rate of somatic hypermutation, and CDR-H3 length and composition. The similarity in these repertoires suggests that classical MBCs and atypical MBCs differentiate in response to similar Ag-dependent selective pressures in malaria-exposed children and that atypical MBCs do not express a unique V gene repertoire. PMID:25556245

Zinöcker, Severin; Schindler, Christine E; Skinner, Jeff; Rogosch, Tobias; Waisberg, Michael; Schickel, Jean-Nicolas; Meffre, Eric; Kayentao, Kassoum; Ongoïba, Aïssata; Traoré, Boubacar; Pierce, Susan K

2015-02-01

107

Human carbon catabolite repressor protein (CCR4)-associative factor 1: cloning, expression and characterization of its interaction with the B-cell translocation protein BTG1.  

PubMed Central

The human BTG1 protein is thought to be a potential tumour suppressor because its overexpression inhibits NIH 3T3 cell proliferation. However, little is known about how BTG1 exerts its anti-proliferative activity. In this study, we used the yeast 'two-hybrid' system to screen for interacting protein partners and identified human carbon catabolite repressor protein (CCR4)-associative factor 1 (hCAF-1), a homologue of mouse CAF-1 (mCAF-1) and Saccharomyces cerevisiae yCAF-1/POP2. In vitro the hCAF-1/BTG1 complex formation was dependent on the phosphorylation of a putative p34cdc2 kinase site on BTG1 (Ser-159). In yeast, the Ala-159 mutant did not interact with hCAF-1. In addition, phosphorylation of Ser-159 in vitro showed specificity for the cell cycle kinases p34CDK2/cyclin E and p34CDK2/cyclin A, but not for p34CDK4/cyclin D1 or p34cdc2/cyclin B. Cell synchrony experiments with primary cultures of rat aortic smooth-muscle cells (RSMCs) demonstrated that message and protein levels of rat CAF-1 (rCAF-1) were up-regulated under conditions of cell contact, as previously reported for BTG1 [Wilcox, Scott, Subramanian, Ross, Adams-Burton, Stoltenborg and Corjay (1995) Circulation 92, I34-I35]. Western blot and immunohistochemical analysis showed that rCAF-1 localizes to the nucleus of contact-inhibited RSMCs, where it was physically associated with BTG1, as determined by co-immunoprecipitation with anti-hCAF-1 antisera. Overexpression of hCAF-1 in NIH 3T3 and osteosarcoma (U-2-OS) cells was itself anti-proliferative with colony formation reduced by 67% and 90% respectively. Taken together, these results indicate that formation of the hCAF-1/BTG1 complex is driven by phosphorylation at BTG1 (Ser-159) and implicates this complex in the signalling events of cell division that lead to changes in cellular proliferation associated with cell-cell contact. PMID:9820826

Bogdan, J A; Adams-Burton, C; Pedicord, D L; Sukovich, D A; Benfield, P A; Corjay, M H; Stoltenborg, J K; Dicker, I B

1998-01-01

108

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

Microsoft Academic Search

BackgroundHexavalent 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\\/ResultsWe established chromate transformed cell lines by chronic exposure

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

2011-01-01

109

Definition of an Fc receptor-related gene (FcRX) expressed in human and mouse B cells.  

PubMed

The recent identification of five human Fc receptor (FcR) homologs, hFcRH1-5, has extended the known FcR family and identified an unanticipated richness of the chromosome 1q region in genes encoding potential Ig-binding proteins. In a database search for additional relatives of this family we identified expressed sequence tag representatives of a new FcR-related molecule (hFcRX) and its mouse ortholog (mFcRX). The FcRX cDNAs were cloned from human lymph node and mouse spleen cDNA libraries. hFcRX is located centromeric of FcgammaRII and FcgammaRIII at 1q23, and its mouse ortholog resides in a syntenic region of chromosome 1. The genes encode proteins with 67% interspecies identity that lack both N-linked glycosylation sites and transmembrane regions. Two of the four FcRX domains are Ig-like, and share characteristics similar to FcgammaRI domains 2 and 3, having 28% overall extracellular identity with hFcgammaRI and 27% identity with mFcgammaRI respectively. FcRX transcripts are found primarily in secondary lymphoid tissues, where they are expressed by B lineage cells. FcRX thus may function as a secreted or intracellular protein in normal and neoplastic B cells. PMID:12202404

Davis, Randall S; Li, Haitao; Chen, Ching-Cheng; Wang, Yui-Hsi; Cooper, Max D; Burrows, Peter D

2002-09-01

110

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

111

Repression of the Proapoptotic Cellular BIK/NBK Gene by Epstein-Barr Virus Antagonizes Transforming Growth Factor ?1-Induced B-Cell Apoptosis  

PubMed Central

ABSTRACT The Epstein-Barr virus (EBV) establishes a lifelong latent infection in humans. EBV infection of primary B cells causes cell activation and proliferation, a process driven by the viral latency III gene expression program, which includes EBV nuclear proteins (EBNAs), latent membrane proteins, and untranslated RNAs, including microRNAs. Some latently infected cells enter the long-lived memory B-cell compartment and express only EBNA1 transiently (Lat I) or no EBV protein at all (Lat 0). Targeting the molecular machinery that controls B-cell fate decisions, including the Bcl-2 family of apoptosis-regulating proteins, is crucial to the EBV cycle of infection. Here, we show that BIK (also known as NBK), which encodes a proapoptotic “sensitizer” protein, is repressed by the EBNA2-driven Lat III program but not the Lat I program. BIK repression occurred soon after infection of primary B cells by EBV but not by a recombinant EBV in which the EBNA2 gene had been knocked out. Ectopic BIK induced apoptosis in Lat III cells by a mechanism dependent on its BH3 domain and the activation of caspases. We show that EBNA2 represses BIK in EBV-negative B-cell lymphoma-derived cell lines and that this host-virus interaction can inhibit the proapoptotic effect of transforming growth factor ?1 (TGF-?1), a key physiological mediator of B-cell homeostasis. Reduced levels of TGF-?1-associated regulatory SMAD proteins were bound to the BIK promoter in response to EBV Lat III or ectopic EBNA2. These data are evidence of an additional mechanism used by EBV to promote B-cell survival, namely, the transcriptional repression of the BH3-only sensitizer BIK. IMPORTANCE Over 90% of adult humans are infected with the Epstein-Barr virus (EBV). EBV establishes a lifelong silent infection, with its DNA residing in small numbers of blood B cells that are a reservoir from which low-level virus reactivation and shedding in saliva intermittently occur. Importantly, EBV DNA is found in some B-cell-derived tumors in which viral genes play a key role in tumor cell emergence and progression. Here, we report for the first time that EBV can shut off a B-cell gene called BIK. When activated by a molecular signal called transforming growth factor ?1 (TGF-?1), BIK plays an important role in killing unwanted B cells, including those infected by viruses. We describe the key EBV–B-cell molecular interactions that lead to BIK shutoff. These findings further our knowledge of how EBV prevents the death of its host cell during infection. They are also relevant to certain posttransplant lymphomas where unregulated cell growth is caused by EBV genes. PMID:24554662

Campion, Eva M.; Hakimjavadi, Roya; Loughran, Sinéad T.; Phelan, Susan; Smith, Sinéad M.; D'Souza, Brendan N.; Tierney, Rosemary J.; Bell, Andrew I.; Cahill, Paul A.

2014-01-01

112

Gene expression shift towards normal B cells, decreased proliferative capacity and distinct surface receptors characterize leukemic blasts persisting during induction therapy in childhood acute lymphoblastic leukemia  

Microsoft Academic Search

In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. In the present study, we address molecular and cell biologic features of blasts persisting after 1 week of induction glucocorticoid therapy. Genome-wide gene expression analysis of leukemic samples from precursor B-cell ALL patients (n=18) identified a set of genes differentially expressed in blasts

P Rhein; S Scheid; R Ratei; C Hagemeier; K Seeger; R Kirschner-Schwabe; A Moericke; M Schrappe; R Spang; W-D Ludwig; L Karawajew

2007-01-01

113

Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma  

Microsoft Academic Search

Deletions affecting the interval between the RB1 gene and marker D13S25 at band 13q14 are the most frequent genetic abnormalities of B-cell chronic lymphocytic leukemia (B-CLL) and indicate the presence of a novel tumor suppressor gene in this region. In the current study, a high resolution physical map of fragments spanning one megabasepair (Mb) of genomic DNA at the critical

Stephan Stilgenbauer; Jeremy Nickolenko; Jens Wilhelm; Stephan Wolf; Sandra Weitz; Konstanze Döhner; Thomas Boehm; Hartmut Döhner; Peter Lichter

1998-01-01

114

Transcription factor CCAAT/enhancer-binding protein alpha and critical circadian clock downstream target gene PER2 are highly deregulated in diffuse large B-cell lymphoma  

PubMed Central

Disturbances of circadian rhythms and mammalian clock genes have been implicated in the etiologies of many chronic illnesses, including cancer. We show that transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha)-regulated PER2 activation is a potential tumor suppressor pathway in diffuse large B-cell lymphoma (DLBCL), one of the commonest types of mature B-cell lymphoma. Expression analysis of human B-cell lymphoma samples including DLBCL (n = 50), mantle cell (n = 21), follicular (n = 25) and Burkitt (n = 18) lymphoma revealed markedly down-regulated CEBPA and PER2 mRNA levels exclusively in DLBCL samples compared to control lymphatic tissue. We demonstrated direct regulation of the circadian core clock gene PER2 by C/EBPalpha in the pro-B cell line Ba/F3, and forced expression of PER2 resulted in decreased proliferation, GO/G1 cell cycle arrest and increased rates of apoptosis. Interestingly, treatment of human DLBCL cell lines with the histone deacetylase-inhibitor suberoylanilide hydroxamic acid (SAHA) significantly increased the expression of C/EBPalpha and Per2, accompanied by cell growth inhibition; in contrast, siRNA knockdown of CEBPA reduced the anti-proliferative effect of SAHA treatment. Our results show for the first time that C/EBPalpha with its associated direct core clock gene target, PER2, are highly deregulated in DLBCL, suggesting an important tumor suppressive pathway in the pathogenesis of this lymphoma entity. PMID:22260161

Thoennissen, Nils H.; Thoennissen, Gabriela B.; Abbassi, Sam; Nabavi-Nouis, Shayan; Sauer, Tim; Doan, Ngan B.; Gery, Sigal; Müller-Tidow, Carsten; Said, Jonathan W.; Koeffler, H. Phillip

2013-01-01

115

The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases.  

PubMed

Ten-Eleven Translocation-2 (TET2) inactivation through loss-of-function mutation, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2 gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate with age in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET (Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNA demethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietic tissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteins recruit the O-linked ?-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, which promotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level is regulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by the microRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal, lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which are viable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiency initiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2 physiological and pathological functions and discusses how this knowledge influences our therapeutic approaches in hematological malignancies and possibly other tumor types. PMID:24220273

Solary, E; Bernard, O A; Tefferi, A; Fuks, F; Vainchenker, W

2014-03-01

116

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

117

B-cell delivered gene transfer of human S-Ag-Ig fusion protein protects from experimental autoimmune uveitis.  

PubMed

Uveitis is an important autoimmune disease affecting an estimated 2.3 million Americans. This disease is manifested by inflammation of the retina mediated by the infiltration of T lymphocytes that recognize "S-Antigen" (S-Ag). Current therapies involve the life-long use of immunosuppressive drugs, including steroids. The ability to induce specific tolerance to S-Ag would be desirable and allow patients to be weaned off of steroid therapy. In this study, we determined that S-Ag-Ig retroviral vector was capable of preventing EAU (experimental autoimmune uveoretinitis) in Lewis rats induced by immunization with bovine S-Ag (BoS-Ag). Importantly, B-cell delivered gene therapy with S-Ag-Ig can ameliorate ongoing EAU when the treatment was initiated after rats had been immunized. Furthermore, we have successfully induced tolerance in HLA-DR3 transgenic mice with respect to the T-cell proliferative response. These results demonstrate proof of principle for future efforts to develop this approach for clinical application in patients with uveoretinitis. PMID:16168712

Liang, Wei; Karabekian, Zaruhi; Mattapallil, Mary; Xu, Qihong; Viley, Angelia M; Caspi, Rachel; Scott, David W

2006-01-01

118

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

119

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

120

Early gene expression changes by Epstein-Barr virus infection of B-cells indicate CDKs and survivin as therapeutic targets for post-transplant lymphoproliferative diseases.  

PubMed

Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered. PMID:23640782

Bernasconi, Michele; Ueda, Seigo; Krukowski, Patricia; Bornhauser, Beat C; Ladell, Kristin; Dorner, Marcus; Sigrist, Juerg A; Campidelli, Cristina; Aslandogmus, Roberta; Alessi, Davide; Berger, Christoph; Pileri, Stefano A; Speck, Roberto F; Nadal, David

2013-11-15

121

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

122

A cohort of balanced reciprocal translocations associated with dyslexia: identification of two putative candidate genes at DYX1.  

PubMed

Dyslexia is one of the most common neurodevelopmental disorders where likely many genes are involved in the pathogenesis. So far six candidate dyslexia genes have been proposed, and two of these were identified by rare chromosomal translocations in affected individuals. By systematic re-examination of all translocation carriers in Denmark, we have identified 16 different translocations associated with dyslexia. In four families, where the translocation co-segregated with the phenotype, one of the breakpoints concurred (at the cytogenetic level) with either a known dyslexia linkage region--at 15q21 (DYX1), 2p13 (DYX3) and 1p36 (DYX8)--or an unpublished linkage region at 19q13. As a first exploitation of this unique cohort, we identify three novel candidate dyslexia genes, ZNF280D and TCF12 at 15q21, and PDE7B at 6q23.3, by molecular mapping of the familial translocation with the 15q21 breakpoint. PMID:20798984

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

2011-01-01

123

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

124

Induction of Interferon-Stimulated Genes on the IL-4 Response Axis by Epstein-Barr Virus Infected Human B Cells; Relevance to Cellular Transformation  

PubMed Central

Epstein-Barr virus (EBV) is an oncogenic virus that is associated with the pathogenesis of several human lymphoid malignancies, including Hodgkin's lymphoma. Infection of normal resting B cells with EBV results in activation to lymphoblasts that are phenotypically similar to those generated by physiological stimulation with CD40L plus IL-4. One important difference is that infection leads to the establishment of permanently growing lymphoblastoid cell lines, whereas CD40L/IL-4 blasts have finite proliferation lifespans. To identify early events which might later determine why EBV infected blasts go on to establish transformed cell lines, we performed global transcriptome analyses on resting B cells and on EBV and CD40L/IL-4 blasts after 7 days culture. As anticipated there was considerable overlap in the transcriptomes of the two types of lymphoblasts when compared to the original resting B cells, reflecting common changes associated with lymphocyte activation and proliferation. Of interest to us was a subset of 255 genes that were differentially expressed between EBV and CD40L/IL-4 blasts. Genes which were more highly expressed in EBV blasts were substantially and significantly enriched for a set of interferon-stimulated genes which on further in silico analyses were found to be repressed by IL-4 in other cell contexts and to be up-regulated in micro-dissected malignant cells from Hodgkin's lymphoma biopsies when compared to their normal germinal center cell counterparts. We hypothesized that EBV and IL-4 were targeting and discordantly regulating a common set of genes. This was supported experimentally in our B cell model where IL-4 stimulation partially reversed transcriptional changes which follow EBV infection and it impaired the efficiency of EBV-induced B cell transformation. Taken together, these data suggest that the discordant regulation of interferon and IL-4 pathway genes by EBV that occurs early following infection of B cells has relevance to the development or maintenance of an EBV-associated malignancy. PMID:23724103

Wei, Wenbin; Vockerodt, Martina; Murray, Paul G.; Woodman, Ciaran B.; Rowe, Martin

2013-01-01

125

DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes.  

PubMed

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

2012-04-01

126

A Microarray Platform-Independent Classification Tool for Cell of Origin Class Allows Comparative Analysis of Gene Expression in Diffuse Large B-cell Lymphoma  

PubMed Central

Cell of origin classification of diffuse large B-cell lymphoma (DLBCL) identifies subsets with biological and clinical significance. Despite the established nature of the classification existing studies display variability in classifier implementation, and a comparative analysis across multiple data sets is lacking. Here we describe the validation of a cell of origin classifier for DLBCL, based on balanced voting between 4 machine-learning tools: the DLBCL automatic classifier (DAC). This shows superior survival separation for assigned Activated B-cell (ABC) and Germinal Center B-cell (GCB) DLBCL classes relative to a range of other classifiers. DAC is effective on data derived from multiple microarray platforms and formalin fixed paraffin embedded samples and is parsimonious, using 20 classifier genes. We use DAC to perform a comparative analysis of gene expression in 10 data sets (2030 cases). We generate ranked meta-profiles of genes showing consistent class-association using ?6 data sets as a cut-off: ABC (414 genes) and GCB (415 genes). The transcription factor ZBTB32 emerges as the most consistent and differentially expressed gene in ABC-DLBCL while other transcription factors such as ARID3A, BATF, and TCF4 are also amongst the 24 genes associated with this class in all datasets. Analysis of enrichment of 12323 gene signatures against meta-profiles and all data sets individually confirms consistent associations with signatures of molecular pathways, chromosomal cytobands, and transcription factor binding sites. We provide DAC as an open access Windows application, and the accompanying meta-analyses as a resource. PMID:23424639

Care, Matthew A.; Barrans, Sharon; Worrillow, Lisa; Jack, Andrew; Westhead, David R.; Tooze, Reuben M.

2013-01-01

127

Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling  

Microsoft Academic Search

The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy chain gene. Signals through the pre-BCR are required for initiating diverse processes in pre-B cells, including proliferation and recombination of the light chain gene, which eventually lead to the differentiation of pre-B cells to immature B cells. However, the molecular mechanisms by which the pre-BCR promotes

Sebastian Herzog; Michael Reth; Hassan Jumaa

2009-01-01

128

Small lymphocytic lymphoma, marginal zone B-cell lymphoma, and mantle cell lymphoma exhibit distinct gene-expression profiles allowing molecular diagnosis.  

PubMed

Non-germinal center small B-cell lymphomas represent a heterogeneous group of non-Hodgkin lymphomas, the most frequent histologic subtypes being small lymphocytic lymphoma (SLL), splenic marginal zone B-cell lymphoma (MZL), and mantle cell lymphoma (MCL). In order to identify genomic signatures specific for each disease, we analyzed 128 primary tumors using high-density microarrays. Several clusters of genes significantly discriminated the 3 histologic subtypes. Genes associated with cell adhesion, angiogenesis, and inhibition of apoptosis were up-regulated in SLL. Genes associated with intracellular signaling via the AKT1 pathway were up-regulated in splenic MZL. Genes associated with cell cycle control and multidrug resistance were up-regulated in MCL. Using 44 genes selected within the gene clusters discriminant for the 3 lymphoma subtypes, we generated a class prediction score that allowed us to classify the 3 entities in 96% of the cases, including borderline cases. Whereas specific transcriptional profiles easily distinguished all MZL samples, SLL samples, and most of the MCL samples into separate groups, few MCL cases exhibited MZL-type transcriptional profiles. This study demonstrates that SLL, splenic MZL, and MCL possess specific transcriptional profiles that may be relevant to the pathogenesis and the diagnosis of these histologic subtypes. PMID:14630827

Thieblemont, Catherine; Nasser, Valéry; Felman, Pascale; Leroy, Karen; Gazzo, Sophie; Callet-Bauchu, Evelyne; Loriod, Béatrice; Granjeaud, Samuel; Gaulard, Philippe; Haioun, Corinne; Traverse-Glehen, Alexandra; Baseggio, Lucile; Bertucci, François; Birnbaum, Daniel; Magrangeas, Florence; Minvielle, Stéphane; Avet-Loiseau, Hervé; Salles, Gilles; Coiffier, Bertrand; Berger, Françoise; Houlgatte, Rémi

2004-04-01

129

Myeloid translocation gene 16 is required for maintenance of haematopoietic stem cell quiescence  

PubMed Central

The t(8;21) and t(16;21) that are associated with acute myeloid leukaemia disrupt two closely related genes termed Myeloid Translocation Genes 8 (MTG8) and 16 (MTG16), respectively. Many of the transcription factors that recruit Mtg16 regulate haematopoietic stem and progenitor cell functions and are required to maintain stem cell self-renewal potential. Accordingly, we found that Mtg16-null bone marrow (BM) failed in BM transplant assays. Moreover, when removed from the animal, Mtg16-deficient stem cells continued to show defects in stem cell self-renewal assays, suggesting a requirement for Mtg16 in this process. Gene expression analysis indicated that Mtg16 was required to suppress the expression of several key cell-cycle regulators including E2F2, and chromatin immunoprecipitation assays detected Mtg16 near an E2A binding site within the first intron of E2F2. BrdU incorporation assays indicated that in the absence of Mtg16 more long-term stem cells were in the S phase, even after competitive BM transplantation where normal stem and progenitor cells are present, suggesting that Mtg16 plays a role in the maintenance of stem cell quiescence. PMID:22266796

Fischer, Melissa A; Moreno-Miralles, Isabel; Hunt, Aubrey; Chyla, Brenda J; Hiebert, Scott W

2012-01-01

130

PCR analysis of the immunoglobulin heavy chain gene in polyclonal processes can yield pseudoclonal bands as an artifact of low B cell number.  

PubMed

Polymerase chain reaction (PCR)-based analysis for detecting immunoglobulin heavy chain gene (IgH) rearrangements in lymphoproliferative disorders is well established. The presence of one or two discrete bands is interpreted as a monoclonal proliferation, whereas a smear pattern represents a polyclonal population. Prompted by our observation of discrete bands in histologically reactive processes with a relative paucity of B cells, we sought to determine whether low numbers of B cells in biopsy specimens could artifactually produce pseudomonoclonal bands. We performed IgH PCR analysis on serially diluted DNA samples from 5 B cell non-Hodgkin's lymphomas (B-NHLs), 5 reactive lymph nodes, 5 reactive tonsils and 10 microdissected germinal centers from a lymph node with follicular hyperplasia. We also assessed multiple aliquots of DNA samples from small biopsy specimens of reactive lymphocytic processes from the stomach (5 cases). PCR products were evaluated using high resolution agarose or polyacrylamide gels, and DNA sequencing was performed on IgH PCR products from two reactive germinal centers, which yielded monoclonal bands of identical size. All 5 B-NHLs harboring monoclonal B cell populations yielded single discrete bands, which were maintained in all dilutions. By contrast, all of the reactive lesions with polyclonal patterns at 50 ng/microl starting template concentration showed strong pseudomonoclonal bands at dilutions of 1:1,000 to 1:1,500 in placental DNA. Two of the microdissected reactive germinal centers that showed bands of identical size on duplicate reactions were proven to have different IgH sequences by sequencing. We conclude that specimens containing low numbers of polyclonal B cells may produce pseudomonoclonal bands on IgH PCR analysis. IgH PCR analysis should be performed on multiple aliquots of each DNA sample, and only samples that yield reproducible bands of identical size can be reliably interpreted as monoclonal. PMID:11272894

Elenitoba-Johnson, K S; Bohling, S D; Mitchell, R S; Brown, M S; Robetorye, R S

2000-05-01

131

A single recessive gene controls cadmium translocation in the cadmium hyperaccumulating rice cultivar Cho-Ko-Koku  

Microsoft Academic Search

The heavy metal cadmium (Cd) is highly toxic to humans and can enter food chains from contaminated crop fields. Understanding\\u000a the molecular mechanisms of Cd accumulation in crop species will aid production of safe Cd-free food. Here, we identified\\u000a a single recessive gene that allowed higher Cd translocation in rice, and also determined the chromosomal location of the\\u000a gene. The

Kouichi Tezuka; Hidenori Miyadate; Kazunao Katou; Ikuko Kodama; Shinichi Matsumoto; Tomohiko Kawamoto; Satoshi Masaki; Hideki Satoh; Masayuki Yamaguchi; Kenji Sakurai; Hidekazu Takahashi; Namiko Satoh-Nagasawa; Akio Watanabe; Tatsuhito Fujimura; Hiromori Akagi

2010-01-01

132

The Pontin series of recombinant alien translocations in bread wheat: single translocations integrating combinations of Bdv2, Lr19 and Sr25 disease-resistance genes from Thinopyrum intermedium and Th. ponticum.  

PubMed

Two bread wheat lines each with a translocation on chromosome 7DL from either Thinopyrum intermedium (TC5 and TC14) or Thinopyrum ponticum (T4m), were hybridized in a ph1b mutant background to enhance recombination between the two translocated chromosomal segments. The frequency of recombinants was high in lines derived from the larger and similar-sized translocations (TC5/T4m), but much lower when derived from different-sized translocations (TC14/T4m). Recombinant translocations contained combinations of resistance genes Bdv2, Lr19 and Sr25 conferring resistance to Barley yellow dwarf virus (BYDV), leaf rust and stem rust, respectively. Their genetic composition was identified using bioassays and molecular markers specific for the two progenitor Thinopyrum species. This set of 7DL Th. ponticum/intermedium recombinant translocations was termed the Pontin series. In addition to Thinopyrum markers, the size of the translocation was estimated with the aid of wheat markers mapped on each of the 7DL deletion bins. Bioassays for BYDV, leaf rust and stem rust were performed under greenhouse and field conditions. Once separated from ph1b background, the Pontin recombinant translocations were stable and showed normal inheritance in successive backcrosses. The reported Pontin translocations integrate important resistance genes in a single linkage block which will allow simultaneous selection of disease resistance. Combinations of Bdv2 + Lr19 or Lr19 + Sr25 in both long and short translocations, are available to date. The smaller Pontins, comprising only 20 % of the distal portion of 7DL, will be most attractive to breeders. PMID:23807636

Ayala-Navarrete, L I; Mechanicos, A A; Gibson, J M; Singh, D; Bariana, H S; Fletcher, J; Shorter, S; Larkin, Philip J

2013-10-01

133

Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens.  

PubMed

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that are distinguished by a combination of histomorphological, phenotypic, and genetic features. A subset of B-cell lymphomas, however, has one or more characteristics that overlap BL and DLBCL, and are categorized as B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U). Molecular analyses support the concept that there is a biological continuum between BL and DLBCL that includes variable activity of MYC, an oncoprotein once thought to be only associated with BL, but now recognized as a major predictor of survival among patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We tested whether a targeted expression profiling panel could be used to categorize tumors as BL and DLBCL, resolve the molecular heterogeneity of BCL-U, and capture MYC activity using RNA from formalin-fixed, paraffin-embedded biopsy specimens. A diagnostic molecular classifier accurately predicted pathological diagnoses of BL and DLBCL, and provided more objective subclassification for a subset of BCL-U and genetic double-hit lymphomas as molecular BL or DLBCL. A molecular classifier of MYC activity correlated with MYC IHC and stratified patients with primary DLBCL treated with R-CHOP into high- and low-risk groups. These results establish a framework for classifying and stratifying MYC-driven, aggressive, B-cell lymphomas on the basis of quantitative molecular profiling that is applicable to fixed biopsy specimens. PMID:25468432

Carey, Christopher D; Gusenleitner, Daniel; Chapuy, Bjoern; Kovach, Alexandra E; Kluk, Michael J; Sun, Heather H; Crossland, Rachel E; Bacon, Chris M; Rand, Vikki; Dal Cin, Paola; Le, Long P; Neuberg, Donna; Sohani, Aliyah R; Shipp, Margaret A; Monti, Stefano; Rodig, Scott J

2015-01-01

134

Evidence that Yaa-induced loss of marginal zone B cells is a result of dendritic cell-mediated enhanced activation.  

PubMed

The development of systemic lupus is accelerated by the Yaa (Y-linked autoimmune acceleration) mutation, which is the consequence of a translocation of the telomeric end containing the Tlr7 gene from the X chromosome onto the Y chromosome. However, the loss of marginal zone (MZ) B cells, one of the Yaa-linked cellular abnormalities, has previously been shown to be unrelated to the Tlr7 gene duplication, and the present study therefore aimed to investigate the mechanism responsible for MZ B-cell loss. Analyses of Yaa and non-Yaa C57BL/6 male mice expressing an MD4 anti-HEL IgM transgene or those deficient in fms-like tyrosine kinase 3 ligand (FL) revealed that the proportion of MZ B cells in these Yaa mice was comparable to that of the respective non-Yaa control mice. Notably, the activation of MZ B cells was compromised in both of these transgenic model systems, due to the absence of cognate antigens or the impaired development of dendritic cells, respectively. These results contrasted with the loss of MZ B cells in non-Yaa mice treated with FL and the lack of accumulation of MZ B cells in Yaa mice treated with a B-cell survival factor, BAFF. Taken together, our results suggest that the persistent and enhanced activation of Yaa-bearing hyperactive MZ B cells by dendritic cells is responsible for the loss of this B-cell subset in Yaa mice. PMID:20149596

Santiago-Raber, Marie-Laure; Amano, Hirofumi; Amano, Eri; Fossati-Jimack, Liliane; Swee, Lee Kim; Rolink, Antonio; Izui, Shozo

2010-06-01

135

Specific 5' and 3' regions of the mu-chain gene are undermethylated at distinct stages of B-cell differentiation.  

PubMed Central

The mu-chain gene is expressed differently in successive stages of B-lymphocyte development. The heavy chain product appears as a cytoplasmic constituent in pre-B-cells, as part of the IgM receptor in maturing B cells, and as a component in the pentamer IgM antibody synthesized and secreted by the antigen-stimulated cell. We have used the methylation of CpG sequences as an assay system to define the chromatin changes associated with different expression of the mu-chain. The methylation status of eight index sites was followed by restriction enzyme analysis of murine cell lines representing the major stages in the developmental pathway. The analyses showed that a single Msp I/Hpa II site 5' to the immunoglobulin enhancer becomes undermethylated with the onset of mu-chain gene transcription. Four midgene Msp I/Hpa II sites exhibit a progressive loss of methyl groups unrelated to changes in mu-chain gene expression, whereas a Msp I/Hpa II site and two Hha I sites surrounding the exon encoding the carboxyl terminus of the secreted form of mu chain (mus) become undermethylated during the transition to IgM secretion. These results indicate that structural changes in local regions of the mu-chain gene correlate with specific developmental events. Images PMID:2582426

Blackman, M A; Koshland, M E

1985-01-01

136

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

137

A Yeast Artificial Chromosome Contig That Spans the RB1-D13S31 Interval on Human Chromosome 13 and Encompasses the Frequently Deleted Region in B-cell Chronic Lymphocytic Leukemia  

Microsoft Academic Search

Abnormalities involving chromosome 13 have been reported as the only cytogenetic change in B-cell chronic lymphocytic leukemia (BCLL). Deletions are the most common cytogenetic abnormality and always involve 13q14, but when translocations are seen, the consistent breakpoint is always in 13q14. It is now established that deletions, distal to the RB1 gene in 13q14, are invariably associated with these translocations.

Lesleyann Hawthorn; Terry Roberts; E. Verlind; R. Frank Kooy; John K. Cowell

1995-01-01

138

Alternative Splicing Of The Trout Pax5 Gene And Identification Of Novel B Cell Populations Using Pax5 Signatures*  

PubMed Central

Pax5 is an alternatively spliced transcription factor that regulates B cell development and activation. The function of specific Pax5 isoforms is unknown. Here we report the existence of seven alternatively spliced isoforms of Pax5 in the rainbow trout. We hypothesized that B cells differentially express specific Pax5 isoforms as a means of modulating Pax5 activity during cell maturation. Flow cytometric analyses using Pax5-specific antibodies recognizing the paired domain, a central (exon 6-encoding) domain, or the C-terminus, revealed the existence of distinct Pax5-expressing cell populations in trout immune tissues. Additionally, using the transcription factor EBF, we show that Pax5 isoforms lacking a paired domain are already expressed at the earliest stages of trout (B) lymphopoiesis, and unexpectedly, that minor populations of such cells reside in blood and spleen. These data support use of differentially expressed Pax5 isoforms to identify novel B cell subsets in the form of Pax5 tissue signatures, and as such, provides new biomarkers for malignancy, infectious disease, and disease resistance in trout and humans. PMID:23796789

MacMurray, Elizabeth; Barr, Maggie; Bruce, Amber; Epp, Lidia; Zwollo, Patty

2013-01-01

139

Corecruitment of the Grg4 repressor by PU.1 is critical for Pax5-mediated repression of B-cell-specific genes  

PubMed Central

PU.1 and Pax5 are important regulators of immunoglobulin heavy-chain (IgH) gene expression in B lineage cells. We have previously shown that PU.1 can potentiate the transcription of an IgH HS1,2 enhancer-linked reporter gene, and that Pax5 represses the same enhancer in transient transfection assays. Here we report that PU.1, like Pax5, can recruit and physically interact with a member of the Groucho family of co-repressors, Grg4. As a consequence, PU.1 in conjunction with Pax5 represses enhancer function in a position-dependent manner when Grg4 is recruited. Interestingly, Grg4 levels decrease following B-cell activation, suggesting temporal regulation of Grg4. Moreover, the joining-chain promoter, with an activity pattern and architecture resembling HS1,2, can also be repressed by the combinatorial action of Pax5/PU.1/Grg4. These data indicate that Pax5 depends on PU.1, acting in cis, for stable recruitment of Grg co-repressors to B-cell-specific genes. PMID:14993928

Linderson, Ylva; Eberhard, Dirk; Malin, Stephen; Johansson, Annica; Busslinger, Meinrad; Pettersson, Sven

2004-01-01

140

Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites.  

E-print Network

Gene rearrangements such as chromosomal translocations have been shown to contribute to cancer development. Human chromosomal fragile sites are regions of the genome especially prone to breakage, and have been implicated ...

Burrow, Allison A.; Williams, Laura E.; Pierce, Levi C. T.; Wang, Yuh-Hwa

2009-01-30

141

Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women.  

PubMed

A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(?)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination. PMID:25100291

Sacha, C R; Vandergrift, N; Jeffries, T L; McGuire, E; Fouda, G G; Liebl, B; Marshall, D J; Gurley, T C; Stiegel, L; Whitesides, J F; Friedman, J; Badiabo, A; Foulger, A; Yates, N L; Tomaras, G D; Kepler, T B; Liao, H X; Haynes, B F; Moody, M A; Permar, S R

2015-03-01

142

Seven novel and stable translocations associated with oncogenic gene expression in malignant melanoma.  

PubMed

Cytogenetics has not only precipitated the discovery of several oncogenes, but has also led to the molecular classification of numerous malignancies. The correct identification of aberrations in many tumors has, however, been hindered by extensive tumor complexity and the limitations of molecular cytogenetic techniques. In this study, we have investigated five malignant melanoma (MM) cell lines from at least three different passages using high-resolution R-banding and the recently developed methods of comparative genomic hybridization and multicolor or multiplex fluorescence in situ hybridization. We subsequently detected nine consistent translocations, seven of which were novel: dic(1;11)(p10;q14), der(9)t(3;9)(p12;p11), der(4)t(9;4;7)(q33:p15-q23:q21), der(14)t(5;14)(q12;q32), der(9)t(9;22)(p21;q11), der(19)t(19;20)(p13.3;p11), der(10)t(2;12;7;10)(q31:p12-->pter:q11.2-->q31:q21), der(19)t(10;19)(q23;q13), and der(20)t(Y;20)(q11.23;q13.3). Furthermore, using the human HG-U133A GeneChip, positive expression levels of oncogenes or tumor-related genes located at the regions of chromosomal breakpoints were identified, including AKT1, BMI1, CDK6, CTNNB1, E2F1, GPNMB, GPRK7, KBRAS2, LDB2, LIMK1, MAPK1, MEL, MP1, MUC18, NRCAM, PBX3, RAB22A, RAB38, SNK, and STK4, indicating an association between chromosomal breakpoints and altered gene expression. Moreover, we also show that growth of all five cell lines can be significantly reduced by downregulating CDK6 gene expression with small interfering RNA (siRNA). Because the majority of these breakpoints have been reported previously in MM, our results support the idea of common mechanisms in this disease. PMID:15967107

Okamoto, Ichiro; Pirker, Christine; Bilban, Martin; Berger, Walter; Losert, Doris; Marosi, Christine; Haas, Oskar A; Wolff, Klaus; Pehamberger, Hubert

2005-04-01

143

Ectopic expression of homeobox gene NKX2-1 in diffuse large B-cell lymphoma is mediated by aberrant chromatin modifications.  

PubMed

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, Jürgen; Quentmeier, Hilmar; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G; MacLeod, Roderick A F

2013-01-01

144

Characterization of a heavy metal translocating P-type ATPase gene from an environmental heavy metal resistance Enterobacter sp. isolate.  

PubMed

Heavy metals are common contaminants found in polluted areas. We have identified a heavy metal translocating P-type ATPase gene (hmtp) via fosmid library and in vitro transposon mutagenesis from an Enterobacter sp. isolate. This gene is believed to participate in the bacterium's heavy metal resistance traits. The complete gene was identified, cloned, and expressed in a suitable Escherichia coli host cell. E. coli W3110, RW3110 (zntA::Km), GG48 (?zitB::Cm zntA::Km), and GG51 (?zitB::Cm) were used to study the possible effects of this gene for heavy metal (cadmium and zinc in particular) resistance. Among the E. coli strains tested, RW3110 and GG48 showed more sensitivity to cadmium and zinc compared to the wild-type E. coli W3110 and strain GG51. Therefore, strains RW3110 and GG48 were chosen for the reference hosts for further evaluation of the gene's effect. The results showed that expression of this heavy metal translocating P-type ATPase gene could increase the ability for zinc and cadmium resistance in the tested microorganisms. PMID:23344939

Chien, Chih-Ching; Huang, Chia-Hsuan; Lin, Yi-Wei

2013-03-01

145

Incidence of Diffuse Large B-Cell Lymphoma of Germinal Center B-Cell Origin in Whole Diffuse Large B-Cell Lymphoma: Tissue Fluorescence In Situ Hybridization Using t(14;18) Compared with Immunohistochemistry  

Microsoft Academic Search

Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important categories such as germinal center B (GCB)-like\\u000a and non-GCB-like groups. The t(14;18)(q32;q21) translocation defines a unique subset of DLBCL cases with a GCB gene expression\\u000a profile. Two-color fluorescence in situ hybridization (FISH) analysis was applied to detect t(14;18) (q32;q21) in the nuclei\\u000a of paraffin-embedded tissue sections from 61 patients

Yuko Hirose; Yasufumi Masaki; Hiromi Karasawa; Kumiko Shimoyama; Toshihiro Fukushima; Hiroshi Kawabata; Noriyoshi Ogawa; Yuji Wano; Mamoru Ozaki

2005-01-01

146

Segmental tandem triplication of the MLL gene in an intravascular large B-cell lymphoma with multisystem involvement: a comprehensive morphologic, immunophenotypic, cytogenetic, and molecular cytogenetic antemortem study.  

PubMed

An association between intravascular large B-cell lymphoma (IVLBCL) and the mixed lineage leukemia (MLL) gene has never been demonstrated. Here, we report an IVLBCL in a 47-year-old Asian man. Morphologically, the atypical lymphoid infiltrate was entirely confined in the lumina of capillaries, small vessels, and sinusoidal space. Within the kidney, the neoplastic lymphoid cells exhibited both the glomerular and peritubular capillary distribution pattern. Conventional cytogenetic analysis from the bone marrow aspirates displayed a complex karyotype, with a notable triple tandem repeat at band segment q22-q25 of chromosome 11. Fluorescence in situ hybridization with an MLL probe set, performed on both interphase cells and metaphase spreads, confirmed the presence of 3 copies of the MLL gene on the derivative chromosome 11. From this finding and 3 other IVLBCL cases reported in the literature, we conclude that MLL may play an important role in the lymphomagenesis of IVLBCL at least in a subset of cases. PMID:19722759

Deisch, Jeremy; Fuda, Franklin Buddy; Chen, Weina; Karandikar, Nitin; Arbini, Arnaldo A; Zhou, Xin J; Wang, Huan-You

2009-09-01

147

Analysis of the major patterns of B cell gene expression changes in response to short-term stimulation with 33 single ligands.  

PubMed

We examined the major patterns of changes in gene expression in mouse splenic B cells in response to stimulation with 33 single ligands for 0.5, 1, 2, and 4 h. We found that ligands known to directly induce or costimulate proliferation, namely, anti-IgM (anti-Ig), anti-CD40 (CD40L), LPS, and, to a lesser extent, IL-4 and CpG-oligodeoxynucleotide (CpG), induced significant expression changes in a large number of genes. The remaining 28 single ligands produced changes in relatively few genes, even though they elicited measurable elevations in intracellular Ca(2+) and cAMP concentration and/or protein phosphorylation, including cytokines, chemokines, and other ligands that interact with G protein-coupled receptors. A detailed comparison of gene expression responses to anti-Ig, CD40L, LPS, IL-4, and CpG indicates that while many genes had similar temporal patterns of change in expression in response to these ligands, subsets of genes showed unique expression patterns in response to IL-4, anti-Ig, and CD40L. PMID:15585835

Zhu, Xiaocui; Hart, Rebecca; Chang, Mi Sook; Kim, Jong-Woo; Lee, Sun Young; Cao, Yun Anna; Mock, Dennis; Ke, Eugene; Saunders, Brian; Alexander, Angela; Grossoehme, Joella; Lin, Keng-Mean; Yan, Zhen; Hsueh, Robert; Lee, Jamie; Scheuermann, Richard H; Fruman, David A; Seaman, William; Subramaniam, Shankar; Sternweis, Paul; Simon, Melvin I; Choi, Sangdun

2004-12-15

148

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

149

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

150

Tcr? translocations that delete the Bcl11b haploinsufficient tumor suppressor gene promote atm-deficient T cell acute lymphoblastic leukemia.  

PubMed

ATM is the master regulator of the cellular response to DNA double strand breaks (DSBs). Deficiency of ATM predisposes humans and mice to ?? T lymphoid cancers with clonal translocations between the T cell receptor (TCR) ?/? locus and a 450 kb region of synteny on human chromosome 14 and mouse chromosome 12. While these translocations target and activate the TCL1 oncogene at 14q32 to cause T cell pro-lymphocytic leukemia (T-PLL), the TCR?/?;14q32 translocations in ATM-deficient T cell acute lymphoblastic leukemia (T-ALL) have not been characterized and their role in cancer pathogenesis remains unknown. The corresponding lesion in Atm-deficient mouse T-ALLs is a chromosome t(12;14) translocation with Tcr? genes fused to sequences on chromosome 12; although these translocations do not activate Tcl1, they delete the Bcl11b haploinsufficient tumor suppressor gene. To assess whether Tcr? translocations that inactivate one copy of Bcl11b promote transformation of Atm-deficient cells, we analyzed Atm(-/-) mice with mono-allelic Bcl11b deletion initiating in thymocytes concomitant with Tcr? recombination. Inactivation of one Bcl11b copy had no effect on the predisposition of Atm(-/-) mice to clonal T-ALLs. Yet, none of these T-ALLs had a clonal chromosome t(12;14) translocation that deleted Bcl11b indicating that Tcr? translocations that inactivate a copy of Bcl11b promote transformation of Atm-deficient thymocytes. Our data demonstrate that antigen receptor locus translocations can cause cancer by deleting a tumor suppressor gene. We discuss the implications of these findings for the etiology and therapy of T-ALLs associated with ATM deficiency and TCR?/? translocations targeting the 14q32 cytogenetic region. PMID:25486566

Ehrlich, Lori A; Yang-Iott, Katherine; Bassing, Craig H

2014-01-01

151

Rapid detection of lymphoma-specific translocations in interphase nuclei of non-Hodgkin's lymphoma by fluorescence in situ hybridization.  

PubMed

We have recently developed a method to detect tumor-specific rearrangement of the IgH gene in interphase nuclei by fluorescence in situ hybridization. Tumor-specific IgH gene rearrangement is equivalent to 14q32.33 translocation. Using this approach, we detected 14q32.33 translocation in 29 of 70 patients with B-cell non-Hodgkin's lymphoma (NHL). Chromosome t(3;14) was found in 10 of these 29 patients, and were demonstrated as a fusion signal of BCL6 and VH gene probes in interphase nuclei. Furthermore, in another series of 11 patients and a NHL cell line, we demonstrated t(14;18) and t(11;14) in interphase and metaphase cells with a combination of BCL2 (or PRAD1) with IgH gene probes. Interphase FISH with lymphoma-associated gene probes is a rapid procedure for cytogenetic diagnosis of B-cell NHL. PMID:9209369

Taniwaki, M; Ueda, Y; Nishida, K; Takashima, T; Kashima, K; Matsuda, F; Silverman, G A

1997-04-01

152

Generation of antibody- and B cell-deficient pigs by targeted disruption of the J-region gene segment of the heavy chain locus.  

PubMed

A poly(A)-trap gene targeting strategy was used to disrupt the single functional heavy chain (HC) joining region (J(H)) of swine in primary fibroblasts. Genetically modified piglets were then generated via somatic cell nuclear transfer (SCNT) and bred to yield litters comprising J(H) wild-type littermate (+/+), J(H) heterozygous knockout (±) and J(H) homozygous knockout (-/-) piglets in the expected Mendelian ratio of 1:2:1. There are only two other targeted loci previously published in swine, and this is the first successful poly(A)-trap strategy ever published in a livestock species. In either blood or secondary lymphoid tissues, flow cytometry, RT-PCR and ELISA detected no circulating IgM(+) B cells, and no transcription or secretion of immunoglobulin (Ig) isotypes, respectively in J(H) -/- pigs. Histochemical and immunohistochemical (IHC) studies failed to detect lymph node (LN) follicles or CD79?(+) B cells, respectively in J(H) -/- pigs. T cell receptor (TCR)(?) transcription and T cells were detected in J(H) -/- pigs. When reared conventionally, J(H) -/- pigs succumbed to bacterial infections after weaning. These antibody (Ab)- and B cell-deficient pigs have significant value as models for both veterinary and human research to discriminate cellular and humoral protective immunity to infectious agents. Thus, these pigs may aid in vaccine development for infectious agents such as the pandemic porcine reproductive and respiratory syndrome virus (PRRSV) and H1N1 swine flu. These pigs are also a first significant step towards generating a pig that expresses fully human, antigen-specific polyclonal Ab to target numerous incurable infectious diseases with high unmet clinical need. PMID:20872248

Mendicino, M; Ramsoondar, J; Phelps, C; Vaught, T; Ball, S; LeRoith, T; Monahan, J; Chen, S; Dandro, A; Boone, J; Jobst, P; Vance, A; Wertz, N; Bergman, Z; Sun, X-Z; Polejaeva, I; Butler, J; Dai, Y; Ayares, D; Wells, K

2011-06-01

153

Inactivation of the DCC tumor suppressor gene in a B-cell lymphoma cell line with the alteration of chromosome 18.  

PubMed

A B-cell lymphoma cell line, designated KML-1, was established from pleural effusion of a patient with non-Hodgkin's lymphoma of large-cell type. The lymphoma arose in the pelvis and ran an aggressive clinical course. Chromosome analysis of the cell line exhibited a complex karyotype including the loss of chromosome 18. To evaluate the molecular events in the cell line that may be associated with the development of the lymphoma, we investigated the expression and/or alterations of several classes of human genes, including oncogenes, tumor suppressor genes, and cytokine genes. The expression of the DCC (deleted in colorectal cancer) gene, located on the chromosome 18q21, was extremely reduced in KML-1 cell line, as compared with that in a normal spleen tissue and other 4 lymphoma cell lines by the reverse transcription-polymerase-chain-reaction (RT-PCR) method. This finding suggests that inactivation of the DCC gene might play a role in the pathogenesis of the case of lymphoma. PMID:7572991

Ikezoe, T; Miyagi, T; Kubota, T; Taguchi, T; Ohtsuki, Y; Miyake, K; Inokuchi, K; Nomura, T; Koeffler, H P; Miyoshi, I

1995-10-01

154

Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig loci in activated B cells  

PubMed Central

After immunization or infection, activation-induced cytidine deaminase (AID) initiates diversification of immunoglobulin (Ig) genes in B cells, introducing mutations within the antigen binding V regions (somatic hypermutation, SHM) and double-strand DNA breaks (DSBs) into switch (S) regions, leading to antibody class switch recombination (CSR). We asked if during B cell activation, AID also induces DNA breaks at genes other than IgH genes. Using a non-biased genome-wide approach, we have identified hundreds of reproducible AID-dependent DSBs in mouse splenic B cells shortly after induction of CSR in culture. Most interestingly, AID induces DSBs at sites syntenic with sites of translocations, deletions, and amplifications found in human B cell lymphomas, including within the oncogene B cell lymphoma11a (bcl11a)/evi9. Unlike AID-induced DSBs in Ig genes, genome-wide AID-dependent DSBs are not restricted to transcribed regions, and frequently occur within repeated sequence elements, including CA-repeats and non-CA tandem repeats, and SINEs. PMID:21255732

Staszewski, Ori; Baker, Richard E.; Ucher, Anna J.; Martier, Raygene; Stavnezer, Janet; Guikema, Jeroen E.J.

2011-01-01

155

Generation of Recombination Activating Gene-1-Deficient Neonatal Piglets: A Model of T and B Cell Deficient Severe Combined Immune Deficiency  

PubMed Central

Although severe combined immune deficiency (SCID) is a very important research model for mice and SCID mice are widely used, there are only few reports describing the SCID pig models. Therefore, additional research in this area is needed. In this study, we describe the generation of Recombination activating gene-1 (Rag-1)-deficient neonatal piglets in Duroc breed using somatic cell nuclear transfer (SCNT) with gene targeting and analysis using fluorescence-activated cell sorting (FACS) and histology. We constructed porcine Rag-1 gene targeting vectors for the Exon 2 region and obtained heterozygous/homozygous Rag-1 knockout cell colonies using SCNT. We generated two Rag-1-deficient neonatal piglets and compared them with wild-type neonatal piglets. FACS analysis showed that Rag-1 disruption causes a lack of Immunoglobulin M-positive B cells and CD3-positive T cells in peripheral blood mononuclear cells. Consistent with FACS analysis, histological analysis revealed structural defects and an absence of mature lymphocytes in the spleen, mesenteric lymph node (MLNs), and thymus in Rag-1-deficient piglets. These results confirm that Rag-1 is necessary for the generation of lymphocytes in pigs, and Rag-1-deficient piglets exhibit a T and B cell deficient SCID (T-B-SCID) phenotype similar to that of rodents and humans. The T-B-SCID pigs with Rag-1 deficiency generated in this study could be a suitably versatile model for laboratory, translational, and biomedical research, including the development of a humanized model and assessment of pluripotent stem cells. PMID:25437445

Ito, Tetsuya; Sendai, Yutaka; Yamazaki, Satoshi; Seki-Soma, Marie; Hirose, Kensuke; Watanabe, Motoo; Fukawa, Kazuo; Nakauchi, Hiromitsu

2014-01-01

156

GenomicScape: An Easy-to-Use Web Tool for Gene Expression Data Analysis. Application to Investigate the Molecular Events in the Differentiation of B Cells into Plasma Cells  

PubMed Central

DNA microarrays have considerably helped to improve the understanding of biological processes and diseases. Large amounts of publicly available microarray data are accumulating, but are poorly exploited due to a lack of easy-to-use bioinformatics resources. The aim of this study is to build a free and convenient data-mining web site (www.genomicscape.com). GenomicScape allows mining dataset from various microarray platforms, identifying genes differentially expressed between populations, clustering populations, visualizing expression profiles of large sets of genes, and exporting results and figures. We show how easily GenomicScape makes it possible to construct a molecular atlas of the B cell differentiation using publicly available transcriptome data of naïve B cells, centroblasts, centrocytes, memory B cells, preplasmablasts, plasmablasts, early plasma cells and bone marrow plasma cells. Genes overexpressed in each population and the pathways encoded by these genes are provided as well as how the populations cluster together. All the analyses, tables and figures can be easily done and exported using GenomicScape and this B cell to plasma cell atlas is freely available online. Beyond this B cell to plasma cell atlas, the molecular characteristics of any biological process can be easily and freely investigated by uploading the corresponding transcriptome files into GenomicScape. PMID:25633866

Kassambara, Alboukadel; Rème, Thierry; Jourdan, Michel; Fest, Thierry; Hose, Dirk; Tarte, Karin; Klein, Bernard

2015-01-01

157

GenomicScape: An Easy-to-Use Web Tool for Gene Expression Data Analysis. Application to Investigate the Molecular Events in the Differentiation of B Cells into Plasma Cells.  

PubMed

DNA microarrays have considerably helped to improve the understanding of biological processes and diseases. Large amounts of publicly available microarray data are accumulating, but are poorly exploited due to a lack of easy-to-use bioinformatics resources. The aim of this study is to build a free and convenient data-mining web site (www.genomicscape.com). GenomicScape allows mining dataset from various microarray platforms, identifying genes differentially expressed between populations, clustering populations, visualizing expression profiles of large sets of genes, and exporting results and figures. We show how easily GenomicScape makes it possible to construct a molecular atlas of the B cell differentiation using publicly available transcriptome data of naïve B cells, centroblasts, centrocytes, memory B cells, preplasmablasts, plasmablasts, early plasma cells and bone marrow plasma cells. Genes overexpressed in each population and the pathways encoded by these genes are provided as well as how the populations cluster together. All the analyses, tables and figures can be easily done and exported using GenomicScape and this B cell to plasma cell atlas is freely available online. Beyond this B cell to plasma cell atlas, the molecular characteristics of any biological process can be easily and freely investigated by uploading the corresponding transcriptome files into GenomicScape. PMID:25633866

Kassambara, Alboukadel; Rème, Thierry; Jourdan, Michel; Fest, Thierry; Hose, Dirk; Tarte, Karin; Klein, Bernard

2015-01-01

158

Deletion mapping of Ig V[sub H] gene segments expressed in human CD5 B cell lines: J[sub H] proximity is not the sole determinant of the restricted fetal V[sub H] gene repertoire  

SciTech Connect

V[sub H] gene segments expressed in a panel of monoclonal human CD5 B cell lines have been positioned on the IgH locus by deletion mapping. The analysis yielded a relative order of V[sub H] fragments of the V[sub H]2, V[sub H]4, V[sub H]5, and V[sub H]6 gene families that was consistent with, and provided a further refinement of existing maps of the human IgH locus. The authors demonstrate that four of six V[sub H] gene segments expressed in the CD5 B cell lines map > 500 kb from the cluster of J[sub H] segments. Two of the gene segments, positioned at [approximately]850 kb (58p2) and [approximately]500 kb (1-9III) from the J[sub H] segments, respectively, belong to the previously identified small cohort of second trimester fetal V[sub H] gene segments. The data show that J[sub H] proximity is not the sole determinant of restricted V[sub H] gene utilization in early human ontogeny. 45 refs., 4 figs., 3 tabs.

Schutte, M.E.M.; Ebeling, S.B.; Akkermans-Koolhaas, K.E.; Logtenberg, T. (University Hospital, Utrecht (Netherlands))

1992-12-15

159

High BCL6 expression predicts better prognosis, independent of BCL6 translocation status, translocation partner, or BCL6-deregulating mutations, in gastric lymphoma.  

PubMed

To investigate the role of BCL6 in the pathogenesis of gastric lymphoma, we analyzed the BCL6 promoter region for BCL6 translocations, somatic hypermutations, and deregulating mutations in 43 gastric lymphomas, including 4 extranodal marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas), 33 diffuse large B-cell lymphomas (DLBCLs), and 6 composite DLBCLs with residual MALT lymphoma (DLCLMLs). BCL6 promoter substitutions by immunoglobulin (Ig) and non-Ig translocation partners, resulting in its deregulation, were frequently involved in DLBCL (36.4%) and DLCLML (50%). Two novel BCL6 translocation partner genes, 28S rRNA and DMRT1, and a new BCL6 translocation breakpoint in intron 2 were also identified. Deregulating mutations were found only in DLBCL (24.2%), which correlated significantly with high BCL6 protein expression. Significantly, high BCL6 expression correlated strongly with longer overall survival (OS), independent of mechanism in gastric DLBCL and DLCLML. Gastric DLBCLs were further subclassified into germinal center B-cell-like (GCB) and non-GCB subgroups immunohistochemically. High BCL6 expression was detected in all GCB cases, irrespective of BCL6 genetic alterations. In the non-GCB subgroup, BCL6-deregulating mutations correlated significantly with high BCL6 expression level. No significant correlation was found between the BCL6 expression level and OS in the non-GCB subgroup, which had significantly poorer prognosis than the GCB subgroup. PMID:16772602

Chen, Yun-Wen; Hu, Xiao-Tong; Liang, Anthony C; Au, Wing-Yan; So, Chi-Chiu; Wong, Michelle L; Shen, Lijun; Tao, Qian; Chu, Kent-Man; Kwong, Yok-Lam; Liang, Raymond H; Srivastava, Gopesh

2006-10-01

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

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

162

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

163

Peripheral B cell subsets  

PubMed Central

Summary Our understanding of the origins and the biological functions of different peripheral B cell subsets continues to evolve. Some understanding has been obtained regarding the synergy between BCR derived signals and other receptors and signaling pathways that drive the development of follicular, marginal zone and B-1 B cells, but this remains a complex and poorly understood issue. More recent information regarding the origins of B-1 and B-2 B cells, the ability of follicular B cells to mature both in the bone marrow and the spleen, the existence of a definable precursor for MZ B cells, and the ability of follicular B cells to occupy two distinct niches are all highlighted in this review. PMID:18434123

Allman, David; Pillai, Shiv

2008-01-01

164

Transcriptional expression analysis of genes involved in regulation of calcium translocation and storage in finger millet (Eleusine coracana L. Gartn.).  

PubMed

Finger millet (Eleusine coracana) variably accumulates calcium in different tissues, due to differential expression of genes involved in uptake, translocation and accumulation of calcium. Ca(2+)/H(+) antiporter (CAX1), two pore channel (TPC1), CaM-stimulated type IIB Ca(2+) ATPase and two CaM dependent protein kinase (CaMK1 and 2) homologs were studied in finger millet. Two genotypes GP-45 and GP-1 (high and low calcium accumulating, respectively) were used to understand the role of these genes in differential calcium accumulation. For most of the genes higher expression was found in the high calcium accumulating genotype. CAX1 was strongly expressed in the late stages of spike development and could be responsible for accumulating high concentrations of calcium in seeds. TPC1 and Ca(2+) ATPase homologs recorded strong expression in the root, stem and developing spike and signify their role in calcium uptake and translocation, respectively. Calmodulin showed strong expression and a similar expression pattern to the type IIB ATPase in the developing spike only and indicating developing spike or even seed specific isoform of CaM affecting the activity of downstream target of calcium transportation. Interestingly, CaMK1 and CaMK2 had expression patterns similar to ATPase and TPC1 in various tissues raising a possibility of their respective regulation via CaM kinase. Expression pattern of 14-3-3 gene was observed to be similar to CAX1 gene in leaf and developing spike inferring a surprising possibility of CAX1 regulation through 14-3-3 protein. Our results provide a molecular insight for explaining the mechanism of calcium accumulation in finger millet. PMID:25101868

Mirza, Neelofar; Taj, Gohar; Arora, Sandeep; Kumar, Anil

2014-10-25

165

Genetic polymorphisms of methylenetetrahydrofolate reductase and promoter methylation of MGMT and FHIT genes in diffuse large B cell lymphoma risk in Middle East.  

PubMed

Diffuse large B cell lymphoma (DLBCL) is one of the most common non-Hodgkin's lymphoma types. Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one carbon metabolism of deoxyribonucleic acid (DNA) synthesis and methylation; both are implicated in carcinogenesis of many types of cancer including lymphoma. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate as a cancer-predisposing factor. The O6 methylguanine DNA methyltransferase (MGMT) and fragile histidine triad (FHIT) genes are transcriptionally silenced by promoter hypermethylation in DLBCL. These genetic differences are highly race specific and have never been screened in the Saudi DLBCL patients. We conducted a hospital-based case-control study including 160 DLBCL cases and 511 Saudi control samples analyzing the MTHFR C677T and A1298C functional polymorphisms by the restriction fragment length polymorphism method and their association with MGMT and FHIT genes promoter hypermethylation. Our data demonstrated that Saudi individuals carrying MTHFR genotype 1298CC (p < 0.001) and the 1298C allele (p = 0.012) had 4.23 and 1.73-fold higher risk of developing DLBCL, respectively. Additionally, combined genotype CCCC (MTHFR 677CC + MTHFR 1298CC) was associated with 3.489-fold, and CTCC (MTHFR 677 CT + 1298CC) was related to 9.515-fold higher risk, compared with full MTHFR enzyme activity. No significant association between MTHFR variant genotypes and methylation of MGMT and FHIT genes were observed. Our findings suggested that polymorphisms of MTHFR enzyme genes might be associated with the individual susceptibility to develop DLBCL. Additionally, the results indicated that MTHFR variants were not related to MGMT or FHIT hypermethylation in DLBCL. PMID:17712558

Siraj, Abdul K; Ibrahim, Muna; Al-Rasheed, Maha; Bu, Rong; Bavi, Prashant; Jehan, Zeenath; Abubaker, Jehad; Murad, Walid; Al-Dayel, Fouad; Ezzat, Adnan; El-Solh, Hassan; Uddin, Shahab; Al-Kuraya, Khawla

2007-12-01

166

Cloning of the anhidrotic ectodermal dysplasia gene: Identification of cDNAs associated with CpG islands mapped near translocation breakpoint in two female patients  

SciTech Connect

The gene for the X chromosomal developmental disorder anhidrotic ectodermal dysplasia (EDA) has been mapped to Xq12-q13 by linkage analysis and is expressed in a few females with chromosomal translocations involving band Xq12-q13. A yeast artificial chromosome (YAC) contig (2.0 Mb) spanning two translocation breakpoints has been assembled by sequence-tagged site (STS)-based chromosomal walking. The two translocation breakpoints (X:autosome translocations from the affected female patients) have been mapped less than 60 kb apart within a YAC contig. Unique probes and intragenic STSs (mapped between the two translocations) have been developed and a somatic cell hybrid carrying the translocated X chromosome from the AK patient has been analyzed by isolating unique probes that span the breakpoint. Several STSs made from intragenic sequences have been found to be conserved in mouse, hamster and monkey, but we have detected no mRNAs in a number of tissues tested. However, a probe and STS developed from the DNA spanning the AK breakpoint is conserved in mouse, hamster and monkey, and we have detected expressed sequences in skin cells and cDNA libraries. In addition, unique sequences have been obtained from two CpG islands in the region that maps proximal to the breakpoints. cDNAs containing these sequences are being studied as candidates for the gene affected in the etiology of EDA.

Srivastava, A.K.; Schlessinger, D. [Washington Univ. School of Medicine, St. Louis, MO (United States); Kere, J. [Univ. of Helsinki (Finland)] [and others

1994-09-01

167

The Role of T-Cell Leukemia Translocation-Associated Gene Protein in Human Tumorigenesis and Osteoclastogenesis  

PubMed Central

Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-?B ligand (RANKL), TNF-?, IL-6, IL-17, and IFN-?. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in regulating bone resorption. In 2009, we demonstrated that novel peptides from T-cell leukemia translocation-associated gene (TCTA) protein expressed in synovial tissues from patients with RA inhibit human osteoclastogenesis, preventing cellular fusion via the interaction between TCTA protein and a putative counterpart molecule. Only a few studies on the role of TCTA protein have been reported. Genomic Southern blots demonstrated a reduced TCTA signal in three of four small cell lung cancer cell lines, suggesting the loss of one of the two copies of the gene. In the current paper, we reviewed the roles of TCTA protein in lung cancer cell lines and human osteoclastogenesis. PMID:22174563

Kotake, Shigeru; Yago, Toru; Kawamoto, Manabu; Nanke, Yuki

2012-01-01

168

Structural organization of the bcr gene and its role in the Ph' translocation  

Microsoft Academic Search

The Philadelphia (Ph') chromosome, an abnormal chromosome 22 (ref. 1), is one of the best-known examples of a specific human chromosomal abnormality strongly associated with one form of human leukaemia, chronic myelocytic leukaemia (CML). The finding2 that a small region of chromosome 9 which includes the c-abl oncogene is translocated to chromosome 22 prompted studies to elucidate the molecular mechanisms

Nora Heisterkamp; Kees Stam; John Groffen; Annelies de Klein; Gerard Grosveld

1985-01-01

169

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

170

GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families  

Microsoft Academic Search

THE Greig cephalopolysyndactyly syndrome (GCPS) is an auto-somal dominant disorder affecting limb and craniofacial development in humans1,2. GCPS-affected individuals are characterized by postaxial polysyndactyly of hands, preaxial polysyndactyly of feet, macroephaly, a broad base of the nose with mild hypertelorism and a prominent forehead. The genetic locus has been pinpointed to chromosome 7pl3 by three balanced translocations associated with GCPS

Andrea Vortkamp; Manfred Gessler; Karl-Heinz Grzeschik

1991-01-01

171

Gene expression profiling indicates that immunohistochemical expression of CD40 is a marker of an inflammatory reaction in the tumor stroma of diffuse large B-cell lymphoma.  

PubMed

Immunohistochemical expression of CD40 is seen in 60-70% of diffuse large B-cell lymphoma (DLBCL) and is associated with a superior prognosis. By using gene expression profiling we aimed to further explore the underlying mechanisms for this effect. Ninety-eight immunohistochemically defined CD40 positive or negative DLBCL tumors, 63 and 35 respectively, were examined using spotted 55K oligonucleotide arrays. CD40 expressing tumors were characterized by up-regulated expression of genes encoding proteins involved in cell-matrix interactions: collagens, integrin ?V, proteoglycans and proteolytic enzymes, and antigen presentation. Immunohistochemistry confirmed that CD40 positive tumors co-express the proinflammatory proteoglycan biglycan (p = 0.005), which in turn correlates with the amount of infiltrating macrophages and CD4 and CD8 positive T-cells. We postulate that immunohistochemical expression of CD40 mainly reflects the inflammatory status in tumors. A high intratumoral inflammatory reaction may correlate with an increased autologous tumor response, and thereby a better prognosis. PMID:22335531

Rydström, Karin; Joost, Patrick; Ehinger, Mats; Edén, Patrik; Jerkeman, Mats; Cavallin-Ståhl, Eva; Linderoth, Johan

2012-09-01

172

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

173

Activation-induced Cytidine Deaminase in B Cell Immunity and Cancers  

PubMed Central

Activation-induced cytidine deaminase (AID) is an enzyme that is predominantly expressed in germinal center B cells and plays a pivotal role in immunoglobulin class switch recombination and somatic hypermutation for antibody (Ab) maturation. These two genetic processes endow Abs with protective functions against a multitude of antigens (pathogens) during humoral immune responses. In B cells, AID expression is regulated at the level of either transcriptional activation on AID gene loci or post-transcriptional suppression of AID mRNA. Furthermore, AID stabilization and targeting are determined by post-translational modifications and interactions with other cellular/nuclear factors. On the other hand, aberrant expression of AID causes B cell leukemias and lymphomas, including Burkitt's lymphoma caused by c-myc/IgH translocation. AID is also ectopically expressed in T cells and non-immune cells, and triggers point mutations in relevant DNA loci, resulting in tumorigenesis. Here, I review the recent literatures on the function of AID, regulation of AID expression, stability and targeting in B cells, and AID-related tumor formation. PMID:23396757

2012-01-01

174

Epigenetic Silencing of MicroRNA34b\\/c and B-Cell Translocation Gene 4 Is Associated with CpG Island Methylation in Colorectal Cancer  

Microsoft Academic Search

Altered expression of microRNA (miRNA) is strongly impli- cated in cancer, and recent studies have shown that, in cancer, expression of some miRNAs cells is silenced in association with CpG island hypermethylation. To identify epigenetically silenced miRNAs in colorectal cancer (CRC), we screened for miRNAs induced in CRC cells by 5-aza-2¶-deoxycytidine (DAC) treatment or DNA methyltransferase knockout. We found that

Minoru Toyota; Hiromu Suzuki; Yasushi Sasaki; Reo Maruyama; Kohzoh Imai; Yasuhisa Shinomura; Takashi Tokino

2008-01-01

175

Estradiol modulates uterine 18 kDa translocator protein gene expression in uterus and kidney of rats.  

PubMed

We examined the effect of ovariectomy, with and without estradiol treatment, on 18 kDa translocator protein (TSPO) gene expression and its binding density in the uterus and kidney of rats. Ovariectomy causes a significant decrease in uterine, but not renal TSPO binding density, while estradiol treatment of ovariectomized rats restored TSPO binding density in the uterus. These TSPO density levels did not correlate with steady state or new RNA transcription. Our in vivo study suggests that estradiol is responsible for the maintenance of uterine TSPO density via transcriptional mechanisms. Our in vivo study also suggests that in the kidney estradiol appears to operate via post-transcriptional mechanisms to maintain TSPO density. PMID:19524125

Mazurika, Caroline; Veenman, Leo; Weizman, Ronit; Bidder, Miri; Leschiner, Svetlana; Golani, Idit; Spanier, Ilana; Weisinger, Gary; Gavish, Moshe

2009-08-13

176

Targeted disruption of the Oct-2 locus in a B cell provides genetic evidence for two distinct cell type-specific pathways of octamer element-mediated gene activation.  

PubMed Central

The Oct-2 protein is a tissue-specific POU-homeodomain transcription factor. It has been considered to represent a developmental regulator of immunoglobulin gene expression by virtue of its interaction with a functionally essential octamer element found in immunoglobulin gene promoters. This proposal has been most strongly challenged by several in vitro transcription analyses which have shown that the related ubiquitous factor Oct-1 can activate transcription from immunoglobulin gene promoters as efficiently as Oct-2. We have genetically analyzed Oct-2 function by using gene targeting to disrupt both alleles of the locus in the murine B cell line WEHI-231. This cell line expresses productively rearranged immunoglobulin genes as well as the Oct-2 gene at high levels which are comparable to those observed in activated murine splenic B cells. In spite of a drastic reduction in Oct-2 levels (20-fold), no effect was observed on the expression of endogenous immunoglobulin genes or on the activity of a transfected immunoglobulin promoter or a heterologous promoter with a single octamer element. In contrast, expression of a reporter construct containing multiple octamer motifs upstream of a heterologous promoter was severely reduced in the double-disruptant cells. The differential responses of the single- and multiple-octamer motif reporter constructs in the mutant B cells are unlikely to be a consequence of differing concentration requirements for activation by Oct-2. The two constructs are activated equivalently over the same range of Oct-2 concentration in a non-B cell. These results provide genetic support for the existence of an Oct-2-independent, but octamer element-dependent, B cell-specific pathway for immunoglobulin gene transcription. They also genetically reveal a distinct Oct-2-dependent pathway of octamer-mediated gene activation. This study demonstrates the feasibility of targeting a diploid locus in a somatic mammalian cell line. Extension of this approach to genes encoding other transcription factors will allow a genetic dissection of their functions within the context of cell lines representing various differentiation states. Images PMID:8334992

Feldhaus, A L; Klug, C A; Arvin, K L; Singh, H

1993-01-01

177

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

178

Disruption of the ATE1 and SLC12A1 Genes by Balanced Translocation in a Boy with Non-Syndromic Hearing Loss.  

PubMed

We report on a boy with non-syndromic hearing loss and an apparently balanced translocation t(10;15)(q26.13;q21.1). The same translocation was found in the normally hearing brother, father and paternal grandfather; however, this does not exclude its involvement in disease pathogenesis, for example, by unmasking a second mutation. Breakpoint analysis via FISH with BAC clones and long-range PCR products revealed a disruption of the arginyltransferase 1 (ATE1) gene on translocation chromosome 10 and the solute carrier family 12, member 1 gene (SLC12A1) on translocation chromosome 15. SNP array analysis revealed neither loss nor gain of chromosomal regions in the affected child, and a targeted gene enrichment panel consisting of 130 known deafness genes was negative for pathogenic mutations. The expression patterns in zebrafish and humans did not provide evidence for ear-specific functions of the ATE1 and SLC12A1 genes. Sanger sequencing of the 2 genes in the boy and 180 GJB2 mutation-negative hearing-impaired individuals did not detect homozygous or compound heterozygous pathogenic mutations. Our study demonstrates the many difficulties in unraveling the molecular causes of a heterogeneous phenotype. We cannot directly implicate disruption of ATE1 and/or SLC12A1 to the abnormal hearing phenotype; however, mutations in these genes may have a role in polygenic or multifactorial forms of hearing impairment. On the other hand, it is conceivable that our patient carries a disease-causing mutation in a so far unidentified deafness gene. Evidently, disruption of ATE1 and/or SLC12A1 gene function alone does not have adverse effects. PMID:24550759

Vona, B; Neuner, C; El Hajj, N; Schneider, E; Farcas, R; Beyer, V; Zechner, U; Keilmann, A; Poot, M; Bartsch, O; Nanda, I; Haaf, T

2014-01-01

179

Disruption of the ATE1 and SLC12A1 Genes by Balanced Translocation in a Boy with Non-Syndromic Hearing Loss  

PubMed Central

We report on a boy with non-syndromic hearing loss and an apparently balanced translocation t(10;15)(q26.13;q21.1). The same translocation was found in the normally hearing brother, father and paternal grandfather; however, this does not exclude its involvement in disease pathogenesis, for example, by unmasking a second mutation. Breakpoint analysis via FISH with BAC clones and long-range PCR products revealed a disruption of the arginyltransferase 1 (ATE1) gene on translocation chromosome 10 and the solute carrier family 12, member 1 gene (SLC12A1) on translocation chromosome 15. SNP array analysis revealed neither loss nor gain of chromosomal regions in the affected child, and a targeted gene enrichment panel consisting of 130 known deafness genes was negative for pathogenic mutations. The expression patterns in zebrafish and humans did not provide evidence for ear-specific functions of the ATE1 and SLC12A1 genes. Sanger sequencing of the 2 genes in the boy and 180 GJB2 mutation-negative hearing-impaired individuals did not detect homozygous or compound heterozygous pathogenic mutations. Our study demonstrates the many difficulties in unraveling the molecular causes of a heterogeneous phenotype. We cannot directly implicate disruption of ATE1 and/or SLC12A1 to the abnormal hearing phenotype; however, mutations in these genes may have a role in polygenic or multifactorial forms of hearing impairment. On the other hand, it is conceivable that our patient carries a disease-causing mutation in a so far unidentified deafness gene. Evidently, disruption of ATE1 and/or SLC12A1 gene function alone does not have adverse effects. PMID:24550759

Vona, B.; Neuner, C.; El Hajj, N.; Schneider, E.; Farcas, R.; Beyer, V.; Zechner, U.; Keilmann, A.; Poot, M.; Bartsch, O.; Nanda, I.; Haaf, T.

2014-01-01

180

Non-Invasive Bioluminescence Imaging to Monitor the Immunological Control of a Plasmablastic Lymphoma-Like B Cell Neoplasia after Hematopoietic Cell Transplantation  

PubMed Central

Abstract To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies. PMID:24349055

Chopra, Martin; Kraus, Sabrina; Schwinn, Stefanie; Ritz, Miriam; Mattenheimer, Katharina; Mottok, Anja; Rosenwald, Andreas; Einsele, Hermann; Beilhack, Andreas

2013-01-01

181

B Cell Super-Enhancers and Regulatory Clusters Recruit AID Tumorigenic Activity.  

PubMed

The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA(+) enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment. PMID:25483777

Qian, Jason; Wang, Qiao; Dose, Marei; Pruett, Nathanael; Kieffer-Kwon, Kyong-Rim; Resch, Wolfgang; Liang, Genqing; Tang, Zhonghui; Mathé, Ewy; Benner, Christopher; Dubois, Wendy; Nelson, Steevenson; Vian, Laura; Oliveira, Thiago Y; Jankovic, Mila; Hakim, Ofir; Gazumyan, Anna; Pavri, Rushad; Awasthi, Parirokh; Song, Bin; Liu, Geng; Chen, Longyun; Zhu, Shida; Feigenbaum, Lionel; Staudt, Louis; Murre, Cornelis; Ruan, Yijun; Robbiani, Davide F; Pan-Hammarström, Qiang; Nussenzweig, Michel C; Casellas, Rafael

2014-12-18

182

Bruton's Tyrosine Kinase Regulates the Activation of Gene Rearrangements at the l Light Chain Locus in Precursor B Cells in the Mouse  

Microsoft Academic Search

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase involved in precursor B (pre-B) cell receptor signaling. Here we demonstrate that Btk-deficient mice have an z 50% reduction in the frequency of immunoglobulin (Ig) l light chain expression, already at the immature B cell stage in the bone marrow. Conversely, transgenic mice expressing the activated mutant Btk E41K showed increased

Gemma M. Dingjan; Sabine Middendorp; Katarina Dahlenborg; Alex Maas; Frank Grosveld; Rudolf W. Hendriks

183

A cryptic wheat–Aegilops triuncialis translocation with leaf rust resistance gene Lr58  

Technology Transfer Automated Retrieval System (TEKTRAN)

Genes transferred to crop plants from wild species are often associated with deleterious traits. Using molecular markers, we detected a cryptic introgression with a leaf rust resistance gene transferred from Aegilops triuncialis L. into common wheat (Triticum aestivum L.). One agronomically desirabl...

184

The Ig heavy chain gene is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization.  

PubMed

Chromosome rearrangement of 14q32.33 has recurrently occurred with variable partner sites, including 11q13.3, 8q24.1, 18q21.3, and 6p21.1 in multiple myeloma (MM). To assess the actual incidence of 14q32.33 translocation and to elucidate its implication in the pathogenesis of MM, we studied 42 patients with MM, plasma cell leukemia, or plasmacytoma and 5 with monoclonal gammopathy with undetermined significance (MGUS) by G-banding and molecular cytogenetic methods. Using double-color fluorescence in situ hybridization (DCFISH) with 2 Ig heavy chain (IgH) gene probes, a yeast artificial chromosome (YAC) clone containing variable region, and a phage clone containing gamma constant region, 14q32.33 translocation was detected as split signals of the IgH gene in 31 patients with plasma cell malignancies and 3 with MGUS. In contrast, of 40 patients who were assessed by G-banding, 3 (7.5%) showed the 14q+ chromosome. DCFISH detected a split of the IgH gene on interphase nuclei in 34 (73.9%) of 46 patients analyzed, whereas on metaphase spreads, it was in 22 (51.2%) of 43 patients analyzed. Interphase DCFISH was particularly useful to detect 14q32.33 translocation in 17 (65.4%) of 26 patients with normal karyotypes. Donor sites were identified in 11 of 22 patients demonstrated as carrying 14q32.33 translocation by metaphase FISH. Chromosome t(11;14)(q13.3; q32.33) was detected in 5 patients, t(8;14)(q24.1;q32.33) in 2, t(14;18)(q32.33;q21.3) in 2, and t(7;14)(q32.1;q32.33) in 1. A complex 14q32.33 translocation involving 3q and 16q24 was detected in 1 patient. Myeloma cells with t(7;14) showed myelomonocytoid surface antigen. Because rearrangements of 14q32.33 were closely associated with translocation of proto-oncogenes into the IgH gene, our findings indicate that 14q32.33 translocation with various partner chromosomes is a critical event in the pathogenesis of MM and MGUS. PMID:9226151

Nishida, K; Tamura, A; Nakazawa, N; Ueda, Y; Abe, T; Matsuda, F; Kashima, K; Taniwaki, M

1997-07-15

185

Enhanced I kappa B alpha degradation is responsible for constitutive NF-kappa B activity in mature murine B-cell lines.  

PubMed Central

Nuclear factor kappa B (NF-kappa B) is a ubiquitous transcription factor which binds to decameric DNA sequences (kappa B sites) and regulates transcription of multiple genes. The activity of NF-kappa B is regulated by an inhibitor protein, I kappa B, which sequesters NF-kappa B in the cytoplasm. Release of I kappa B and subsequent nuclear translocation of NF-kappa B generally require activating signals. However, in mature murine B cells, the DNA-binding activity of NF-kappa B is constitutively nuclear and activates the Ig kappa gene, a marker for mature B cells. To understand the basis for the constitutive NF-kappa B activation, we examined the properties of NF-kappa B and I kappa B in both pre-B and mature B cells, the regulated and constitutive states, respectively. We found that expression of I kappa B alpha and p105, members of the I kappa B family, and Rel, a member of the NF-kappa B family, is augmented in mature B cells. Both I kappa B alpha and p 105 are associated with NF-kappa B proteins and sequester most of these proteins in the cytoplasm of mature B cells. However, rapid I kappa B alpha dissociation and degradation lead to continuous nuclear translocation of a small fraction of NF-kappa B proteins, which represent the constitutively active NF-kappa B in mature B cells. We estimate that the protease activity is at least 35-fold greater in mature B cells than in pre-B cells. Rapid degradation of I kappa B alpha is directly involved in constitutive NF-kappa B activation, because stabilization of I kappa B alpha by a protease inhibitor causes loss of NF-kappa B activity in mature B cells. These results provide evidence that continuous and rapid degradation of I kappa B alpha in the absence pf external stimuli is causally involved in the constitutive activation of NF-kappa B in mature murine B cells. Images PMID:8164680

Miyamoto, S; Chiao, P J; Verma, I M

1994-01-01

186

Driven by the same Ig enhancer and SV40 T promoter ras induced lung adenomatous tumors, myc induced pre-B cell lymphomas and SV40 large T gene a variety of tumors in transgenic mice.  

PubMed Central

Different types of tumors developed in transgenic mice following the introduction of the entire coding region of ras, myc or SV40 large T gene (T) linked to the same regulatory unit, consisting of a human immunoglobulin gene enhancer (Ig) and SV40 early gene promoter (Tp) with a 21-bp repeat. All the 12 transgenic mice harboring the intact T gene developed a variety of tumors including choroid plexus tumor, B cell lymphoma, histiocytic lymphoma, thymoma and others. This suggests that the Ig/Tp regulatory unit has transcriptional activity in these heterologous tissues. With this regulatory unit, myc gene induced solely pre-B cell lymphomas (five out of nine mice). Contrary to our expectation, however, the mutated ras gene induced lung adenomatous tumors in six out of eight transgenic mice over the 10-month observation period; the tumors are histologically comparable to adenocarcinomas in man. The tumors developed as early as 4 weeks after birth and the introduced ras gene was as efficiently expressed in both normal and neoplastic bronchioloalveolar epithelial cells as in normal lymphoid cells. An unidentified secondary event thus appears to be necessary for these ras-expressing cells to become neoplastic, as observed for myc (Leder et al., 1986). In a variety of tumors induced by Ig/Tp-T, on the other hand, T gene was expressed only in the tumor cells, but not in normal cells. Thus, derepression of T gene in normal cells appears to be closely related to their malignant change as observed in development of pancreatic acinar cell tumors by the T gene (Ornitz et al., 1985). These results suggest that ras and myc oncogenes penetrate differentially specific types of cells, while the SV40 T gene is tumorigenic in a variety of cell types. Images Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 7. PMID:2832150

Suda, Y; Aizawa, S; Hirai, S; Inoue, T; Furuta, Y; Suzuki, M; Hirohashi, S; Ikawa, Y

1987-01-01

187

MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy  

PubMed Central

MYC alterations influence the survival of patients with diffuse large B-cell lymphoma. Most studies have focused on MYC translocations but there is little information regarding the impact of numerical alterations and protein expression. We analyzed the genetic alterations and protein expression of MYC, BCL2, BCL6, and MALT1 in 219 cases of diffuse large B-cell lymphoma. MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple-hit) in 4%, MYC amplifications in 2% and MYC gains in 19%. MYC single-hit, MYC double/triple-hit and MYC amplifications, but not MYC gains or other gene rearrangements, were associated with unfavorable progression-free survival and overall survival. MYC protein expression, evaluated using computerized image analysis, captured the unfavorable prognosis of MYC translocations/amplifications and identified an additional subset of patients without gene alterations but with similar poor prognosis. Patients with tumors expressing both MYC/BCL2 had the worst prognosis, whereas those with double-negative tumors had the best outcome. High MYC expression was associated with shorter overall survival irrespectively of the International Prognostic Index and BCL2 expression. In conclusion, MYC protein expression identifies a subset of diffuse large B-cell lymphoma with very poor prognosis independently of gene alterations and other prognostic parameters. PMID:23716551

Valera, Alexandra; López-Guillermo, Armando; Cardesa-Salzmann, Teresa; Climent, Fina; González-Barca, Eva; Mercadal, Santiago; Espinosa, Íñigo; Novelli, Silvana; Briones, Javier; Mate, José L.; Salamero, Olga; Sancho, Juan M.; Arenillas, Leonor; Serrano, Sergi; Erill, Nadina; Martínez, Daniel; Castillo, Paola; Rovira, Jordina; Martínez, Antonio; Campo, Elias; Colomo, Luis

2013-01-01

188

Transcriptional analysis of the B cell germinal center reaction  

PubMed Central

The germinal center (GC) reaction is crucial for T cell-dependent immune responses and is targeted by B cell lymphomagenesis. Here we analyzed the transcriptional changes that occur in B cells during GC transit (naïve B cells ? centroblasts ? centrocytes ? memory B cells) by gene expression profiling. Naïve B cells, characterized by the expression of cell cycle-inhibitory and antiapoptotic genes, become centroblasts by inducing an atypical proliferation program lacking c-Myc expression, switching to a proapoptotic program, and down-regulating cytokine, chemokine, and adhesion receptors. The transition from GC to memory cells is characterized by a return to a phenotype similar to that of naïve cells except for an apoptotic program primed for both death and survival and for changes in the expression of cell surface receptors including IL-2 receptor ?. These results provide insights into the dynamics of the GC reaction and represent the basis for the analysis of B cell malignancies. PMID:12604779

Klein, Ulf; Tu, Yuhai; Stolovitzky, Gustavo A.; Keller, Jeffrey L.; Haddad, Joseph; Miljkovic, Vladan; Cattoretti, Giorgio; Califano, Andrea; Dalla-Favera, Riccardo

2003-01-01

189

Microarray Reveals Differences in Both Tumors and Vascular Specific Gene Expression in de Novo CD5 and CD5 Diffuse Large B-Cell Lymphomas1  

Microsoft Academic Search

Malignant lymphoma is a heterogeneous disease with different clinical features. Among diffuse large B-cell lymphomas (DLBCLs), a unique subtype has been identified recently based on cell surface marker CD5 and clinicopathological features. These de novo CD5 DLBCLs account for 10% of all of the DLBCLs and have poorer prognosis. To addition- ally understand this subtype of DLBCLs at the molecular

Tohru Kobayashi; Motoko Yamaguchi; Seungchan Kim; Jun Morikawa; Shoko Ogawa; Satoshi Ueno; Edward Suh; Edward Dougherty; Ilya Shmulevich; Hiroshi Shiku; Wei Zhang

190

T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus.  

PubMed

CD40 ligand (CD40LG), encoded on the X chromosome, has been reported to be overexpressed on lupus T cells. Herein, we investigated the effect of DNA demethylation on T cell CD40LG expression and the production of IgG by autologous B cells in lupus. We found normal human T cells transfected with CD40LG induced autologous B cell activation and plasma cell differentiation. Both female lupus CD4+ T cells and demethylating agents treated CD4+ T cells overexpressed CD40LG mRNA. Further, lupus T cells from both genders or demethylated CD4+ T cells from healthy women overstimulated autologous B cells, and this could be reversed with anti-CD40LG Ab in only females. We demonstrated that female lupus CD4+ T cells and demethylated CD4+ T cells express high level of CD40LG and overstimulate B cells to produce IgG. This is due to DNA demethylation and thereby reactivation of the inactive X chromosome in female. PMID:19520616

Zhou, Ying; Yuan, Jun; Pan, Yujun; Fei, Yiping; Qiu, Xiangning; Hu, Nan; Luo, Yongqi; Lei, Wenzhi; Li, Yaping; Long, Hai; Sawalha, Amr H; Richardson, Bruce; Lu, Qianjin

2009-09-01

191

B cell receptor signal strength determines B cell fate  

Microsoft Academic Search

B cell receptor (BCR)-mediated antigen recognition is thought to regulate B cell differentiation. BCR signal strength may also influence B cell fate decisions. Here, we used the Epstein-Barr virus protein LMP2A as a constitutively active BCR surrogate to study the contribution of BCR signal strength in B cell differentiation. Mice carrying a targeted replacement of Igh by LMP2A leading to

Kevin L Otipoby; Marat Alimzhanov; Sibille Humme; Nathalie Uyttersprot; Jeffery L Kutok; Michael C Carroll; Stefano Casola; Klaus Rajewsky

2004-01-01

192

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

SciTech Connect

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

Golub, T.; Barker, G.; Gilliland, D.G. [Harvard Medical School, Boston, MA (United States)] [and others

1994-09-01

193

Homeostasis of Peripheral B Cells in the Absence of B Cell Influx from the Bone Marrow  

PubMed Central

To study homeostasis of peripheral B lymphocytes in the absence of B cell influx from the bone marrow, we generated a mouse mutant in which the recombination-activating gene (RAG)-2 can be inducibly deleted. When RAG-2 was deleted at the age of 8–10 wk, splenic naive follicular B cells were gradually lost over a year of observation, with a half-life of ?4.5 mo. By contrast, the pool of marginal zone B cells in the spleen and of B-1 cells in the peritoneal cavity were kept at normal level. In lymph nodes, ?90% of the B cells were lost within 4 mo, and B cell numbers remained constant thereafter. Mice in which RAG-2 was deleted at birth maintained a small population of activated B cells with an increased proportion of marginal zone B cells. Additionally, an increase of the pool of IgM secreting cells and B-1a cells was observed. PMID:11602643

Hao, Zhenyue; Rajewsky, Klaus

2001-01-01

194

Intravascular large B cell lymphoma  

PubMed Central

Intravascular large B cell lymphoma (IVBCL) is a rare type of extranodal large B cell lymphoma characterized by selective growth of lymphoma cells within the microvasculature. We present an illustrative case of intravascular B cell lymphoma suspected by the presence of a very small monoclonal B cell population identified by immunophenotype and polymerase chain reaction in bone marrow. The diagnosis was confirmed by skin biopsy. PMID:24596677

García-Muñoz, Ricardo; Rubio-Mediavilla, Susana; Robles-de-Castro, Diego; Muñoz, Aura; Herrera-Pérez, Pilar; Rabasa, Pilar

2014-01-01

195

ATAD5 Deficiency Decreases B Cell Division and Igh Recombination.  

PubMed

Mammalian ATPase family AAA domain-containing protein 5 (ATAD5) and its yeast homolog enhanced level of genomic instability 1 are responsible for unloading proliferating cell nuclear antigen from newly synthesized DNA. Prior work in HeLa and yeast cells showed that a decrease in ATAD5 protein levels resulted in accumulation of chromatin-bound proliferating cell nuclear antigen, slowed cell division, and increased genomic instability. In this study, B cells from heterozygous (Atad5(+/m)) mice were used to examine the effects of decreased cell proliferation on Ab diversity. ATAD5 haploinsufficiency did not change the frequency or spectrum of somatic hypermutation in Ab genes, indicating that DNA repair and error-prone DNA polymerase ? usage were unaffected. However, immunized Atad5(+/m) mice had decreased serum IgG1 Abs, demonstrating a functional effect on class switch recombination. The mechanism of this altered immune response was then examined following ex vivo stimulation of splenic B cells, where Atad5(+/m) cells accumulated in the S phase of the cell cycle and had reduced proliferation compared with wild-type cells. These haploinsufficient cells underwent a significant decline in activation-induced deaminase expression, resulting in decreased switch region DNA double-strand breaks and interchromosomal translocations in the Igh locus. Class switch recombination to several isotypes was also reduced in Atad5(+/m) cells, although the types of end-joining pathways were not affected. These results describe a defect in DNA replication that affects Igh recombination via reduced cell division. PMID:25404367

Zanotti, Kimberly J; Maul, Robert W; Castiblanco, Diana P; Yang, William; Choi, Yong Jun; Fox, Jennifer T; Myung, Kyungjae; Saribasak, Huseyin; Gearhart, Patricia J

2015-01-01

196

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

197

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

198

Innate control of B cell responses  

PubMed Central

Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus it must be integrated with a faster, T cell-independent pathway for B cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly at the mucosal interface. We also review the role of innate signals in the regulation of Ig diversification and production PMID:21419699

Cerutti, Andrea; Puga, Irene; Cols, Montserrat

2011-01-01

199

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

200

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

201

Fusion of the ZC3H7B and BCOR genes in endometrial stromal sarcomas carrying an X;22-translocation.  

PubMed

Endometrial stromal sarcomas (ESS) are genetically heterogeneous uterine tumors in which a JAZF1-SUZ12 chimeric gene resulting from the chromosomal translocation t(7;17)(p15;q21) as well as PHF1 rearrangements (in chromosomal band 6p21) with formation of JAZF1-PHF1, EPC1-PHF1, and MEAF6-PHF1 chimeras have been described. Here, we investigated two ESS characterized cytogenetically by the presence of a der(22)t(X;22)(p11;q13). Whole transcriptome sequencing one of the tumors identified a ZC3H7-BCOR chimeric transcript. Reverse transciptase-PCR with the ZC3H7B forward and BCOR reverse primer combinations confirmed the presence of a ZC3H7-BCOR chimeric transcript in both ESS carrying a der(22)t(X;22) but not in a control ESS with t(1;6) and the MEAF6-PHF1 fusion. Sequencing of the amplified cDNA fragments showed that in both cases ESS exon 10 of ZC3H7B (from 22q13; accession number NM_017590 version 4) was fused to exon 8 of BCOR (from Xp11; accession number NM_001123385 version 1). Reciprocal multiple BCOR-ZC3H7B cDNA fragments were amplified in only one case suggesting that ZC3H7B-BCOR, on the der(22)t(X;22), is the pathogenetically important fusion gene. The putative ZC3H7B-BCOR protein would contain the tetratricopeptide repeats and LD motif from ZC3H7B and the AF9 binding site (1093-1233aa), the 3 ankyrin repeats (1410-1509 aa), and the NSPC1 binding site of BCOR. Although the presence of these motifs suggests various functions of the chimeric protein, it is possible that its most important role may be in epigenetic regulation. Whether or not the (patho)genetic subsets JAZF1-SUZ12, PHF1 rearrangements, and ZC3H7B-BCOR correspond to any phenotypic, let alone clinically important, differences in ESS remain unknown. PMID:23580382

Panagopoulos, Ioannis; Thorsen, Jim; Gorunova, Ludmila; Haugom, Lisbeth; Bjerkehagen, Bodil; Davidson, Ben; Heim, Sverre; Micci, Francesca

2013-07-01

202

Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire  

PubMed Central

The human peripheral B cell compartment displays a large population of IgM+IgD+CD27+ “memory” B cell carrying a mutated Ig receptor. We show here, by phenotypic analysis, CDR3 spectratyping during a T-independent response and gene expression profiling of the different blood and splenic B cell subsets, that blood IgM+IgD+CD27+ cells correspond to circulating splenic marginal zone B cells. Furthermore, analysis of this peripheral subset in normal children below 2 years shows that these B cells develop and mutate their Ig receptor during ontogeny, prior to their differentiation into T-independent antigen-responsive cells. It is therefore proposed that these IgM+IgD+CD27+ B cells provide the splenic marginal zone with a diversified and protective pre-immune repertoire in charge of the responses against encapsulated bacteria. PMID:15191950

Weller, Sandra; Braun, Moritz C.; Tan, Bruce K.; Rosenwald, Andreas; Cordier, Corinne; Conley, Mary Ellen; Plebani, Alessandro; Kumararatne, Dinakhanta S.; Bonnet, Damien; Tournilhac, Olivier; Tchernia, Gil; Steiniger, Birte; Staudt, Louis M.; Casanova, Jean-Laurent; Reynaud, Claude-Agnès; Weill, Jean-Claude

2004-01-01

203

Extra Copies of der(21)t(12;21) plus Deletion of ETV6 Gene due to dic(12;18) in B-Cell Precursor ALL with Poor Outcome.  

PubMed

Acute lymphoblastic leukemia (ALL), CD10+ B-cell precursor, represents the most frequent type of childhood ALL from 3 to 6 years of age. The t(12;21)(p13;q22) occurs in 25% of cases of B-cell precursor ALL, it is rare in children less than 24 months and have been related to good prognosis. Some relapse cases and unfavorable prognosis in ALL CD10+ are associated with t(12;21) bearing additional aberrations as extra copies of chromosome 21 and ETV6 gene loss. This report describes the case of a 15 month-year old girl, who displayed a karyotype with addition on chromosome 12p plus trisomy 10 and tetrasomy of chromosome 21. Molecular cytogenetic studies revealed two extra copies of the der(21) t(12;21), trisomy 10 and deletion of the second ETV6 gene due to the dic(12;18). These findings show the great importance of molecular cytogenetic studies to clarify complex karyotypes, to define prognostic, to carry out risk group stratification and to support correctly disease treatment in childhood acute lymphoblastic leukemia. PMID:23074685

Hernandes, Marina Araújo Fonzar; Marques-Salles, Terezinha de Jesus; Mkrtchyan, Hasmik; Soares-Ventura, Eliane Maria; Leite, Edinalva Pereira; Muniz, Maria Tereza Cartaxo; Cornélio, Maria Teresa Marquim Nogueira; Liehr, Thomas; Santos, Neide; Silva, Maria Luiza Macedo

2012-01-01

204

Extra Copies of der(21)t(12;21) plus Deletion of ETV6 Gene due to dic(12;18) in B-Cell Precursor ALL with Poor Outcome  

PubMed Central

Acute lymphoblastic leukemia (ALL), CD10+ B-cell precursor, represents the most frequent type of childhood ALL from 3 to 6 years of age. The t(12;21)(p13;q22) occurs in 25% of cases of B-cell precursor ALL, it is rare in children less than 24 months and have been related to good prognosis. Some relapse cases and unfavorable prognosis in ALL CD10+ are associated with t(12;21) bearing additional aberrations as extra copies of chromosome 21 and ETV6 gene loss. This report describes the case of a 15 month-year old girl, who displayed a karyotype with addition on chromosome 12p plus trisomy 10 and tetrasomy of chromosome 21. Molecular cytogenetic studies revealed two extra copies of the der(21) t(12;21), trisomy 10 and deletion of the second ETV6 gene due to the dic(12;18). These findings show the great importance of molecular cytogenetic studies to clarify complex karyotypes, to define prognostic, to carry out risk group stratification and to support correctly disease treatment in childhood acute lymphoblastic leukemia. PMID:23074685

Hernandes, Marina Araújo Fonzar; Marques-Salles, Terezinha de Jesus; Mkrtchyan, Hasmik; Soares-Ventura, Eliane Maria; Leite, Edinalva Pereira; Muniz, Maria Tereza Cartaxo; Cornélio, Maria Teresa Marquim Nogueira; Liehr, Thomas; Santos, Neide; Silva, Maria Luiza Macedo

2012-01-01

205

Role of Bruton's Tyrosine Kinase in B Cell Development  

PubMed Central

X-linked agammaglobulinemia (XLA) is one of the most frequent inherited immunodeficiency diseases in man and is characterized by an almost complete arrest of B cell differentiation at the pre-B cell stage. The gene defective in XLA encodes the cytoplasmic signaling molecule Bruton's tyrosine kinase (Btk). Next to the CBA/N strain of mice, carrying a single amino acid substitution mutation in the Btk gene, which results in the X-linked immunodeficiency (xid) phenotype, additional mouse models have been developed to study the role of Btk in vivo. This review discusses the analyses of Btk null-mutants, obtained by gene targeting in embryonic stem cells, and transgenic mice that express wild-type or mutated forms of the Btk gene. These studies provided information on the function of Btk at several important checkpoints throughout B cell development. Analyses of the mouse models indicated that Btk is not essential for pre-B cell receptor signaling in the mouse. By contrast, Btk-mediated B cell receptor signaling appears to be required for the survival of immature B cells in the bone marrow, that have performed a successful immunoglobulin (Ig) L chain locus rearrangement, resultirig in the expression of a non-autoreactive Ig on the membrane. Btk is also shown to be involved in signaling pathways that govern the development of peripheral B cells, including follicular entry, follicular maturation and plasma cell differentiation. PMID:11785667

Maas, Alex

2001-01-01

206

A homozygous balanced reciprocal translocation suggests LINC00237 as a candidate gene for MOMO (macrosomia, obesity, macrocephaly, and ocular abnormalities) syndrome.  

PubMed

Macrosomia, obesity, macrocephaly, and ocular abnormalities syndrome (MOMO syndrome) has been reported in only four patients to date. In these sporadic cases, no chromosomal or molecular abnormality has been identified thus far. Here, we report on the clinical, cytogenetic, and molecular findings in a child of healthy consanguineous parents suffering from MOMO syndrome. Conventional karyotyping revealed an inherited homozygous balanced reciprocal translocation (16;20)(q21;p11.2). Uniparental disomy testing showed bi-parental inheritance for both derivative chromosomes 16 and 20. The patient's oligonucleotide array-comparative genomic hybridization profile revealed no abnormality. From the homozygous balanced reciprocal translocation (16;20)(q21;p11.2), a positional cloning strategy, designed to narrow 16q21 and 20p11.2 breakpoints, revealed the disruption of a novel gene located at 20p11.23. This gene is now named LINC00237, according to the HUGO (Human Genome Organization) nomenclature. The gene apparently leads to the production of a non-coding RNA. We established that LINC00237 was expressed in lymphocytes of control individuals while normal transcripts were absent in lymphocytes of our MOMO patient. LINC00237 was not ubiquitously expressed in control tissues, but it was notably highly expressed in the brain. Our results suggested autosomal recessive inheritance of MOMO syndrome. LINC00237 could play a role in the pathogenesis of this syndrome and could provide new insights into hyperphagia-related obesity and intellectual disability. PMID:23034868

Vu, Phi Yen; Toutain, Jérôme; Cappellen, David; Delrue, Marie-Ange; Daoud, Hussein; El Moneim, Azza Abd; Barat, Pascal; Montaubin, Orianne; Bonnet, Françoise; Dai, Zong Qi; Philippe, Christophe; Tran, Cong Toai; Rooryck, Caroline; Arveiler, Benoît; Saura, Robert; Briault, Sylvain; Lacombe, Didier; Taine, Laurence

2012-11-01

207

Transcription of the Tollip gene is elevated in intestinal epithelial cells through impaired O-GlcNAcylation-dependent nuclear translocation of the negative regulator Elf-1  

SciTech Connect

Highlights: {yields} Transcriptional activation of the Tollitip gene is higher in IECs than in monocytes. {yields} Nt -194/-186 region acts as a cis-element and is recognized by Elf-1. {yields} Elf-1 suppresses Tollip gene transcription in monocytes but not in IECs. {yields} O-GlcNAc modification is necessary for nuclear translocation of Elf-1. {yields} O-GlcNAcylation-dependent nuclear translocation of Elf-1 is impaired in IECs. -- Abstract: Intestinal epithelial cells (IECs) must be tolerant of the large number of commensal bacteria inhabiting the intestinal tract to avoid excessive inflammatory reactions. Toll-interacting protein (Tollip), a negative regulator of Toll-like receptor signaling, is known to be expressed at high levels in IECs, and to thereby contribute to the hyporesponsiveness of IECs to commensals. In this study, we analyzed the underlying mechanisms for elevated transcription of the Tollip gene in IECs using a human IEC line, Caco-2, and a human monocyte line, THP-1, as a control. Elf-1 was identified as a transcription factor that negatively regulates Tollip gene expression. The transcription factor Elf-1 was localized in the nucleus by O-linked N-acetylglucosamine (O-GlcNAc) modification, whereas the unmodified form was detected only in the cytoplasm. Comparison of Caco-2 and THP-1 cells revealed that O-GlcNAc modification of Elf-1 was significantly lower in IECs than in monocytes. Collectively, the results indicate that insufficient O-GlcNAc modification prevents Elf-1-mediated transcriptional repression and thereby upregulates Tollip gene expression in IECs.

Sugi, Yutaka [College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880 (Japan)] [College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880 (Japan); Takahashi, Kyoko, E-mail: ktaka@brs.nihon-u.ac.jp [College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880 (Japan)] [College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880 (Japan); Nakano, Kou; Hosono, Akira; Kaminogawa, Shuichi [College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880 (Japan)] [College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880 (Japan)

2011-09-09

208

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; Compérat, Eva; Couturier, Jérôme; Molinié, 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

209

Memory B cells: effectors of long-lived immune responses.  

PubMed

Immunological memory is the phenomenon whereby B and T cells have the unique ability to respond with heightened kinetics and efficacy to subsequent encounter with Ag relative to the initial exposure. In this review, we examine recent developments in the phenotypic characterisation of memory B cells, with an emphasis on the definition and functional properties of memory B-cell subsets in humans. Gene expression differences are also considered in light of the unique functional and survival properties of memory B cells, and mutations that alter memory formation and function are also examined. Finally, we consider recent advances in the understanding of germinal center B-cell differentiation through analysis of transcription factor networks operating in these B cells. PMID:19637202

Tangye, Stuart G; Tarlinton, David M

2009-08-01

210

Inter-organ signaling in plants: regulation of ATP sulfurylase and sulfate transporter genes expression in roots mediated by phloem-translocated compound.  

PubMed

Sulfate uptake and ATP sulfurylase activity in the roots of Arabidopsis thaliana and Brassica napus were enhanced by S deprivation and reduced following resupply of SO4(2-). Similar responses occurred in split-root experiments where only a portion of the root system was S-deprived, suggesting that the regulation involves inter-organ signaling. Phloem-translocated glutathione (GSH) was identified as the likely transducing molecule responsible for regulating SO4(2-) uptake rate and ATP sulfurylase activity in roots. The regulatory role of GSH was confirmed by the finding that ATP sulfurylase activity was inhibited by supplying Cys except in the presence of buthionine sulfoximine, an inhibitor of GSH synthesis. In direct and remote (split-root) exposures, levels of protein detected by antibodies against the Arabidopsis APS3 ATP sulfurylase increased in the roots of A. thaliana and B. napus during S starvation, decreased after SO4(2-) restoration, and declined after feeding GSH. RNA blot analysis revealed that the transcript level of APS1, which codes for ATP sulfurylase, was reduced by direct and remote GSH treatments. The abundance of AST68 (a gene encoding an SO4(2-) transporter) was similarly affected by altered sulfur status. This report presents the first evidence for the regulation of root genes involved in nutrient acquisition and assimilation by a signal that is translocated from shoot to root. PMID:10341446

Lappartient, A G; Vidmar, J J; Leustek, T; Glass, A D; Touraine, B

1999-04-01

211

ABSENCE OF SCLEROSTIN ADVERSELY AFFECTS B CELL SURVIVAL  

PubMed Central

Increased osteoblast activity in sclerostin-knockout (Sost?/?) mice results in generalized hyperostosis and bones with small bone marrow cavities due to hyperactive mineralizing osteoblast populations. Hematopoietic cell fate decisions are dependent on their local microenvironment, which contains osteoblast and stromal cell populations that support both hematopoietic stem cell quiescence and facilitate B cell development. In this study, we investigated whether high bone mass environments affect B cell development via the utilization of Sost?/? mice, a model of sclerosteosis. We found the bone marrow of Sost?/? mice to be specifically depleted of B cells, due to elevated apoptosis at all B cell developmental stages. In contrast, B cell function in the spleen was normal. Sost expression analysis confirmed that Sost is primarily expressed in osteocytes and is not expressed in any hematopoietic lineage, which indicated that the B cell defects in Sost?/? mice are non-cell autonomous and this was confirmed by transplantation of wildtype (WT) bone marrow into lethally irradiated Sost?/? recipients. WT?Sost?/? chimeras displayed a reduction in B cells, whereas reciprocal Sost?/??WT chimeras did not, supporting the idea that the Sost?/? bone environment cannot fully support normal B cell development. Expression of the pre-B cell growth stimulating factor, Cxcl12, was significantly lower in bone marrow stromal cells of Sost?/? mice while the Wnt target genes Lef-1 and Ccnd1 remained unchanged in B cells. Taken together, these results demonstrate a novel role for Sost in the regulation of bone marrow environments that support B cells. PMID:22434688

Cain, Corey J.; Rueda, Randell; McLelland, Bryce; Collette, Nicole M.; Loots, Gabriela G.; Manilay, Jennifer O.

2012-01-01

212

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

213

IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity  

PubMed Central

The transcription factor interferon regulatory factor-4 (IRF4) is expressed in B cells at most developmental stages. In antigen-activated B cells, IRF4 controls germinal center formation, class-switch recombination, and the generation of plasma cells. Here we describe a novel function for IRF4 in the homeostasis of mature B cells. Inducible deletion of irf4 specifically in B cells in vivo led to the aberrant accumulation of irf4-deleted follicular B cells in the marginal zone (MZ) area. IRF4-deficient B cells showed elevated protein expression and activation of NOTCH2, a transmembrane receptor and transcriptional regulator known to be required for MZ B cell development. Administration of a NOTCH2-inhibitory antibody abolished nuclear translocation of NOTCH2 in B cells within 12 h and caused a rapid and progressive disintegration of the MZ that was virtually complete 48 h after injection. The disappearance of the MZ was accompanied by a transient increase of MZ-like B cells in the blood rather than increased B cell apoptosis, demonstrating that continued NOTCH2 activation is critical for the retention of B cells in the MZ. Our results suggest that IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression. These findings may have implications for the understanding of B cell malignancies with dysregulated IRF4 and NOTCH2 activity. PMID:24323359

Simonetti, Giorgia; Carette, Amanda; Silva, Kathryn; Wang, Haowei; De Silva, Nilushi S.; Heise, Nicole; Siebel, Christian W.; Shlomchik, Mark J.

2013-01-01

214

Human B cell defects in perspective  

PubMed Central

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

2012-01-01

215

B cell biology: an overview.  

PubMed

In this review we summarize recent insights into the development of human B cells primarily by studying immunodeficiencies. Development and differentiation of B cells can be considered as a paradigm for many other developmental processes in cell biology. However, it differs from the development of many other cell types by phases of extremely rapid cell division and by defined series of somatic recombination and mutation events required to assemble and refine the B cell antigen receptors. Both somatic DNA alteration and proliferation phases take place in defined sites but in different organs. Thus, cell migration and timely arrival at defined sites are additional features of B cell development. By comparing experimental mouse models with insights gained from studying defined genetic defects leading to primary immunodeficiencies and hypogammaglobulinemia, we address important features that are characteristic for human B cells. We also summarize recent advances made by developing improved in vitro and in vivo systems allowing the development of human B cells from hematopoietic stem cells. Combined with genetic and functional studies of immunodeficiencies, these models will contribute not only to a better understanding of disease affecting the B lymphocyte compartment, but also to designing better and safer novel B cell-targeted therapies in autoimmunity and allergy. PMID:24633618

Eibel, Hermann; Kraus, Helene; Sic, Heiko; Kienzler, Anne-Kathrin; Rizzi, Marta

2014-05-01

216

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

217

The Rice COLEOPTILE PHOTOTROPISM1 gene encoding an ortholog of Arabidopsis NPH3 is required for phototropism of coleoptiles and lateral translocation of auxin.  

PubMed

We isolated a mutant, named coleoptile phototropism1 (cpt1), from gamma-ray-mutagenized japonica-type rice (Oryza sativa). This mutant showed no coleoptile phototropism and severely reduced root phototropism after continuous stimulation. A map-based cloning strategy and transgenic complementation test were applied to demonstrate that a NPH3-like gene deleted in the mutant corresponds to CPT1. Phylogenetic analysis of putative CPT1 homologs of rice and related proteins indicated that CPT1 has an orthologous relationship with Arabidopsis thaliana NPH3. These results, along with those for Arabidopsis, demonstrate that NPH3/CPT1 is a key signal transduction component of higher plant phototropism. In an extended study with the cpt1 mutant, it was found that phototropic differential growth is accompanied by a CPT1-independent inhibition of net growth. Kinetic investigation further indicated that a small phototropism occurs in cpt1 coleoptiles. This response, induced only transiently, was thought to be caused by the CPT1-independent growth inhibition. The 3H-indole-3-acetic acid applied to the coleoptile tip was asymmetrically distributed between the two sides of phototropically responding coleoptiles. However, no asymmetry was induced in cpt1 coleoptiles, indicating that lateral translocation of auxin occurs downstream of CPT1. It is concluded that the CPT1-dependent major phototropism of coleoptiles is achieved by lateral auxin translocation and subsequent growth redistribution. PMID:15598797

Haga, Ken; Takano, Makoto; Neumann, Ralf; Iino, Moritoshi

2005-01-01

218

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

219

Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins  

PubMed Central

The Mef2 family transcriptional regulator Mef2c (myocyte enhancer factor 2c) is highly expressed in maturing bone marrow and peripheral mature B-cells. To evaluate the role of this transcription factor in B-cell development, we generated a B-cell-specific conditional deletion of Mef2c using the Mb-1-Cre transgene that is expressed during the early stages of immunoglobulin rearrangement. Young mice possessing this defect demonstrated a significant impairment in B-cell numbers in bone marrow and spleen. This phenotype was evident in all B-cell subsets; however, as the animals mature, the deficit in the peripheral mature B-cell compartments was overcome. The absence of Mef2c in mature B-cells led to unique CD23+ and CD23? subsets that were evident in Mef2c knockout primary samples as well as Mef2c-deficient cultured, differentiated B-cells. Genome-wide expression analysis of immature and mature B-cells lacking Mef2c indicated altered expression for a number of key regulatory proteins for B-cell function including Ciita, CD23, Cr1/Cr2 and Tnfsf4. Chromatin immunoprecipitation analysis confirmed Mef2c binding to the promoters of these genes indicating a direct link between the presence (or absence) of Mef2c and altered transcriptional control in mature B-cells. PMID:23087187

Debnath, Irina; Roundy, Kirstin M.

2013-01-01

220

Accumulation of Self-Reactive Naïve and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjögren’s Syndrome  

PubMed Central

Sjögren’s syndrome (SS) is an autoimmune disease characterised by breach of self-tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naïve and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naïve and memory compartment of SS patients. Single CD27?IgD+ naïve, CD27+IgD+ memory unswitched and CD27+IgD? memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig VH and VL genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs) displaying identical specificity of the original B cells. IgVH and VL gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD). From a total of 353 VH and 293 VL individual sequences, we obtained 114 rmAbs from circulating naïve (n?=?66) and memory (n?=?48) B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naïve B cells (with germline VH and VL genes) displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%). Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naïve (9.3%), memory unswitched (22.2%) and memory switched (27.3%) B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naïve and memory B cells. PMID:25535746

Corsiero, Elisa; Sutcliffe, Nurhan; Pitzalis, Costantino; Bombardieri, Michele

2014-01-01

221

A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia  

Microsoft Academic Search

FISH identified a cryptic t(5;14)(q35;q32) in T acute lymphoblastic leukemia (ALL), whereas it was not observed in B ALL samples. This translocation is present in five out of 23 (22%) children and adolescents with T ALL tested. RanBP17, a gene coding for a member of the importin ? protein family, and Hox11Like2, an orphan homeobox gene were mapped close to

OA Bernard; M Busson-LeConiat; P Ballerini; M Mauchauffé; V Della Valle; R Monni; F Nguyen Khac; T Mercher; V Penard-Lacronique; P Pasturaud; L Gressin; R Heilig; M-T Daniel; M Lessard; R Berger

2001-01-01

222

PDK1 regulates B cell differentiation and homeostasis  

PubMed Central

Successful B cell differentiation and prevention of cell transformation depends on balanced and fine-tuned activation of cellular signaling pathways. The phosphatidyl inositol-3 kinase (PI3K) signaling pathway has emerged as a major regulator of B lymphocyte homeostasis and function. Phosphoinositide-dependent protein kinase-1 (PDK1) is the pivotal node in the PI3K pathway, regulating the stability and activity of downstream AGC kinases (including Akt, RSK, S6K, SGK, and PKC). Although the importance of PI3K activity in B cell differentiation is well documented, the role of PDK1 and other downstream effectors is underexplored. Here we used inducible and stage-specific gene targeting approaches to elucidate the role of PDK1 in early and peripheral B cell differentiation. PDK1 ablation enhanced cell cycle entry and apoptosis of IL-7–dependent pro-B cells, blocking Ig synthesis and B cell maturation. PDK1 also was essential for the survival and activation of peripheral B cells via regulation of PKC and Akt-dependent downstream effectors, such as GSK3?/? and Foxo1. We found that PDK1 deletion strongly impaired B cell receptor (BCR) signaling, but IL-4 costimulation was sufficient to restore BCR-induced proliferation. IL-4 also normalized PKC? activation and hexokinase II expression in BCR-stimulated cells, suggesting that this signaling pathway can act independent of PDK1 to support B cell growth. In summary, our results demonstrate that PDK1 is indispensable for B cell survival, proliferation, and growth regulation. PMID:24979759

Baracho, Gisele V.; Cato, Matthew H.; Zhu, Zilu; Jaren, Olav R.; Hobeika, Elias; Reth, Michael; Rickert, Robert C.

2014-01-01

223

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

224

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

225

The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22)(q24.13;q11.21) in a young girl with dysgerminoma  

PubMed Central

Background RNF139/TRC8 is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. TRC8 has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC) and thyroid cancers. Haploinsufficiency of TRC8 may facilitate development of clear cell-RCC in association with VHL mutations, and may increase risk for other tumor types. We report a paternally inherited balanced translocation t(8;22) in a proposita with dysgerminoma. Methods The translocation was characterized by FISH and the breakpoints cloned, sequenced, and compared. DNA isolated from normal and tumor cells was checked for abnormalities by array-CGH. Expression of genes TRC8 and TSN was tested both on dysgerminoma and in the proposita and her father. Results The breakpoints of the translocation are located within the LCR-B low copy repeat on chromosome 22q11.21, containing the palindromic AT-rich repeat (PATRR) involved in recurrent and non-recurrent translocations, and in an AT-rich sequence inside intron 1 of the TRC8 tumor-suppressor gene at 8q24.13. TRC8 was strongly underexpressed in the dysgerminoma. Translin is underexpressed in the dysgerminoma compared to normal ovary. TRC8 is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells. Conclusion A role for TRC8 in dysgerminoma may relate to its interaction with Translin. We propose a model in which one copy of TRC8 is disrupted by a palindrome-mediated translocation followed by complete loss of expression through suppression, possibly mediated by miRNA. PMID:19642973

Gimelli, Stefania; Beri, Silvana; Drabkin, Harry A; Gambini, Claudio; Gregorio, Andrea; Fiorio, Patrizia; Zuffardi, Orsetta; Gemmill, Robert M; Giorda, Roberto; Gimelli, Giorgio

2009-01-01

226

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

PubMed

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. PMID:8455624

Baler, R; Dahl, G; Voellmy, R

1993-04-01

227

BACH2-BCL6 balance regulates selection at the pre-B cell receptor checkpoint.  

PubMed

At the pre-B cell receptor (BCR) checkpoint, developing pre-B cells are selected for successful rearrangement of V(H)-DJ(H) gene segments and expression of a pre-BCR. Reduced stringency at this checkpoint may obstruct the B cell repertoire with nonfunctional B cell clones. Earlier studies have described that activation of B cell lymphoma/leukemia (BCL)6 by a functional pre-BCR mediates positive selection of pre-B cells that have passed the checkpoint. This concept is now further elaborated by the recent finding that the BTB and CNC homology 1 basic leucine zipper transcription factor 2 (BACH2) induces negative selection and opposes BCL6 function prior to the pre-BCR checkpoint. Here, we discuss the antagonism between BCL6 and BACH2 during early B cell development, as well as its implications in both repertoire selection and counter-selection of premalignant clones for leukemia suppression. PMID:24332591

Swaminathan, Srividya; Duy, Cihangir; Müschen, Markus

2014-03-01

228

Interleukin-6 plasma levels are modulated by a polymorphism in the NF-?B1 gene and are associated with outcome following rituximab-combined chemotherapy in diffuse large B-cell non-Hodgkin lymphoma.  

PubMed

Peripheral blood cytokines are known prognostic parameters in diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy, but their role after the introduction of rituximab is unknown. Seven polymorphisms in the promoter regions of IL-6, IL-10 and NF-?B1 genes were assessed in 167 patients with DLBCL and 99 controls and correlated with interleukin-6 (IL-6) and IL-10 plasma levels. Outcome was analyzed in 137 patients treated with rituximab-based chemotherapy. The NF-?B1 - 94ATTG deletion was associated with increased IL-6 and IL-10 in DLBCL. High IL-6 concentration correlated with unfavorable prognostic factors included in the international prognostic index (IPI) and predicted for inferior progression-free (p = 0.007) and overall survival (p = 0.02). IL-6 levels remained a significant outcome predictor also including IPI as a covariate (p = 0.006 for progression-free survival). Our data suggest that the NF-?B1 genetic background influences IL-6 production in DLBCL, and that high IL-6 concentration is an independent prognostic factor also in the "rituximab era." PMID:21902578

Giachelia, Manuela; Voso, Maria Teresa; Tisi, Maria Chiara; Martini, Maurizio; Bozzoli, Valentina; Massini, Giuseppina; D'Aló, Francesco; Larocca, Luigi Maria; Leone, Giuseppe; Hohaus, Stefan

2012-03-01

229

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; García, Diego; Vicente, Yolanda; Kilany, Linah; Abraira, Victor; Navarro, Belen; Provencio, Mariano; Martín, Paloma

2014-01-01

230

Nonequilibrium Dynamics of Polymer Translocation  

NASA Astrophysics Data System (ADS)

When a flexible chain is pulled or sucked, it can initially respond only locally, and sequential nonequilibrium processes with large conformational distortion follow in line with the propagation of tensile force along the chain backbone. This is a generic dynamical response property of polymers, the understanding of which provides us with a viewpoint to capture an essential aspect of the driven translocation process. In the meeting, I will summarize a basic framework to analyze the nonequilibrium dynamics of driven translocation process alongside of recent progresses. [4pt] References:[0pt] T. Sakaue, Phys. Rev. E, 76, 021803 (2007) ``Nonequilibrium dynamics of polymer translocation and straightening''[0pt] T. Sakaue, Phys. Rev. E, 81, 041808 (2010) ``Sucking genes into pores: Insight into driven translocation''[0pt] T. Saito and T. Sakaue, Eur. Phys. J. E, 34, 145 (2011) ``Dynamical diagram and scaling in polymer driven translocation''[0pt] T. Saito and T. Sakaue, Phys. Rev. E, 85, 061803 (2012) ``Process time distribution of driven polymer transport''

Sakaue, Takahiro

2013-03-01

231

Overexpression of BclXL in B Cells Promotes Th1 Response and Exacerbates Collagen-Induced Arthritis  

Microsoft Academic Search

B cells play a pathogenic or regulatory role in many autoimmune diseases through production of autoantibodies, cytokine pro- duction, and Ag presentation. However, the mechanisms that regulate these B cell functions under different autoimmune settings remain unclear. In the current study, we found that when B cells overexpress an antiapoptotic gene, BclXL, they significantly increased production of IFN- and enhanced

Biao Zheng; Ekaterina Marinova; Kirsten Switzer; Daniel Wansley; Hongxia He; Roy Bheekha-Escura; Timothy W. Behrens; Shuhua Han

2007-01-01

232

Expression pattern of the most J[sub H]-proximal human V[sub H] gene segment (V[sub H]6) in the B cell and antibody repertoire suggests a role of V[sub H]6-encoded IgM antibodies in early ontogeny  

SciTech Connect

The authors have developed a mAb (JE-6) that recognizes an Id encoded by the most J[sub H]-proximal human V[sub H] gene segment (V[sub H]6) in or near germ-line configuration. This mAb was used to determine the frequency of Id JE6[sup +] B cells in large collections of monoclonal EBV-transformed and short term B cell lines derived from fetal, neonatal, and adult lymphoid tissues. Moreover, they investigated the presence of Id JE-6[sup +] lg in sera from neonates and adults and determined the (auto)antigen binding properties of V[sub H]6-encoded IgM mAb. They detected a fivefold overrepresentation of V[sub H]6-expression IgM producing B cells in fetal tissues, cord blood, and adult bone marrow relative to adult blood. In cord blood, but not in adult blood sera, germ-line V[sub H]6-encoded IgM molecules were readily detectable. IgM secreted by V[sub H]6-expressing B cell clones displayed highly conserved and virtually identical autoantigen binding properties, independent of the length and composition of the IgH chain CDR3 region and L chain isotype. Collectively, these results suggest that the V[sub H]6 gene and the antibodies it encodes play an important role in early human ontogeny. 31 refs., 3 figs., 2 tabs.

Van Es, J.H.; Tol, M.J.D. van; Gmelig Meyling, F.H.J.; Logtenberg, T. (University Hospital, Utrecht (Netherlands)); Raaphorst, F.M. (University Hospital, Leiden (Netherlands))

1993-01-01

233

FOXP1 potentiates Wnt/?-catenin signaling in diffuse large B cell lymphoma.  

PubMed

The transcription factor FOXP1 (forkhead box protein P1) is a master regulator of stem and progenitor cell biology. In diffuse large B cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased abundance of FOXP1 in DLBCL is a predictor of poor prognosis and resistance to therapy. We developed a genome-wide, mass spectrometry-coupled, gain-of-function genetic screen, which revealed that FOXP1 potentiates ?-catenin-dependent, Wnt-dependent gene expression. Gain- and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved enhancer of Wnt signaling. In a Wnt-dependent fashion, FOXP1 formed a complex with ?-catenin, TCF7L2 (transcription factor 7-like 2), and the acetyltransferase CBP [CREB (adenosine 3',5'-monophosphate response element-binding protein)-binding protein], and this complex bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of ?-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of ?-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking ?-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with ?-catenin-dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL. PMID:25650440

Walker, Matthew P; Stopford, Charles M; Cederlund, Maria; Fang, Fang; Jahn, Christopher; Rabinowitz, Alex D; Goldfarb, Dennis; Graham, David M; Yan, Feng; Deal, Allison M; Fedoriw, Yuri; Richards, Kristy L; Davis, Ian J; Weidinger, Gilbert; Damania, Blossom; Major, Michael B

2015-02-01

234

Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma.  

PubMed

The pathogenesis of primary mediastinal large B-cell lymphoma (PMBCL) is incompletely understood. Recently, specific genotypic and phenotypic features have been linked to tumor cell immune escape mechanisms in PMBCL. We studied 571 B-cell lymphomas with a focus on PMBCL. Using fluorescence in situ hybridization here, we report that the programmed death ligand (PDL) locus (9p24.1) is frequently and specifically rearranged in PMBCL (20%) as compared with diffuse large B-cell lymphoma, follicular lymphoma, and Hodgkin lymphoma. Rearrangement was significantly correlated with overexpression of PDL transcripts. Utilizing high-throughput sequencing techniques, we characterized novel translocations and chimeric fusion transcripts involving PDLs at base-pair resolution. Our data suggest that recurrent genomic rearrangement events underlie an immune privilege phenotype in a subset of B-cell lymphomas. PMID:24497532

Twa, David D W; Chan, Fong Chun; Ben-Neriah, Susana; Woolcock, Bruce W; Mottok, Anja; Tan, King L; Slack, Graham W; Gunawardana, Jay; Lim, Raymond S; McPherson, Andrew W; Kridel, Robert; Telenius, Adele; Scott, David W; Savage, Kerry J; Shah, Sohrab P; Gascoyne, Randy D; Steidl, Christian

2014-03-27

235

Complement receptor 2/CD21? human naive B cells contain mostly autoreactive unresponsive clones  

PubMed Central

Complement receptor 2–negative (CR2/CD21?) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21?/lo B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21?/lo B cells in their blood. A majority of CD21?/lo B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21?/lo B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21?/lo B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans. PMID:20231422

Isnardi, Isabelle; Ng, Yen-Shing; Menard, Laurence; Meyers, Greta; Saadoun, David; Srdanovic, Iva; Samuels, Jonathan; Berman, Jessica; Buckner, Jane H.; Cunningham-Rundles, Charlotte

2010-01-01

236

Selected Lactic Acid-Producing Bacterial Isolates with the Capacity to Reduce Salmonella Translocation and Virulence Gene Expression in Chickens  

PubMed Central

Background Probiotics have been used to control Salmonella colonization/infection in chickens. Yet the mechanisms of probiotic effects are not fully understood. This study has characterized our previously-selected lactic acid-producing bacterial (LAB) isolates for controlling Salmonella infection in chickens, particularly the mechanism underlying the control. Methodology/Principal Findings In vitro studies were conducted to characterize 14 LAB isolates for their tolerance to low pH (2.0) and high bile salt (0.3–1.5%) and susceptibility to antibiotics. Three chicken infection trials were subsequently carried out to evaluate four of the isolates for reducing the burden of Salmonella enterica serovar Typhimurium in the broiler cecum. Chicks were gavaged with LAB cultures (106–7 CFU/chick) or phosphate-buffered saline (PBS) at 1 day of age followed by Salmonella challenge (104 CFU/chick) next day. Samples of cecal digesta, spleen, and liver were examined for Salmonella counts on days 1, 3, or 4 post-challenge. Salmonella in the cecum from Trial 3 was also assessed for the expression of ten virulence genes located in its pathogenicity island-1 (SPI-1). These genes play a role in Salmonella intestinal invasion. Tested LAB isolates (individuals or mixed cultures) were unable to lower Salmonella burden in the chicken cecum, but able to attenuate Salmonella infection in the spleen and liver. The LAB treatments also reduced almost all SPI-1 virulence gene expression (9 out of 10) in the chicken cecum, particularly at the low dose. In vitro treatment with the extracellular culture fluid from a LAB culture also down-regulated most SPI-1 virulence gene expression. Conclusions/Significance The possible correlation between attenuation of Salmonella infection in the chicken spleen and liver and reduction of Salmonella SPI-1 virulence gene expression in the chicken cecum by LAB isolates is a new observation. Suppression of Salmonella virulence gene expression in vivo can be one of the strategies for controlling Salmonella infection in chickens. PMID:24728092

Yang, Xiaojian; Brisbin, Jennifer; Yu, Hai; Wang, Qi; Yin, Fugui; Zhang, Yonggang; Sabour, Parviz; Sharif, Shayan; Gong, Joshua

2014-01-01

237

B Cells in Pregnancy: Functional Promiscuity or Tailored Function?  

PubMed

During pregnancy, the maternal immune and endocrine systems undergo significant adaptations in order to maintain immune tolerance towards the semi-allogeneic fetus. Pregnancy related hormones, such as estradiol, progesterone and glucocorticoids soar, and leukocyte subsets of the innate and adaptive immune response systems functionally engage in ensuring successful implantation of the embryo, placentation and maintenance of pregnancy until term. Over the last two decades, a considerable amount of research has been devoted first to understand the functional role of natural killer (NK) cells, dendritic cells (DC) and T cells, and then to dissect potential cross talk between these cells and pregnancy-related hormones, decidual stroma cells and fetal trophoblast cells [1,2].It is now evident that immune responses against fetal antigens are suppressed by multiple pathways that lead to dampening of T effector cells, generation of regulatory T cells [3,4,5] and modulation of DC [6] and NK cell functions [7], along with epigenetic modifications of the decidual stroma [8]. Remarkably, the amalgamation of these pathways ensures pregnancy success, whereas single cell subsets or markers are largely redundant, as learned from reductionist approaches of single gene knock out or in vivo cellular depletion experiments [1]. This profound maternal adaptation to pregnancy has certain collateral effects on maternal health. These effects including both, health advantages, such as amelioration of certain autoimmune diseases including multiple sclerosis (MS) [9], as well as disadvantages, such as increased risk for certain infections, including influenza virus [10]. Considering the relevance of maternal immunological adaptation during pregnancy to autoimmunity, infectious disease and fetal health, the importance of understanding these changes has become increasingly clear. In this context, one leukocyte subset has largely been neglected in reproductive immunology: the B cells (Figure 1). As critical, non-redundant players in the adaptive immune response, B cells mediate humoral immunity by producing antibodies; more recently, research has unveiled antibody-independent immune-modulatory functions of certain B cell subsets. These findings have resulted in a re-classification of B cell subsets based on their potential to secrete a distinct cytokine profile [11]. Hereby, B cells activate or suppress immune responses via their interactions with DC, NK cells and T cells [12,13]. Furthermore, a wealth of evidence supports that B cell subsets can be functionally promiscuous, capable of maintaining health as well as aggravating immune pathologies [11, 14, 15]. The recent publication by Frederico Jensen and colleagues at the University of Greifswald in Germany has begun to close the gap in knowledge on the function and modifications of B cell subsets and their function during pregnancy [16]. In their study, the Greifswald group provides evidence that B cell development undergoes significant adaptations over the course of pregnancy in allogenically mated mice [16]. These adaptations include a gradual reduction in numbers of pre/pro and, to a lesser extent, immature B cells in the bone marrow early during gestation, prior to the completion of placentation. These findings overcome a limitation of previously published evidence, in which a similar suppression of B lymphopoiesis during gestation had also been observed, but cells from different gestational stages had been pooled [17].By mid gestation, the Greifswald group observed a clear reduction in numbers of B cell precursors together with an increase in numbers of mature B cells, which together suggest an a reduction in B cell lymphopoiesis. Subsequent in-depth analyses of B cell development in the periphery unveiled a preponderance of marginal zone B cells in the spleen. Splenic marginal zone B cells can give rise to antibody-secreting memory B cells and plasma cells, which are required to deal with infections such as the influenza A virus. Hence, it is possible that mechanisms are activated to overcome p

Arck, Petra Clara; Hecher, Kurt; Solano, María Emilia

2014-11-26

238

Monoclonal B-Cell Lymphocytosis  

PubMed Central

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition defined by the presence of a small (<5 x 109/L) clonal B-cell population in the peripheral blood in the absence of lymph-node enlargement, cytopenias or autoimmune diseases. It is found in approximately 3-12% of normal persons depending on the accuracy of analytical techniques applied. According to the immunophenotypic profile of clonal B-cells, the majority of MBL cases (75%) are classified as chronic lymphocytic leukemia (CLL)-like. This form may progress into CLL at a rate of 1–2% per year. It is thought that CLL is always preceded by MBL. The remaining MBL cases are defined as atypical CLL-like (CD5+/CD20bright) and CD5- MBL. The MBL clone size is quite heterogenous. Accordingly, two forms of MBL are identified: i) high-count, or ‘clinical’ MBL, in which an evidence of lymphocytosis (<5 x 109/L clonal B-cells) is seen, and ii) a low-count MBL, in which a normal leukocyte count is found and that is identified only in population-screening studies. Both forms of MBL may carry the cytogenetic abnormalities that are the hallmark of CLL, including 13q-, 17p- and trisomy 12. Consistent with the indolent phenotype of this condition, genetic lesions, such as TP53, ATM, NOTCH1 and SF3B1 mutations, usually associated with high-risk CLL, are rarely seen. Overall, no prognostic indicator of evolution of MBL to overt CLL has been found at present time. However, taking into account this possibility, a clinical and lab monitoring (at least annually), is recommended. PMID:24779000

D’Arena, G.; Musto, P.

2014-01-01

239

BCL6 is critical for the development of a diverse primary B cell repertoire.  

PubMed

BCL6 protects germinal center (GC) B cells against DNA damage-induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7-dependent B cell precursors, we report that IL-7Ralpha-Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a mu heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Ralpha-Stat5 signaling is attenuated. At the transition from IL-7-dependent to -independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre-B cells from DNA damage-induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre-B cell self-renewal and the formation of a diverse polyclonal B cell repertoire. PMID:20498019

Duy, Cihangir; Yu, J Jessica; Nahar, Rahul; Swaminathan, Srividya; Kweon, Soo-Mi; Polo, Jose M; Valls, Ester; Klemm, Lars; Shojaee, Seyedmehdi; Cerchietti, Leandro; Schuh, Wolfgang; Jäck, Hans-Martin; Hurtz, Christian; Ramezani-Rad, Parham; Herzog, Sebastian; Jumaa, Hassan; Koeffler, H Phillip; de Alborán, Ignacio Moreno; Melnick, Ari M; Ye, B Hilda; Müschen, Markus

2010-06-01

240

Therapy-related pro-B cell acute lymphoblastic leukemia: report of two patients with MLL amplification.  

PubMed

Improvements in chemotherapy and medical support of patients treated with chemotherapy and radiation have led to an ever-increasing number of cancer survivors. Unfortunately, a small fraction of these patients develop secondary hematologic malignancies as a consequence of their exposure to genotoxic anti-cancer regimens. Most of these are myeloid malignancies, therapy-related acute myeloid leukemia (t-AML) or myelodysplasia (t-MDS); however, a small but growing body of literature exists, which describes therapy-related acute lymphoblastic leukemias (t-ALL). Nearly all these cases are reportedly associated with translocations involving chromosome 11q23, the site of the MLL gene. We herein report two cases of ALL occurring after chemotherapy for other malignancies that showed complex karyotypic abnormalities and distinct MLL amplification by fluorescence in situ hybridization analysis. Immunophenotypic analysis showed that both cases expressed a pro-B cell (CD10-) phenotype with aberrant myeloid antigen expression. Although MLL amplification has been reported in therapy-related myeloid disease, to our knowledge this is the first report of MLL amplification occurring in therapy-related B cell ALL. PMID:23238285

Racke, Frederick; Cole, Carol; Walker, Alison; Jones, Jeffrey; Heerema, Nyla A

2012-12-01

241

Expression of AID transgene is regulated in activated B cells but not in resting B cells and kidney  

PubMed Central

Activation-induced DNA cytosine deaminase (AID) is required for somatic hypermutation (SHM) and efficient class switch recombination (CSR) of immunoglobulin (Ig) genes. We created AID-transgenic mice that express AID ubiquitously under the control of a ?–actin promoter. When crossed with AID?/? mice, the AID-transgenic, AID?/? mice carried out SHM and CSR, showing that the AID transgenes were functional. However, the frequencies of SHM in V- and switch-regions, and CSR were reduced compared to those in a wildtype AID background. Several criteria suggested that the inefficiency of SHM was due to reduced AID activity, rather than lack of recruiting error-prone DNA repair. High levels of AID mRNA were produced in resting B cells and kidney, cells that do not express AID in wildtype mice. Compared with these cells, activated B cells expressed about an order of magnitude less AID mRNA suggesting that there may be a post-transcriptional mechanism that regulates AID mRNA levels in professional AID producers but not other cells. The AID protein expressed in resting B cells and kidney was phosphorylated at serine-38. Despite this modification, known to enhance AID activity, resting B cells did not undergo SHM. Apparently, the large amounts of AID in resting B cells are not targeted to Ig genes in vivo, in contrast to findings in vitro. PMID:18067961

Shen, Hong Ming; Bozek, Grazyna; Pinkert, Carl A.; McBride, Kevin; Wang, Lilly; Kenter, Amy; Storb, Ursula

2008-01-01

242

B-cell memory: are subsets necessary?  

Microsoft Academic Search

B-cell memory is provided by populations of quiescent memory B cells and long-lived plasma cells. Whereas it is clear that both of these cell populations arise from germinal centres, the signals and circumstances that trigger germinal-centre B cells to enter and then persist in memory compartments are poorly defined. Here, I propose that germinal centres produce memory B cells and

David Tarlinton

2006-01-01

243

The Impact of Inflammation and Immune Activation on B Cell Differentiation during HIV-1 Infection  

PubMed Central

One important pathogenic feature of human immunodeficiency virus (HIV)-1 infection is chronic immune activation and impaired survival of T and B cells. A decline of resting memory B cells was reported to occur in both children and adults infected with HIV-1; these cells are responsible for maintaining an adequate serological response to antigens previously encountered in life through natural infection or vaccination. Further understanding of the mechanisms leading to impaired B cell differentiation and germinal center reaction might be essential to design new HIV vaccines and therapies that could improve humoral immune responses in HIV-1 infected individuals. In the present article we summarize the literature and present our view on critical mechanisms of B cell development impaired during HIV-1 infection. We also discuss the impact of microbial translocation, a driving force for persistent inflammation during HIV-1 infection, on survival of terminally differentiated B cells and how the altered expression of cytokines/chemokines pivotal for communication between T and B cells in lymphoid tissues may impair formation of memory B cells. PMID:22566879

Ruffin, Nicolas; Thang, Pham Hong; Rethi, Bence; Nilsson, Anna; Chiodi, Francesca

2012-01-01

244

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

245

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

246

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

247

Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid?screen  

PubMed Central

The natural product rapamycin has been used to provide temporal and quantitative control of gene expression in animals through its ability to interact with two proteins simultaneously. A shortcoming of this approach is that rapamycin is an inhibitor of cell proliferation, the result of binding to FKBP12–rapamycin-associated protein (FRAP). To overcome this limitation, nontoxic derivatives of rapamycin bearing bulky substituents at its C16-position were synthesized, each in a single step. The isosteric isopropoxy and methallyl substituents with the nonnatural C16-configuration abolish both binding to FRAP and inhibition of T cell proliferation. Binding proteins for these derivatives were identified from libraries of cDNAs encoding mutants of the FKBP12–rapamycin-binding (FRB) domain of FRAP by using a mammalian three-hybrid transcription assay. Targeting of the mutations was guided by the structure of the FKBP12-rapamycin–FRB ternary complex. Three compensatory mutations in the FRB domain, all along one face of an ?-helix in a rapamycin-binding pocket, were identified that together restore binding of the rapamycin derivatives. Using this mutant FRB domain, one of the nontoxic rapamycin derivatives induced targeted gene expression in Jurkat T cells with an EC50 below 10 nM. Another derivative was used to recruit a cytosolic protein to the plasma membrane, mimicking a process involved in many signaling pathways. PMID:9223271

Liberles, Stephen D.; Diver, Steven T.; Austin, David J.; Schreiber, Stuart L.

1997-01-01

248

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

249

Selective Induction of DNA Repair Pathways in Human B Cells Activated by CD4+ T Cells  

PubMed Central

Greater than 75% of all hematologic malignancies derive from germinal center (GC) or post-GC B cells, suggesting that the GC reaction predisposes B cells to tumorigenesis. Because GC B cells acquire expression of the highly mutagenic enzyme activation-induced cytidine deaminase (AID), GC B cells may require additional DNA repair capacity. The goal of this study was to investigate whether normal human B cells acquire enhanced expression of DNA repair factors upon AID induction. We first demonstrated that several DNA mismatch repair, homologous recombination, base excision repair, and ATR signaling genes were overexpressed in GC B cells relative to naïve and memory B cells, reflecting activation of a process we have termed somatic hyperrepair (SHR). Using an in vitro system, we next characterized activation signals required to induce AID expression and SHR. Although AID expression was induced by a variety of polyclonal activators, SHR induction strictly required signals provided by contact with activated CD4+ T cells, and B cells activated in this manner displayed reduced levels of DNA damage-induced apoptosis. We further show the induction of SHR is independent of AID expression, as GC B cells from AID -/- mice retained heightened expression of SHR proteins. In consideration of the critical role that CD4+ T cells play in inducing the SHR process, our data suggest a novel role for CD4+ T cells in the tumor suppression of GC/post-GC B cells. PMID:21179576

Wu, Xiaosheng; Tschumper, Renee C.; Gutierrez, Albert; Mihalcik, Stephen A.; Nowakowski, Grzegorz S.; Jelinek, Diane F.

2010-01-01

250

Simultaneous Evaluation of T- and B-Cell Clonality, t(11;14) and t(14;18), in a Single Reaction by a Four-Color Multiplex Polymerase Chain Reaction Assay and Automated High-Resolution Fragment Analysis  

PubMed Central

Current polymerase chain reaction (PCR) methods for the molecular diagnosis of B- and T-cell lymphomas by determination of clonality of immunoglobulin heavy chain (IgH) and T-cell receptor-? rearrangements and by detection of the chromosomal translocations t(14;18) and t(11;14), require several laborious and costly PCR assays for each of these diagnostic tests. We have developed a multiplex PCR assay for the simultaneous determination of B- and T-cell clonality and the detection of the chromosomal translocations t(14;18) and t(11;14) in a single reaction, using four-color fluorescence and automated high-resolution fragment analysis. The 26 primers combined in the multiplex PCR correspond to the sequences of >90% of the 69 variables and 6 join IgH genes and 100% of the T-cell receptor-? variables and join genes that could participate in the respective rearrangements. In addition, they detect the major and the minor breakpoint regions of the t(14;18) and the major breakpoint region of the t(11;14), and amplify the ?-globin gene as an internal control. The specificity of the multiplex PCR was confirmedby analysis of 39 T-cell lymphomas and 58 B-cell lymphomas, including 11 mantle cell lymphomas bearing the t(11;14) and 25 follicular lymphomas bearing the t(14;18), with known rearrangements and/or translocations. Fifteen samples of reactive lymphadenitis remained negative. PMID:11733354

Meier, Verena S.; Rufle, Alex; Gudat, Fred

2001-01-01

251

Phagocytic B cells in a reptile  

PubMed Central

Evidence for a developmental relationship between B cells and macrophages has led to the hypothesis that B cells evolved from a phagocytic predecessor. The recent identification of phagocytic IgM+ cells in fishes and amphibians supports this hypothesis, but raises the question of when, evolutionarily, was phagocytic capacity lost in B cells? To address this, leucocytes were isolated from red-eared sliders, Trachemys scripta, incubated with fluorescent beads and analysed using flow cytometry and confocal microscopy. Results indicate that red-eared slider B cells are able to ingest foreign particles and suggest that ectothermic vertebrates may use phagocytic B cells as part of a robust innate immune response. PMID:19846448

Zimmerman, Laura M.; Vogel, Laura A.; Edwards, Kevin A.; Bowden, Rachel M.

2010-01-01

252

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

253

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

254

Memory B cells in mouse models.  

PubMed

One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases. PMID:23679222

Bergmann, B; Grimsholm, O; Thorarinsdottir, K; Ren, W; Jirholt, P; Gjertsson, I; Mårtensson, I-L

2013-08-01

255

Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC.  

PubMed

Initial cell surface expression of the pre-B cell receptor induces proliferation. After 2 to 5 divisions, however, large pre-BII (Fraction C') cells exit cell cycle to become resting, small pre-BII cells (Fraction D). The mechanism by which pre-BII cells exit cell cycle, however, is currently unclear. The checkpoint at the Fraction C'-D transition is critical for immunoglobulin light chain gene recombination and to prevent malignant transformation into acute lymphoblastic leukemia. Here we demonstrate that inducible activation of pre-B cell receptor signaling induces cell-cycle exit through up-regulation of the transcriptional repressor BCL6. Inducible activation of BCL6 downstream of the pre-B cell receptor results in transcriptional repression of MYC and CCND2. Hence, pre-B cell receptor-mediated activation of BCL6 limits pre-B cell proliferation and induces cellular quiescence at the small pre-BII (Fraction D) stage. PMID:21856866

Nahar, Rahul; Ramezani-Rad, Parham; Mossner, Maximilian; Duy, Cihangir; Cerchietti, Leandro; Geng, Huimin; Dovat, Sinisa; Jumaa, Hassan; Ye, B Hilda; Melnick, Ari; Müschen, Markus

2011-10-13

256

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

257

Clinicopathologic Characterization of Diffuse-Large-B-Cell Lymphoma with an Associated Serum Monoclonal IgM Component  

PubMed Central

Recently, diffuse-large-B-cell lymphoma (DLBCL) associated with serum IgM monoclonal component (MC) has been shown to be a very poor prognostic subset although, detailed pathological and molecular data are still lacking. In the present study, the clinicopathological features and survival of IgM-secreting DLBCL were analyzed and compared to non-secreting cases in a series of 151 conventional DLBCL treated with R-CHOP. IgM MC was detected in 19 (12.5%) out of 151 patients at disease onset. In 17 of these cases secretion was likely due to the neoplastic clone, as suggested by the expression of heavy chain IgM protein in the cytoplasm of tumor cells. In IgM-secreting cases immunoblastic features (p<.0001), non-GCB-type (p?=?.002) stage III-IV(p?=?.003), ?2 extra nodal sites (p<.0001), bone-marrow (p?=?.002), central-nervous-system (CNS) involvement at disease onset or relapse (p<.0001), IPI-score 3–5 (p?=?.009) and failure to achieve complete remission (p?=?.005), were significantly more frequent. FISH analyses for BCL2, BCL6 and MYC gene rearrangements detected only two cases harboring BCL2 gene translocation and in one case a concomitant BCL6 gene translocation was also observed. None of the IgM-secreting DLBCL was found to have L265P mutation of MYD88 gene. Thirty-six month event-free (11.8% vs 66.4% p<.0001), progression-free (23.5% vs 75.7%, p<.0001) and overall (47.1% vs 74.8%, p<.0001) survivals were significantly worse in the IgM-secreting group. In multivariate analysis IgM-secreting (p?=?.005, expB?=?0.339, CI?=?0.160-0.716) and IPI-score 3–5 (p?=?.010, expB?=?0.274, CI?=?0.102–0.737) were the only significant factors for progression-free-survival. Notably, four relapsed patients, who were treated with salvage immmunochemotherapy combined with bortezomib or lenalidomide, achieved lasting remission. Our data suggests that IgM-secreting cases are a distinct subset of DLBCL, originating from activated-B-cells with terminally differentiated features, prevalent extra nodal dissemination and at high risk of CNS involvement. PMID:24705344

Scarpino, Stefania; Salerno, Gerardo; Tatarelli, Caterina; Talerico, Caterina; Lombardi, Mariangela; Monarca, Bruno; Amadori, Sergio; Ruco, Luigi

2014-01-01

258

Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11)(q21;q23)/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia  

PubMed Central

Translocation t(4;11)(q21;q23) leading to formation of MLL-AF4 fusion gene is found in about 10% of newly diagnosed B-cell acute lymphoblastic leukemia (ALL) in adult patients. Patients expressing this chromosomal aberration present typical biological, immunophenotypic, and clinical features. This form of leukemia is universally recognized as high-risk leukemia and treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) could be a valid option to improve prognosis, but data obtained from the literature are controversial. In this review, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11)(q21;q23)/MLL-AF4 positive ALL and provide a review of the clinical outcome reported by the most important cooperative groups worldwide. PMID:22190943

Marchesi, F.; Girardi, K.; Avvisati, G.

2011-01-01

259

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells  

PubMed Central

Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non–antigen-binding antibody region: the heavy-chain variable (VH)–encoded “elbow” between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in VH gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use VH genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential VH gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection. PMID:24927543

Kaplinsky, Joseph; Li, Anthony; Sun, Amy; Coffre, Maryaline; Koralov, Sergei B.; Arnaout, Ramy

2014-01-01

260

Clonal Evolution in a Primary Cutaneous Follicle Center B Cell Lymphoma Revealed by Single Cell Analysis in Sequential Biopsies  

Microsoft Academic Search

B cell neoplasias descending from germinal center cells harbor the hallmark of intraclonal diversity resulting from ongoing mutation in the variable parts of their immunoglobulin-encoding genes. To characterize a primary cutaneous follicle center B cell lymphoma in more detail, we analyzed the respective VH and VL genes in single cells mobilized from four sequential biopsies, three taken from the skin

Sven Golembowski; Sylke Gellrich; Malgorszata Von Zimmermann; Sascha Rutz; Steffen Lippert; Heike Audring; Pamela Lorenz; Wolfram Sterry; Sigbert Jahn

2000-01-01

261

A single copy of linker H1 genes is enough for proliferation of the DT40 chicken B cell line, and linker H1 variants participate in regulation of gene expression  

Microsoft Academic Search

Background: There is general agreement that large numbers of histone H1 are necessary for main- tenance of the higher order structure of chromatin in higher eukaryotes. The chicken H1 gene family comprises six members per haploid genome, the total copy number being 12, and they encode six H1 variants which are considerably different from each other in amino acid sequence.

Yasunari Takami; Tatsuo Nakayama

1997-01-01

262

Critical role of Bcl10 in BAFF-regulated NF-?B activation and survival of anergic B cells  

PubMed Central

Anergy is a key physiological mechanism for restraining self-reactive B cells. A marked portion of peripheral B cells are anergic B cells that largely depend on B cell-activating factor (BAFF) for survival. BAFF activates the canonical and noncanonical NF-?B pathways, both of which are required for B cell survival. Here we report that deficiency of the adaptor protein B cell lymphoma 10 (Bcl10) impaired the ability of BAFF to support B cell survival in vitro, and specifically increased apoptosis in anergic B cells in vivo, dramatically reducing anergic B cells in mice. Bcl10-dependent survival of self-reactive anergic B cells was confirmed in the IgHELsHEL double-transgenic mouse model of B cell anergy. Further, we found that BAFF stimulation induced Bcl10 association with IKK?, a key component of the canonical NF-?B pathway. Consistently, Bcl10-deficient B cells were impaired in BAFF-induced I?B? phosphorylation and formation of nuclear p50:c-Rel complexes. Bcl10-deficient B cells also displayed reduced expression of NF-?B2/p100, severely reducing BAFF-induced nuclear accumulation of noncanonical p52:RelB complexes. Consequently, Bcl10-deficient B cells failed to express Bcl-xL, a BAFF-induced NF-?B target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-?B activation directly and noncanonical NF-?B activation indirectly. The BAFF-R/Bcl10/NF-?B signaling axis plays a critical role in peripheral B cell tolerance by regulating the survival of self-reactive anergic B cells. PMID:23087406

Yu, Mei; Chen, Yuhong; He, Yinghong; Podd, Andrew; Fu, Guoping; Wright, Jacqueline A.; Kleiman, Eden; Khan, Wasif N.; Wen, Renren; Wang, Demin

2013-01-01

263

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

264

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

265

Molecular characterization of the cervical and systemic B-cell repertoire  

PubMed Central

The cervical mucosa of women who are highly exposed to HIV-1, yet remain persistently seronegative (HEPS), presents a unique opportunity to study the dynamics of an immune compartment potentially capable of preventing HIV-1 infection. Herein, we provide a detailed characterization of the immunoglobulin repertoire of cervical and systemic B cells from one such HEPS individual from Nairobi, Kenya. Analysis was done on 512 VH sequences that were RT-PCR amplified from B cells in a paired sample from the cervix and peripheral blood. The VH3 and DH repertoire of class switched cervical B cells differs significantly from that of systemic B cells, indicating that the cervical environment affects local B-cell populations and hence VH gene expression. Six networks of clonally related, heavily mutated B cells were identified that spanned the systemic and cervical B-cell compartments. Analysis of somatic mutations suggests this is likely the result of systemic, class switched B cells homing to the cervical mucosa. Multiple networks of somatically mutated V-gene sequences, unique to the cervical mucosa, were also identified. This supports the notion that site specific responses occur and have unique regulation of tolerance and recruitment into local memory or blast B-cell compartments. We conclude that while the nature of the cervical environment shapes the local B cell repertoire, the infusion of post germinal center B cells to the human cervix is a common occurrence, and represents a means by which systemic immunization could provide the local antibodies necessary to prevent HIV-1 at the site of initial contact. PMID:21293180

Gaudet, Ryan G; Breden, Felix; Plummer, Frank

2011-01-01

266

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

267

Proteomic Changes during B Cell Maturation: 2D-DIGE Approach  

PubMed Central

B cells play a pivotal role in adaptive immune system, since they maintain a delicate balance between recognition and clearance of foreign pathogens and tolerance to self. During maturation, B cells progress through a series of developmental stages defined by specific phenotypic surface markers and the rearrangement and expression of immunoglobulin (Ig) genes. To get insight into B cell proteome during the maturation pathway, we studied differential protein expression in eight human cell lines, which cover four distinctive developmental stages; early pre-B, pre-B, plasma cell and immature B cell upon anti-IgM stimulation. Our two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry based proteomic study indicates the involvement of large number of proteins with various functions. Notably, proteins related to cytoskeleton were relatively highly expressed in early pre-B and pre-B cells, whereas plasma cell proteome contained endoplasmic reticulum and Golgi system proteins. Our long time series analysis in anti-IgM stimulated Ramos B cells revealed the dynamic regulation of cytoskeleton organization, gene expression and metabolic pathways, among others. The findings are related to cellular processes in B cells and are discussed in relation to experimental information for the proteins and pathways they are involved in. Representative 2D-DIGE maps of different B cell maturation stages are available online at http://structure.bmc.lu.se/BcellProteome/. PMID:24205016

Salonen, Johanna; Rönnholm, Gunilla; Kalkkinen, Nisse; Vihinen, Mauno

2013-01-01

268

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

269

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

270

Genomic organisation and expression of BCL6 in murine B-cell lymphomas.  

PubMed

BCL6 encodes a transcription factor deregulated by chromosomal translocations in human diffuse large cell B lymphomas (DLCL). This study was designed to determine whether Bcl6 might also be involved in lymphomas of mice. BCL6 protein was expressed at high levels in 90% or more of DLCL but not in low grade B lymphomas. Southern hybridisation studies demonstrated altered organisation of Bcl6 in three primary DLCL and the WEHI 231 B-cell lymphoma cell line but not in low grade tumours. Chromosomal painting and fluorescence in situ hybridisation (FISH) analyses of the WEHI 231 metaphase spreads revealed a T(5;16) translocation with Bcl6 on Chromosome 16 at the translocation breakpoint. Deregulated expression of BCL6 is thus likely to contribute to the genesis of DLCL of mice as well as of humans. PMID:10936424

Qi, C F; Hori, M; Coleman, A E; Torrey, T A; Taddesse-Heath, L; Ye, B H; Chattopadhyay, S K; Hartley, J W; Morse, H C

2000-08-01

271

Protein Translocation across Membranes  

Microsoft Academic Search

Many newly synthesized proteins must be translocated across a membrane to reach their final destinations. Translocation requires a signal on the protein itself, a loose conformation of the protein, energy, and receptor-like components in the cytosol and on the target membrane.

Keith Verner; Gottfried Schatz

1988-01-01

272

New case of trichorinophalangeal syndrome-like phenotype with a de novo t(2;8)(p16.1;q23.3) translocation which does not disrupt the TRPS1 gene  

PubMed Central

Background Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterised by distinctive craniofacial and skeletal abnormalities. TRPS is generally associated with mutations in the TRPS1 gene at 8q23.3 or microdeletions of the 8q23.3-q24.11 region. However, three deletions affecting the same chromosome region and a familial translocation t(8;13) co-segregating with TRPS, which do not encompass or disrupt the TRPS1 gene, have been reported. A deregulated expression of TRPS1 has been hypothesised as cause of the TRPS phenotype of these patients. Case presentation We report the clinical and molecular characterisation of a 57-year-old Caucasian woman carrying the t(2;8)(p16.1;q23.3) de novo balanced translocation. The proband presented with peculiar clinical features (severe craniofacial dysmorphism, alopecia universalis, severe scoliosis, mitral valve prolapse, mild mental impairment and normal growth parameters) that partially overlap with TRPS I. Mutational and array CGH analyses ruled out any genetic defect affecting TRPS1 or genomic alteration at the translocation breakpoint or elsewhere in the genome. Breakpoint mapping excluded disruption of TRPS1, and revealed that the chromosome 8q23.3 breakpoint was located within the IVS10 of the long intergenic non-coding RNA LINC00536, at approximately 300 kb from the TRPS1 5’ end. Conversely, the 2p16.1 breakpoint mapped within a LINE sequence, in a region that lacks transcriptional regulatory elements. As a result of the translocation, nucleotide base pair additions and deletions were detected at both breakpoint junction fragments, and an evolutionarily conserved VISTA enhancer element from 2p16.1 was relocated at approximately 325 kb from the TRPS1 promoter. Conclusions We suggest that the disruption of the genomic architecture of cis regulatory elements downstream the TRPS1 5? region, combined with the translocation of a novel enhancer element nearby TRPS1, might be the pathogenetic mechanism underpinning the proband’s phenotype. The clinical and genetic characterisation of the present subject allowed us to make a genetic diagnosis in the context of a known syndrome, contributing to a better comprehension of the complex transcriptional regulation of TRPS1 and TRPS ethiopathogenesis. PMID:24886451

2014-01-01

273

Clonal analysis of B cells in the osteoarthritis synovium  

PubMed Central

OBJECTIVES—Cellular and humoral immunity to collagen and cartilage proteoglycan were shown in patients with osteoarthritis (OA). Inflammatory infiltration containing T and B lymphocytes and macrophages, which are HLA-DR positive, is often seen in the synovial membrane of patients with OA. An analysis of the DNA restriction enzyme patterns of T lymphocytes from the OA synovium showed an oligoclonal pattern of T cell receptor ? chain gene rearrangements. No similar studies of B cell clonality have previously been performed. This study aimed at determining the clonal characteristics of the B cells in the OA synovium.?METHODS—A reverse transcriptase-polymerase chain reaction of the immunoglobulin transcripts of B cells in the synovial membranes from six patients with OA was performed and the products were analysed by a single strand conformation polymorphism analysis.?RESULTS—Several dominant bands were seen in all samples and some of the dominant bands were common among the two or three separate regions of each synovial sample.?CONCLUSION—Infiltrated B cells are oligoclonal, and an antigen driven immune response may play a part in the progression of the disease process in OA.?? PMID:11454647

Shiokawa, S; Matsumoto, N; Nishimura, J

2001-01-01

274

Involvement of the NUP98 Gene in a Chromosomal Translocation t(11;20)(p15;q11.2) in a Patient With Acute Monocytic Leukemia (FAB-M5b)  

Microsoft Academic Search

We report here a case of acute monocytic leukemia (M5b subtype according to the French-American-British [FAB]classification)\\u000a with chromosomal translocation t(11;20)(p15;q11.2). Fluorescence in situ hybridization analysis with a probe for theNUP98 gene, which is located at chromosome band 11p15, showed that the probe hybridized to both derivative chromosomes 11 and 20\\u000a as well as to the remaining normal chromosome 11, indicating

Naoki Kakazu; Isaku Shinzato; Yasuhito Arai; Saori Gotoh; Akiko Matsushita; Takayuki Ishikawa; Kenichi Nagai; Takayuki Takahashi; Tatsuji Ohno; Takayuki Tsuchiya; Misao Ohki; Tatsuo Abe

2001-01-01

275

Cutaneous hidradenocarcinoma: a clinicopathological, immunohistochemical, and molecular biologic study of 14 cases, including Her2/neu gene expression/amplification, TP53 gene mutation analysis, and t(11;19) translocation.  

PubMed

We present a series of 14 cases of cutaneous hidradenocarcinomas. The patients included 6 women and 8 men ranging in age at diagnosis from 34 to 93 years. All but 1 patient presented with a solitary nodule. There was no predilection site. One patient presented with multiple lesions representing metastatic nodules. Of 12 patients with available follow-up, 2 died of disease, whereas the remaining 10 patients were alive but 3 of them experienced a local recurrence in the course of the disease. Grossly, the tumors ranged in size from 1.2 to 6 cm. Microscopically, of the 14 primary tumors, 9 showed low-grade cytomorphology, whereas the remaining 5 neoplasms were high-grade lesions. The residuum of a hidradenoma was present in 5 of the 14 primaries. The mitotic rate was highly variable, ranging from 2 to 64 mitoses per 10 high-power field. The cellular composition of the tumors varied slightly, with clear cells, epidermoid cells, and transitional forms being present in each case. In 1 case, there was metaplastic transformation into sarcomatoid carcinoma. Glandular differentiation varied from case to case and appeared most commonly as simple round glands or as cells with intracytoplasmic lumens. Necrosis en masse was detected in 8 specimens. One specimen represented a reexcision and was unusual as it showed a well-demarcated intradermal proliferation of relatively bland clear cells accompanied by an overlying intraepidermal growth of clear cells resembling hidradenoacanthoma simplex. Despite the bland appearance, the tumor metastasized to a lymph node. Immunohistochemically, 5 of the 8 specimens studied for Her2/neu expression were negative, whereas 3 specimens from 2 cases yielded score +2, but all the 3 specimens with score 2+ subsequently proved negative for Her2/neu gene amplification by fluorescence in situ hybridization. Of 10 primaries studied, 4 tumors showed positive p53 immunoreaction in more than 25% of the cells comprising the malignant portion of the lesions, in 2 cases, a minority of the neoplastic cells (10%-20%) demonstrated nuclear staining, whereas the remaining 4 cases were negative. Of 9 specimens of hidradenocarcinoma studied for TP53 mutations, 2 harbored mutations, whereas the remaining 7 specimens showed the wild-type sequence. Of 11 specimens studied for translocation t(11;19), 2 cases harbored the translocation. It is concluded that cutaneous hidradenocarcinomas show some microscopic heterogeneity and comprise both low- and high-grade lesions that cytologically are similar to their benign counterpart, the hidradenoma. Within the spectrum of low-grade lesions, there seem to exist tumors almost indistinguishable from hidradenomas but still being capable of regional or distant metastasis. Similar to hidradenomas, hidradenocarcinomas show a t(11;19) translocation, but it is a significantly rarer event. Even rarer is the amplification of the Her2/neu gene. Of note is the relatively low frequency of TP53 mutations despite a high rate of p53 protein expression at the immunohistochemical level. PMID:19384064

Kazakov, Dmitry V; Ivan, Doina; Kutzner, Heinz; Spagnolo, Dominic V; Grossmann, Petr; Vanecek, Tomas; Sima, Radek; Kacerovska, Denisa; Shelekhova, Ksenia V; Denisjuk, Natalja; Hillen, Uwe; Kuroda, Naoto; Mukensnabl, Petr; Danis, Dusan; Michal, Michal

2009-05-01

276

Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions.  

PubMed

The generation and functions of human peripheral blood (PB) IgM(+)IgD(+)CD27(+) B lymphocytes with somatically mutated IgV genes are controversially discussed. We determined their differential gene expression to naive B cells and to IgM-only and IgG(+) memory B cells. This analysis revealed a high similarity of IgM(+)(IgD(+))CD27(+) and IgG(+) memory B cells but also pointed at distinct functional capacities of both subsets. In vitro analyses revealed a tendency of activated IgM(+)IgD(+)CD27(+) B cells to migrate to B-cell follicles and undergo germinal center (GC) B-cell differentiation, whereas activated IgG(+) memory B cells preferentially showed a plasma cell (PC) fate. This observation was supported by reverse regulation of B-cell lymphoma 6 and PR domain containing 1 and differential BTB and CNC homology 1, basic leucine zipper transcription factor 2 expression. Moreover, IgM(+)IgD(+)CD27(+) B lymphocytes preferentially responded to neutrophil-derived cytokines. Costimulation with catecholamines, carcinoembryonic antigen cell adhesion molecule 8 (CEACAM8), and IFN-? caused differentiation of IgM(+)IgD(+)CD27(+) B cells into PCs, induced class switching to IgG2, and was reproducible in cocultures with neutrophils. In conclusion, this study substantiates memory B-cell characteristics of human IgM(+)IgD(+)CD27(+) B cells in that they share typical memory B-cell transcription patterns with IgG(+) post-GC B cells and show a faster and more vigorous restimulation potential, a hallmark of immune memory. Moreover, this work reveals a functional plasticity of human IgM memory B cells by showing their propensity to undergo secondary GC reactions upon reactivation, but also by their special role in early inflammation via interaction with immunomodulatory neutrophils. PMID:25624468

Seifert, Marc; Przekopowitz, Martina; Taudien, Sarah; Lollies, Anna; Ronge, Viola; Drees, Britta; Lindemann, Monika; Hillen, Uwe; Engler, Harald; Singer, Bernhard B; Küppers, Ralf

2015-02-10

277

Separation of the PROX1 gene from upstream conserved elements in a complex inversion\\/translocation patient with hypoplastic left heart  

Microsoft Academic Search

Hypoplastic left heart (HLH) occurs in at least 1 in 10 000 live births but may be more common in utero. Its causes are poorly understood but a number of affected cases are associated with chromosomal abnormalities. We set out to localize the breakpoints in a patient with sporadic HLH and a de novo translocation. Initial studies showed that the

Harinder K Gill; Sian R Parsons; Cosma Spalluto; Angela F Davies; Victoria J Knorz; Clare EG Burlinson; Bee Ling Ng; Nigel P Carter; Caroline Mackie Ogilvie; David I Wilson; Roland G Roberts

2009-01-01

278

Chimeric Ecotropic MLV Envelope Proteins that Carry EGF Receptor-Specific Ligands and the Pseudomonas Exotoxin A Translocation Domain to Target Gene Transfer to Human Cancer Cells  

Microsoft Academic Search

Redirecting retroviral vector transduction simply by insertion of a ligand into the envelope (Env) protein has met with several obstacles. For example, virions targeted to epidermal growth factor receptor (EGFR), after receptor binding, rapidly traffic to the lysosomes, where they are degraded. Exotoxin A of Pseudomonas aeruginosa has the ability to translocate from endosomes to the cytoplasm by means of

Otto Erlwein; Winfried Wels; Barbara S. Schnierle

2002-01-01

279

Appropriate management of molecular subtypes of diffuse large B-cell lymphoma.  

PubMed

In recent years, we have made huge strides in our understanding of the molecular complexity of diffuse large B-cell lymphoma (DLBCL). New technologies, such as gene expression profiling, RNA interference screening, and DNA sequencing, have identified several new signaling pathways and therapeutic targets for drug development. While we once considered DLBCL to be a single disease entity, recent insights have helped identify the existence of at least three distinct molecular diseases: a germinal center B-cell-like subtype, an activated B-cell-like subtype, and a primary mediastinal B-cell lymphoma subtype. All three subtypes originate from different stages of B-cell differentiation and are characterized by distinct mechanisms of oncogenic activation. This classification of DLBCL has laid the foundation for the development of new agents and novel strategies that target individual subtypes. PMID:24839807

Dunleavy, Kieron; Wilson, Wyndham H

2014-04-01

280

Follicular B cell trafficking within the spleen actively restricts humoral immune responses  

PubMed Central

Summary Follicular (FO) and marginal zone (MZ) B cells are maintained in distinct locations within the spleen but the genetic basis for this separation is still enigmatic. We now report that B cell sequestration requires lineage-specific regulation of migratory receptors by the transcription factor, Klf2. Moreover, using gene-targeted mice we show that altered splenic B cell migration confers a significant in vivo gain-of-function phenotype to FO B cells, including the ability to quickly respond to MZ-associated antigens and pathogens in a T cell-dependent manner. This work demonstrates that in wild-type animals, naïve FO B cells are actively removed from the MZ, thus restricting their capacity to respond to blood-borne pathogens. PMID:20691614

Hoek, Kristen L.; Gordy, Laura E.; Collins, Patrick L.; Parekh, Vrajesh V.; Aune, Thomas M.; Joyce, Sebastian; Thomas, James W.; Van Kaer, Luc; Sebzda, Eric

2010-01-01

281

Expression and function of a novel isoform of Sox5 in malignant B cells.  

PubMed

Using a mouse model with the tumor suppressor TRAF3 deleted from B cells, we identified Sox5 as a gene strikingly up-regulated in B lymphomas. Sox5 proteins were not detected in normal or premalignant TRAF3(-/-) B cells even after treatment with B cell stimuli. The Sox5 expressed in TRAF3(-/-) B lymphomas represents a novel isoform of Sox5, and was localized in the nucleus of malignant B cells. Overexpression of Sox5 inhibited cell cycle progression, and up-regulated the protein levels of p27 and ?-catenin in human multiple myeloma cells. Together, our findings indicate that Sox5 regulates the proliferation of malignant B cells. PMID:24418753

Edwards, Shanique K E; Desai, Anand; Liu, Yan; Moore, Carissa R; Xie, Ping

2014-03-01

282

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

283

Pi 1 binding sites are negative regulators of bcl-2 expression in pre-B cells.  

PubMed Central

The bcl-2 gene is differentially regulated during B-cell development, with low-level expression in pre-B cells and higher-level expression in mature B cells. These changes correlate with susceptibility to cell death by apoptosis and suggest that the Bcl-2 protein may play a role in the control of cell death during B-cell development. We have identified two negative regulatory regions in the human bcl-2 5' flanking and 5' untranslated regions in pre-B cells; these regions have no significant function in mature B cells. Further investigation of these regions revealed two pre-B-cell-specific enhancer elements (pi 1 sites) in the 5' negative regulatory region and one in the 3' negative regulatory region. Mutational analysis confirmed that these three sites functioned as negative regulators of the bcl-2 promoter in the pre-B-cell line Nalm-6. Electrophoretic mobility shift assays with each of the three sites demonstrated a complex of identical mobility to that formed with the immunoglobulin heavy-chain enhancer pi 1 site. UV cross-linking experiments revealed that a protein with a molecular mass of 58 kDa bound to the three bcl-2 sites and to the immunoglobulin enhancer site. This protein reacted with an antibody against Ets family proteins. Constructs with the isolated pi 1 sites linked to the simian virus 40 promoter were used in transient transfection experiments in the pre-B-cell line. The bcl-2 sites decreased expression of the simian virus 40 promoter, while the immunoglobulin enhancer site increased its expression. The pi 1 sites in the bcl-2 gene may play a role in the developmental regulation of bcl-2 expression during B-cell differentiation. PMID:7791791

Chen, H M; Boxer, L M

1995-01-01

284

B-cell markers in malignant B-cell lymphoma with scleroderma-like manifestation.  

PubMed

A case is described of malignant B-cell lymphoma with scleroderma-like manifestation. Using different monoclonals as B-cell markers the tumor appeared to be positive for surface immunoglobulins (SmIg) and for B2-antigen, but negative for intracytoplasmic immunoglobulin (CIg), BA2- and FMC7-antigens. Therefore, the tumor could be determined as a highly differentiated Sm-positive early B-cell type of B-cell lymphoma. In this clinically rare manifestation of cutaneous B-cell lymphoma aspects of the cell morphology and of cellular mediated immunity are briefly discussed. PMID:6335153

Van Joost, T; Stolz, E; Blog, F B; Van der Kwast, T H; Vuzevski, V D; Van Dongen, J M

1984-12-01

285

Themis2 Is Not Required for B Cell Development, Activation, and Antibody Responses  

PubMed Central

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

2014-01-01

286

Mad3 Negatively Regulates B Cell Differentiation in the Spleen by Inducing Id2 Expression  

PubMed Central

Immature B cells migrate to the spleen where they differentiate into mature cells. This final maturation step is crucial to enable B cells to become responsive to antigens and to participate in the immune response. Previously, we showed that Id2 acts as a negative regulator of the differentiation of immature B cells occurring in the spleen. Id2 expression has been found to depend on Myc–Max–Mad transcriptional complexes in mammary epithelial cells. Nearly all studies to date have shown that Mad proteins inhibit proliferation, presumably by antagonizing the function of Myc proteins. In the current study, we followed the Mad family members during peripheral B cell differentiation. We show that Mad3 actively regulates B cell differentiation. Our results demonstrate that high expression levels of Mad3 in immature B cells induce Id2 expression, which inhibits transcription of genes essential for B cell differentiation. During their differentiation to mature cells, B cells reduce their Mad3 expression, enabling the maturation process to occur. PMID:20375148

Gore, Yael; Lantner, Frida; Hart, Gili

2010-01-01

287

Occult B-cell lymphoproliferative disorders.  

PubMed

The term monoclonal B-cell lymphocytosis (MBL) was recently introduced to identify individuals with a population of monoclonal B cells in the absence of other features that are diagnostic of a B-cell lymphoproliferative disorder. MBL is often identified through hospital investigation of a mild lymphocytosis, and approximately 1% of such individuals develop progressive disease requiring treatment per year. However, in population studies using high-sensitivity flow cytometry, MBL may be detectable in more than 10% of adults aged over 60 years, and clinical progression is rare. The majority of MBL cases have features that are characteristic of chronic lymphocytic leukaemia, but an increasing amount of information is becoming available about MBL with the features of other B-cell lymphoproliferative disorders. In addition to flow cytometry findings, the incidental detection of an occult B-cell lymphoproliferative disorder is also occurring in a significant proportion of tissue biopsy samples. In this review, the clinical and biological relationship between MBL and B-cell lymphoproliferative disorders will be discussed, with a focus on identifying the differences between low levels of peripheral blood or bone marrow involvement with lymphoma and the monoclonal B-cell populations that commonly occur in elderly adults. PMID:21261685

Rawstron, Andy C

2011-01-01

288

Interferon-Alpha Triggers B Cell Effector 1 (Be1) Commitment  

PubMed Central

B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-? play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-? triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-? gene imprinting factors. IFN-? primed naive B-cells for IFN-? production and increased IFN-? gene responsiveness to IL-12. IFN-? continues this polarization by re-inducing T-bet and up-regulating IL-12R?2 expression. IFN-? and IFN-? therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-?, IFN-? and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity. PMID:21559410

de Goër de Herve, Marie-Ghislaine; Durali, Deniz; Dembele, Bamory; Giuliani, Massimo; Tran, Tu-Anh; Azzarone, Bruno; Eid, Pierre; Tardieu, Marc; Delfraissy, Jean-François; Taoufik, Yassine

2011-01-01

289

Interferon-alpha triggers B cell effector 1 (Be1) commitment.  

PubMed

B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-? play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-? triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-? gene imprinting factors. IFN-? primed naive B-cells for IFN-? production and increased IFN-? gene responsiveness to IL-12. IFN-? continues this polarization by re-inducing T-bet and up-regulating IL-12R?2 expression. IFN-? and IFN-? therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-?, IFN-? and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity. PMID:21559410

de Goër de Herve, Marie-Ghislaine; Durali, Deniz; Dembele, Bamory; Giuliani, Massimo; Tran, Tu-Anh; Azzarone, Bruno; Eid, Pierre; Tardieu, Marc; Delfraissy, Jean-François; Taoufik, Yassine

2011-01-01

290

Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations  

SciTech Connect

Two genes have been implicated in leukemias of patients with abnormalities of chromosome 3, band q26: EVI1, which can be activated over long distances by chromosomal rearrangements involving 3q26, and EAP, a ribosomal gene that fuses with AML1 in a therapy-related myelodysplasia patient with a t(3;21)(q26.2;q22). AML1 was identified by its involvement in the t(8;21)(q22;q22) of acute myeloid leukemia. Here the authors report the consistent identification of fusion transcripts between AML1 and EAP or between AML1 and previously unidentified sequences that was named MDS1 (MDS)-associated sequences in the leukemic cells of four patients with therapy-related myelodysplasia/acute myeloid leukemia and in one patient with chronic myelogenous leukemia in blast crisis, all of whom had a t(3;21). In addition, they have identified a third chimeric transcript, AML1/EVI1, in one of the therapy-related acute myeloid leukemia patients. Pulsed-field gel electrophoresis established the order of the genes as EAP, the most telomeric, and EVI1, the most centromeric, gene. The results indicate that translocations could involve multiple genes and affect gene expression over long distances.

Nucifora, G.; Begy, C.R.; Kobayashi, H.; Roulston, D.; Rowley, J.D. [Univ. of Chicago, IL (United States); Claxton, D. [Univ. of Texas, Houston, TX (United States); Pedersen-Bjergaard, J. [Dept. of Hematology, Copenhagen (Denmark); Parganas, E.; Ihle, J.N. [St. Jude Children`s Research Hospital, Memphis, TN (United States)

1994-04-26

291

Analysis of the cluster of ribosomal protein genes in the plastid genome of a unicellular red alga Cyanidioschyzon merolae: translocation of the str cluster as an early event in the rhodophyte-chromophyte lineage of plastid evolution.  

PubMed

The nucleotide sequence of a cluster of ribosomal protein genes in the plastid genome of a unicellular red alga, Cyanidioschyzon merolae, which has been supposed to be the most primitive alga, was determined. The phylogenetic tree inferred from the amino acid sequence of ribosomal proteins of two rhodophytes, a chromophyte, a glaucophyte, two chlorophytes (land plants), a cyanobacterium, and three eubacteria suggested a close relationship between the cyanobacterium Synechocystis PCC6803 and the plastids of various species in the kingdom Plantae, which is consistent with the hypothesis of the endosymbiotic origin of plastids. In this tree, the two species of rhodophytes were grouped with the chromophyte, and the glaucophyte was grouped with the chlorophytes. Analysis of the organization of the genes encoding the ribosomal proteins suggested that the translocation of the str cluster occurred early in the lineage of rhodophytes and chromophytes after these groups had been separated from chlorophytes and glaucophytes. PMID:9419246

Ohta, N; Sato, N; Nozaki, H; Kuroiwa, T

1997-12-01

292

Translocating Laysan Teal  

USGS Multimedia Gallery

John Klavitter of the US Fish and Wildlife Service, left, and USGS biologist Michelle Reynolds attach transmitters to critically endangered Laysan teal that were translocated from Laysan to Midway Island to expand the species' population and range. ...

293

Marginal zone lymphoma of both spleen and kidney displaying transformation into large B-cell lymphoma  

Microsoft Academic Search

We report a case of simultaneous involvement of the spleen and the left kidney in a marginal zone lymphoma with a monotypic\\u000a lymphoplasmacytic cell component, which transformed into a diffuse large B-cell lymphoma of the immunoblastic type. PCR showed\\u000a that the small and large B-cell populations carried the same type of immunoglobulin heavy chain gene rearrangement. This type\\u000a of rearrangement

A. Canelhas; E. Compérat; A. Le Tourneau; T. Molina; M. Ramos; P. Ribeiro; A. Pimenta; J. Diebold; J. Audouin

2006-01-01

294

Ets1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease  

Microsoft Academic Search

It has been shown that mice with a targeted mutation in the Ets-1 gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this Ets-1 hypomorphic allele possess very few marginal zone B cells and have

Duncheng Wang; Shinu A. John; James L. Clements; Dean H. Percy; Kevin P. Barton; Lee Ann Garrett-Sinha

2005-01-01

295

Eur J Immunol. Author manuscript Splenic marginal zone B cells in humans: where do they mutate their Ig  

E-print Network

cells have mutated Ig genes and harbor a splenic marginal zone phenotype. The group of R. K ppers has ; genetics ; Mutation ; Spleen ; cytology ; immunology Introduction: Memory B cell subsets in humans" " R. K at their surface and a mutated Ig receptor . Among these­ % [1] memory B cells, about half of them are switched

Boyer, Edmond

296

Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal  

PubMed Central

B cells and their immunoglobulin products participate in allograft rejection of transplanted human kidneys in which an interesting feature is the presence of a germinal center like B-cell clusters in the allograft. We report here that the immunoglobulin repertoires of these infiltrating B cells are highly restricted and the B cells within a cluster are clonal. Antibody libraries made from the infiltrating B cells of individual patients unexpectedly revealed that each patient utilizes a particular set of dominant germ line genes as well as dominant complementarity determining region 3. Comparison of kidney and peripheral blood from the same patient showed that the immunoglobulin genes from both compartments had dominant clones, but they differed. The lymphocytes that infiltrate the kidneys express the immunoglobulin gene somatic recombination machinery usually restricted to highly activated lymphocytes in germinal centers and lymphomas. An analogy can be made between the inescapable antigenic drive in chronic infection versus that in an allograft, both of which may lead to emergence of dominant B-cell clones and even lymphoid malignancy. PMID:21415369

Cheng, Julong; Torkamani, Ali; Grover, Rajesh K.; Jones, Teresa M.; Ruiz, Diana I.; Schork, Nicholas J.; Quigley, Michael M.; Hall, F. Wesley; Salomon, Daniel R.; Lerner, Richard A.

2011-01-01

297

Primary Hepatosplenic Large B-Cell Lymphoma  

Microsoft Academic Search

Diffuse large B-cell lymphoma is the most common form of lymphoma. It usually begins in the lymph nodes; up to 40% may have an extranodal presentation. According to a definition of primary extranodal lymphoma with presentation only in extranodal sites, there are reports of large B-cell lymphomas limited to liver or spleen as separate entities, and to date there have

M. R. Morales-Polanco; R. Drijansky-Morgenstern; E. Murillo-Meza; E. Gómez-Morales

2008-01-01

298

Tolerogenicity of Resting and Activated B Cells  

Microsoft Academic Search

Summary Antigen presentation by resting splenic B cells has been shown previously to induce T helper I cell (Thl) anergy. In contrast to expectations, it was found here that B cells treated with F(ab')2 goat anti-mouse immunoglobulin (IgM) for 24 or 48 h also presented antigen (Ag) to Thl cells in a manner that induced dramatic Ag-specific proliferative inactivation. The

Kathleen M. Gilbert; William O. Weigle

299

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

300

Isotype Control of B Cell Signaling  

NSDL National Science Digital Library

The B cell receptor (BCR) consists of an antigen-binding membrane immunoglobulin (mIg) associated with the CD79α and CD79β heterodimer. Nai¨ve B cells express the IgM and IgD isotypes, which have very short cytoplasmic tails and therefore depend on CD79α and CD79β for signal transduction. After antigenic stimulation, B cells undergo isotype switching to yield IgG, IgE, or IgA. Recent research suggests that the ability of the B cell coreceptor CD22 to regulate BCR signaling depends on the isotype of the mIg cytoplasmic tail. Cell lines that express a BCR with the cytoplasmic tail from IgG, the isotype found in memory B cells, are not subject to CD22 regulation, whereas cell lines that express BCRs with IgM cytoplasmic tails are subject to CD22 regulation. Moreover, stimulation through BCRs containing an IgG cytoplasmic tail causes increased numbers of antigen-specific clones to accumulate. These observations are a valuable step toward understanding the difference in B cell signaling between nai¨ve and memory cells. Here, we discuss the implications of these findings for CD22 regulation and signaling through the mIgG-containing BCR.

Karlee Silver (Headington;Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital REV); Richard J. Cornall (Headington;Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital REV)

2003-05-27

301

p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors  

Microsoft Academic Search

We propose that the apoptotic function of p53 has an important role in B-cell homeostasis, which is important for the prevention of B-cell lymphomas. We created a mouse model (m?pro) that lacked residues 58–88 of the proline-rich domain of p53. m?pro is defective for apoptosis, but is able to arrest cell-cycle progression in hematopoietic tissues. m?pro develops late-onset B-cell lymphoma,

T L Slatter; P Ganesan; C Holzhauer; R Mehta; C Rubio; G Williams; M Wilson; J A Royds; M A Baird; A W Braithwaite

2010-01-01

302

Through an ITIM-independent mechanism the Fc?RIIB blocks B cell activation by disrupting the colocalized microclustering of the B cell receptor and CD19.  

PubMed

B cell activation is regulated through the interplay of the BCR with the inhibitory coreceptor Fc?RIIB and the activating coreceptor CD19. Recent studies suggest that Ag-driven BCR microclusters are efficiently converted to a signaling active state on colocalization with CD19 microclusters. Using total internal reflection fluorescence microscopy-based, high-resolution, high-speed live-cell and molecule imaging approaches, we show that when co-ligated to the BCR, the Fc?RIIB can inhibit B cell activation by blocking the colocalization of BCR and CD19 microclusters within the B cell immunological synapse. Remarkably, this inhibitory function of Fc?RIIB is dependent not on its well-characterized ITIM-containing cytoplasmic domain, but its transmembrane domain. Indeed, human primary B cells from systemic lupus erythematosus patients homozygous for gene encoding the loss-of-function transmembrane domain mutant Fc?RIIB-I232T fail to block the synaptic colocalization of the BCR with CD19, leading to dysregulated recruitment of downstream signaling molecule p-PI3K to membrane proximal signalosome. This inhibitory function of Fc?RIIB in impairing the spatial-temporal colocalization of BCR and CD19 microclusters in the B cell immunological synapse may help explain the hyper-reactive features of systemic lupus erythematosus patient B cells in reported studies. These observations may also provide new targets for therapies for systemic autoimmune disease. PMID:24790152

Xu, Liling; Li, Gen; Wang, Jing; Fan, Yilin; Wan, Zhengpeng; Zhang, Shaosen; Shaheen, Samina; Li, Jing; Wang, Li; Yue, Cai; Zhao, Yan; Wang, Fei; Brzostowski, Joseph; Chen, Ying-Hua; Zheng, Wenjie; Liu, Wanli

2014-06-01

303

Magnetic Resonance Imaging and Computed Tomography Characteristics of Renal Cell Carcinoma Associated with Xp11.2 Translocation/TFE3 Gene Fusion  

PubMed Central

Purpose To characterize Xp11.2 translocation renal cell carcinoma (RCC) using magnetic resonance imaging (MRI) and computed tomography (CT). Methods This study retrospectively collected the MRI and CT data of twelve patients with Xp11.2 translocation RCC confirmed by pathology. Nine cases underwent dynamic contrast-enhanced MRI (DCE-MRI) and 6 cases underwent CT, of which 3 cases underwent MRI and CT simultaneously. The MRI and CT findings were analyzed in regard to tumor position, size, hemorrhagic, cystic or necrotic components, calcification, tumor density, signal intensity and enhancement features. Results The age of the 12 patients ranged from 13 to 46 years (mean age: 23 years). T2WI revealed heterogeneous intensity, hyper-intensity, and slight hypo-intensity in 6 cases, 2 cases, and 1 case, respectively. On DCE-MR images, mild, moderate, and marked rim enhancement of the tumor in the corticomedullary phase (CMP) were observed in 1, 6, and 2 cases, respectively. The tumor parenchyma showed iso-attenuation (n?=?4) or slight hyper-attenuation (n?=?1) compared to the normal renal cortex on non-contrast CT images. Imaging findings were suggestive of hemorrhage (n?=?4) or necrosis (n?=?8) in the tumors, and there was evidence of calcification in 8 cases by CT (n?=?3) and pathology (n?=?8). On dynamic contrast-enhanced CT images, 3 cases and 1 case manifested moderate and strong CMP enhancement, respectively. Nine tumors by MRI and 4 tumors by CT showed prolonged enhancement. Three neoplasms presented at stage I, 2 at stage II, 3 at stage III, and 4 at stage IV according the 2010 AJCC staging criteria. Conclusions XP11.2 translocation RCC should be considered when a child or young adult patient presents with a renal tumor with heterogeneous features such as hemorrhage, necrosis, cystic changes, and calcification on CT and MRI and/or is accompanied by metastatic evidence. PMID:24926688

Li, Yuan; Wang, Chaofu; Zhou, Liangping; Zhu, Hui; Peng, Weijun

2014-01-01

304

B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny.  

PubMed

The long-term immunologic effects of B cell depletion with rituximab and the characteristics of the reconstituting B cell pool in lymphoma patients are not well defined, despite the widespread usage of this therapy. Here we report that during the B cell reconstitution phase a majority of the peripheral blood B cells have an immature transitional phenotype (47.8%+/-25.2% vs. 4.4%+/-2.4% for normal controls, p<0.0001), similar to what has been described during the original ontogeny of the immune system and following bone marrow transplantation. Moreover, the recovery of the CD27+ memory B cell pool was delayed compared to normal B cell ontogeny, remaining below normal controls at 1 year post-rituximab (4.4%+/-3% vs. 31%+/-7%, p<0.0001). Expansion of functionally immature B cells and decreased memory B cells may contribute to an immunodeficient state in patients recovering from rituximab mediated B cell depletion, particularly with repeated treatment. PMID:17008130

Anolik, Jennifer H; Friedberg, Jonathan W; Zheng, Bo; Barnard, Jennifer; Owen, Teresa; Cushing, Emily; Kelly, Jennifer; Milner, Eric C B; Fisher, Richard I; Sanz, Iñaki

2007-02-01

305

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

306

Cathepsin-K immunoreactivity distinguishes MiTF\\/TFE family renal translocation carcinomas from other renal carcinomas  

Microsoft Academic Search

The microphthalmia transcription factor\\/transcription factor E (TFE)-family translocation renal cell carcinomas bear specific translocations that result in overexpression of TFE3 or TFEB. TFE3 fusion gene product overexpression occurs as consequence of different translocations involving chromosome Xp11.2, whereas TFEB overexpression is the result of the specific translocation t(6;11)(p21;q12), which fuses the Alpha gene to TFEB. Both TFE3 and TFEB are closely

G Martignoni; M Pea; S Gobbo; M Brunelli; F Bonetti; D Segala; Chin-Chen Pan; G Netto; C Doglioni; O Hes; P Argani; M Chilosi

2009-01-01

307

Characterising B cell numbers and memory B cells in HIV infected and uninfected Malawian adults  

PubMed Central

Background Untreated human immunodeficiency virus (HIV) disease disrupts B cell populations causing reduced memory and reduced naïve resting B cells leading to increases in specific co-infections and impaired responses to vaccines. To what extent antiretroviral treatment reverses these changes in an African population is uncertain. Methods A cross-sectional study was performed. We recruited HIV-uninfected and HIV-infected Malawian adults both on and off antiretroviral therapy attending the Queen Elizabeth Central hospital in Malawi. Using flow cytometry, we enumerated B cells and characterized memory B cells and compared these measurements by the different recruitment groups. Results Overall 64 participants were recruited - 20 HIV uninfected (HIV-), 30 HIV infected ART naïve (HIV+N) and 14 HIV-infected ART treated (HIV+T). ART treatment had been taken for a median of 33 months (Range 12-60 months). Compared to HIV- the HIV+N adults had low absolute number of naïve resting B cells (111 vs. 180 cells/?l p = 0.008); reduced memory B cells (27 vs. 51 cells/?l p = 0.0008). The HIV+T adults had B-cell numbers similar to HIV- except for memory B cells that remained significantly lower (30 vs. 51 cells/?l p = 0.02). In the HIV+N group we did not find an association between CD4 count and B cell numbers. Conclusions HIV infected Malawian adults have abnormal B-cell numbers. Individuals treated with ART show a return to normal in B-cell numbers but a persistent deficit in the memory subset is noted. This has important implications for long term susceptibility to co-infections and should be evaluated further in a larger cohort study. PMID:20860822

2010-01-01

308

Detection of complement receptors 1 and 2 on mouse splenic B cells using flow cytometry.  

PubMed

The complement receptor 2 (Cr2) gene is exclusively expressed in B cells and follicular dendritic cells (FDC) in mice and in humans. However, mice also express an alternative splice variant, CR1, of the Cr2 gene. CR2 and CR1 are receptors for the complement component 3 (C3) cleavage fragments C3d(g) and iC3b. Additionally, CR1 is a receptor for C3b and regulates complement convertase activity. CR1 and CR2 have various functions including antigen retention by FDC, regulation of surface complement convertases, and canonically as the B cell coreceptor in which CR2 acts to lower the threshold for B cell activation. Detection of CR1 and CR2 can be utilized to identify B cells and, depending on expression level, to delineate various B cell populations. This protocol describes methods for detecting CR1/2 expression on splenic B cell subsets via flow cytometry. PMID:24218269

Donius, Luke R; Weis, John H

2014-01-01

309

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

310

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

311

Role of Tyrosine Phosphorylation of HS1 in B Cell Antigen Receptor-mediated Apoptosis  

PubMed Central

The 75-kD HS1 protein is highly tyrosine-phosphorylated during B cell antigen receptor (BCR)-mediated signaling. Owing to low expression of HS1, WEHI-231-derived M1 cells, unlike the parental cells, are insensitive to BCR-mediated apoptosis. Here, we show that BCR-associated tyrosine kinases Lyn and Syk synergistically phosphorylate HS1, and that Tyr378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. In addition, unlike wild-type HS1, a mutant HS1 carrying the mutations Phe-378 and Phe-397 was unable to render M1 cells sensitive to apoptosis. Wild-type HS1, but not the mutant, localized to the nucleus under the synergy of Lyn and Syk. Thus, tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID:9104825

Yamanashi, Yuji; Fukuda, Takahiro; Nishizumi, Hirofumi; Inazu, Tetsuya; Higashi, Ken-ichi; Kitamura, Daisuke; Ishida, Takaomi; Yamamura, Hirohei; Watanabe, Takeshi; Yamamoto, Tadashi

1997-01-01

312

A Brucella Virulence Factor Targets Macrophages to Trigger B-cell Proliferation*  

PubMed Central

Brucella spp. and Trypanosoma cruzi are two intracellular pathogens that have no evolutionary common origins but share a similar lifestyle as they establish chronic infections for which they have to circumvent the host immune response. Both pathogens have a virulence factor (prpA in Brucella and tcPrac in T. cruzi) that induces B-cell proliferation and promotes the establishment of the chronic phase of the infectious process. We show here that, even though PrpA promotes B-cell proliferation, it targets macrophages in vitro and is translocated to the cytoplasm during the intracellular replication phase. We observed that PrpA-treated macrophages induce the secretion of a soluble factor responsible for B-cell proliferation and identified nonmuscular myosin IIA (NMM-IIA) as a receptor required for binding and function of this virulence factor. Finally, we show that the Trypanosoma cruzi homologue of PrpA also targets macrophages to induce B-cell proliferation through the same receptor, indicating that this virulence strategy is conserved between a bacterial and a protozoan pathogen. PMID:23720774

Spera, Juan M.; Herrmann, Claudia K.; Roset, Mara S.; Comerci, Diego J.; Ugalde, Juan E.

2013-01-01

313

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

314

Persistent Polyclonal B Cell Lymphocytosis B Cells Can Be Activated through CD40-CD154 Interaction  

PubMed Central

Persistent polyclonal B cell lymphocytosis (PPBL) is a rare disorder, diagnosed primarily in adult female smokers and characterized by an expansion of CD19+CD27+IgM+ memory B cells, by the presence of binucleated lymphocytes, and by a moderate elevation of serum IgM. The clinical course is usually benign, but it is not known whether or not PPBL might be part of a process leading to the emergence of a malignant proliferative disorder. In this study we sought to investigate the functional response of B cells from patients with PPBL by use of an optimal memory B cell culture model based on the CD40-CD154 interaction. We found that the proliferation of PPBL B cells was almost as important as that of B cells from normal controls, resulting in high immunoglobulin secretion with in vitro isotypic switching. We conclude that the CD40-CD154 activation pathway is functional in the memory B cell population of PPBL patients, suggesting that the disorder may be due to either a dysfunction of other cells in the microenvironment or a possible defect in another B cell activation pathway. PMID:25580126

Néron, Sonia; Darveau, André; Delage, Robert

2014-01-01

315

B cell lymphoma in hiv transgenic mice  

PubMed Central

Background Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice. Results The transformed B cell population consists of CD19+pre-BCR+CD127+CD43+CD93+ precursor B cells. The tumor cells are clonal and characterized by an increased expression of several cellular oncogenes. Expression of B cell-stimulatory cytokines IL-1?, IL-6, IL-10, IL-12p40, IL-13 and TNF? and HIV proteins p17, gp120 and nef were elevated in the Tg mice with lymphoma. Conclusions Increased expression of HIV proteins and the B-cell stimulatory factors is consistent with the interpretation that one or more of these factors play a role in lymphoma development. The lymphomas share many similarities with those occurring in HIV/AIDS+ patients and may provide a valuable model for understanding AIDS-related lymphomagenesis and elucidating the role played by HIV-1. PMID:23985023

2013-01-01

316

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. PMID:25360073

Chang, Jae-Hoon

2014-01-01

317

High-level DNA amplifications are common genetic aberrations in B-cell neoplasms.  

PubMed Central

Gene amplification is one of the molecular mechanisms resulting in the up-regulation of gene expression. In non-Hodgkin's lymphomas, such gene amplifications have been identified rarely. Using comparative genomic hybridization, a technique that has proven to be very sensitive for the detection of high-level DNA amplifications, we analyzed 108 cases of B-cell neoplasms (42 chronic B-cell leukemias, 5 mantle cell lymphomas, and 61 aggressive B-cell lymphomas). Twenty-four high-level amplifications were identified in 13% of the patients and mapped to 15 different genomic regions. Regions most frequently amplified were bands Xq26-28, 2p23-24, and 2p14-16 as well as 18q21 (three times each). Amplification of several proto-oncogenes and a cell cycle control gene (N-MYC (two cases), BCL2, CCND2, and GLI) located within the amplified regions was demonstrated by Southern blot analysis or fluorescence in situ hybridization to interphase nuclei of tumor cells. These data demonstrate that gene amplifications in B-cell neoplasms are much more frequent than previously assumed. The identification of highly amplified DNA regions and genes included in the amplicons provides important information for further analyses of genetic events involved in lymphomagenesis. Images Figure 2 Figure 3 PMID:9250147

Werner, C. A.; Döhner, H.; Joos, S.; Trümper, L. H.; Baudis, M.; Barth, T. F.; Ott, G.; Möller, P.; Lichter, P.; Bentz, M.

1997-01-01

318

Enforced Expression of the Transcriptional Coactivator OBF1 Impairs B Cell Differentiation at the Earliest Stage of Development  

PubMed Central

OBF1, also known as Bob.1 or OCA-B, is a B lymphocyte-specific transcription factor which coactivates Oct1 and Oct2 on B cell specific promoters. So far, the function of OBF1 has been mainly identified in late stage B cell populations. The central defect of OBF1 deficient mice is a severely reduced immune response to T cell-dependent antigens and a lack of germinal center formation in the spleen. Relatively little is known about a potential function of OBF1 in developing B cells. Here we have generated transgenic mice overexpressing OBF1 in B cells under the control of the immunoglobulin heavy chain promoter and enhancer. Surprisingly, these mice have greatly reduced numbers of follicular B cells in the periphery and have a compromised immune response. Furthermore, B cell differentiation is impaired at an early stage in the bone marrow: a first block is observed during B cell commitment and a second differentiation block is seen at the large preB2 cell stage. The cells that succeed to escape the block and to differentiate into mature B cells have post-translationally downregulated the expression of transgene, indicating that expression of OBF1 beyond the normal level early in B cell development is deleterious. Transcriptome analysis identified genes deregulated in these mice and Id2 and Id3, two known negative regulators of B cell differentiation, were found to be upregulated in the EPLM and preB cells of the transgenic mice. Furthermore, the Id2 and Id3 promoters contain octamer-like sites, to which OBF1 can bind. These results provide evidence that tight regulation of OBF1 expression in early B cells is essential to allow efficient B lymphocyte differentiation. PMID:19104664

Du Roure, Camille; Bartholdy, Boris; Kohler, Hubertus; Matthias, Gabriele; Rolink, Antonius G.; Matthias, Patrick

2008-01-01

319

Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL).  

PubMed

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and recently described entity. The review of the literature show PPBL is diagnosed predominantly but not exclusively in women, usually smokers. PPBL is recognized by a moderate, chronic and absolute lymphocytosis (>4 × 10(9)/l) in the peripheral blood. In 10% of cases without lymphocytosis, the PPBL diagnosis has to be suggested by peripheral blood examination showing in all cases atypical binucleated lymphocytes. A polyclonal serum IgM is also associated and HLA-DR7 expression is present in most cases. Contrary to B-cell chronic lymphoproliferative disorders (B-CLPD), peripheral B cells are polyclonal with kappa and lambda light-chain expression and no clonal rearrangement of immunoglobulin heavy chain genes is usually demonstrated. The detection of an extra isochromosome for the long arm of chromosome 3 +i(3)(q10) has to be considered as a specific marker of PPBL. We performed conventional cytogenetic analysis (CCA) in 111 patients with typical PPBL we followed-up more than 4 years. +i(3q) was detected in 34% (33/98), PCC in 8% (8/98) and both abnormalities in 31% (30/98). CCA showed neither +i(3q) nor PCC in 28% (27/98). Fluorescence in situ hybridization (FISH) was also performed in 84 cases and +i(3q) was detected in 71% (60/84). When combining both procedures in 84 patients, +i(3q) was detected in 17 patients with negative CCA and was confirmed in 43 patients with positive CCA. CCA and FISH were both negative in 24 cases. Whether patients with PPBL are at increased risk of hematological malignancy remains unclear. After a median follow-up of 4.4 years, most PPBL patients presented a stable clinical and biological course. Six patients died from pulmonary cancer, myocardial infarction, cerebral aneurysm rupture or diffuse large B-cell lymphoma. Two patients had IgM monoclonal gammopathy of undetermined significance (MGUS) at the time of PPBL diagnosis and two other patients developed IgM MGUS respectively 12 and 22 years after PPBL diagnosis. A malignant non Hodgkin's lymphoma (NHL) appeared in 3 additional patients: two patients presented diffuse large B cell lymphoma and 1 patient a splenic marginal zone lymphoma. In conclusion, the possibility of PPBL to evolve toward a clonal proliferation, malignant lymphoma or secondary solid cancer lead us to consider PPBL not as a benign pathology. We recommend a careful and continued clinical and biological long-term follow-up in all PPBL patients. PMID:21127753

Troussard, Xavier; Cornet, Edouard; Lesesve, Jean-François; Kourel, Carine; Mossafa, Hossein

2008-01-01

320

Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL)  

PubMed Central

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and recently described entity. The review of the literature show PPBL is diagnosed predominantly but not exclusively in women, usually smokers. PPBL is recognized by a moderate, chronic and absolute lymphocytosis (>4 × 109/l) in the peripheral blood. In 10% of cases without lymphocytosis, the PPBL diagnosis has to be suggested by peripheral blood examination showing in all cases atypical binucleated lymphocytes. A polyclonal serum IgM is also associated and HLA-DR7 expression is present in most cases. Contrary to B-cell chronic lymphoproliferative disorders (B-CLPD), peripheral B cells are polyclonal with kappa and lambda light-chain expression and no clonal rearrangement of immunoglobulin heavy chain genes is usually demonstrated. The detection of an extra isochromosome for the long arm of chromosome 3 +i(3)(q10) has to be considered as a specific marker of PPBL. We performed conventional cytogenetic analysis (CCA) in 111 patients with typical PPBL we followed-up more than 4 years. +i(3q) was detected in 34% (33/98), PCC in 8% (8/98) and both abnormalities in 31% (30/98). CCA showed neither +i(3q) nor PCC in 28% (27/98). Fluorescence in situ hybridization (FISH) was also performed in 84 cases and +i(3q) was detected in 71% (60/84). When combining both procedures in 84 patients, +i(3q) was detected in 17 patients with negative CCA and was confirmed in 43 patients with positive CCA. CCA and FISH were both negative in 24 cases. Whether patients with PPBL are at increased risk of hematological malignancy remains unclear. After a median follow-up of 4.4 years, most PPBL patients presented a stable clinical and biological course. Six patients died from pulmonary cancer, myocardial infarction, cerebral aneurysm rupture or diffuse large B-cell lymphoma. Two patients had IgM monoclonal gammopathy of undetermined significance (MGUS) at the time of PPBL diagnosis and two other patients developed IgM MGUS respectively 12 and 22 years after PPBL diagnosis. A malignant non Hodgkin's lymphoma (NHL) appeared in 3 additional patients: two patients presented diffuse large B cell lymphoma and 1 patient a splenic marginal zone lymphoma. In conclusion, the possibility of PPBL to evolve toward a clonal proliferation, malignant lymphoma or secondary solid cancer lead us to consider PPBL not as a benign pathology. We recommend a careful and continued clinical and biological long-term follow-up in all PPBL patients. PMID:21127753

Troussard, Xavier; Cornet, Edouard; Lesesve, Jean-François; Kourel, Carine; Mossafa, Hossein

2008-01-01

321

Loss of signalling via G?13 in germinal centre B-cell-derived lymphoma.  

PubMed

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a G?12 and G?13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding G?13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. G?13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and G?13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in G?13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the G?13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of G?13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via G?13. These findings identify a G?13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma. PMID:25274307

Muppidi, Jagan R; Schmitz, Roland; Green, Jesse A; Xiao, Wenming; Larsen, Adrien B; Braun, Sterling E; An, Jinping; Xu, Ying; Rosenwald, Andreas; Ott, German; Gascoyne, Randy D; Rimsza, Lisa M; Campo, Elias; Jaffe, Elaine S; Delabie, Jan; Smeland, Erlend B; Braziel, Rita M; Tubbs, Raymond R; Cook, J R; Weisenburger, Dennis D; Chan, Wing C; Vaidehi, Nagarajan; Staudt, Louis M; Cyster, Jason G

2014-12-11

322

Control of B Cell Development by the Histone H2A Deubiquitinase MYSM1  

PubMed Central

Epigenetic histone modifications play critical roles in the control of gene transcription. Recently, an increasing number of histone H2A deubiquitinases have been identified and characterized. However, the physiological functions for this entire group of histone H2A deubiquitinases remain unknown. In this study, we revealed that the histone H2A deubiquitinase MYSM1 plays an essential and intrinsic role in early B-cell development. MYSM1 deficiency results in a block in early B-cell commitment and a defect of B-cell progenitors in expression of EBF1 and other B-lymphoid genes. We further demonstrated that MYSM1 de-represses EBF1 transcription in B-cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus. Thus, this study not only uncovers the essential role for MYSM1 in gene transcription during early B cell development, but also underscores the biological significance of reversible epigenetic histone H2A ubiquitination. PMID:22169041

Jiang, Xiao-Xia; Nguyen, Quan; Chou, YuChia; Wang, Tao; Nandakumar, Vijayalakshmi; Yates, Peter; Jones, Lindsey; Wang, Lifeng; Won, Hae-Jung; Lee, Hye-Ra; Jung, Jae U; Muschen, Markus; Huang, Xue F; Chen, Si-Yi

2013-01-01

323

Efficient Induction of Wheat-Agropyron cristatum 6P Translocation Lines and GISH Detection  

PubMed Central

The narrow genetic background restricts wheat yield and quality improvement. The wild relatives of wheat are the huge gene pools for wheat improvement and can broaden its genetic basis. Production of wheat-alien translocation lines can transfer alien genes to wheat. So it is important to develop an efficient method to induce wheat-alien chromosome translocation. Agropyroncristatum (P genome) carries many potential genes beneficial to disease resistance, stress tolerance and high yield. Chromosome 6P possesses the desirable genes exhibiting good agronomic traits, such as high grain number per spike, powdery mildew resistance and stress tolerance. In this study, the wheat-A. cristatum disomic addition was used as bridge material to produce wheat-A. cristatum translocation lines induced by 60Co-?irradiation. The results of genomic in situ hybridization showed that 216 plants contained alien chromosome translocation among 571 self-pollinated progenies. The frequency of translocation was 37.83%, much higher than previous reports. Moreover, various alien translocation types were identified. The analysis of M2 showed that 62.5% of intergeneric translocation lines grew normally without losing the translocated chromosomes. The paper reported a high efficient technical method for inducing alien translocation between wheat and Agropyroncristatum. Additionally, these translocation lines will be valuable for not only basic research on genetic balance, interaction and expression of different chromosome segments of wheat and alien species, but also wheat breeding programs to utilize superior agronomic traits and good compensation effect from alien chromosomes. PMID:23874966

Song, Liqiang; Jiang, Lili; Han, Haiming; Gao, Ainong; Yang, Xinming; Li, Lihui; Liu, Weihua

2013-01-01

324

Efficient induction of Wheat-agropyron cristatum 6P translocation lines and GISH detection.  

PubMed

The narrow genetic background restricts wheat yield and quality improvement. The wild relatives of wheat are the huge gene pools for wheat improvement and can broaden its genetic basis. Production of wheat-alien translocation lines can transfer alien genes to wheat. So it is important to develop an efficient method to induce wheat-alien chromosome translocation. Agropyroncristatum (P genome) carries many potential genes beneficial to disease resistance, stress tolerance and high yield. Chromosome 6P possesses the desirable genes exhibiting good agronomic traits, such as high grain number per spike, powdery mildew resistance and stress tolerance. In this study, the wheat-A. cristatum disomic addition was used as bridge material to produce wheat-A. cristatum translocation lines induced by (60)Co-?irradiation. The results of genomic in situ hybridization showed that 216 plants contained alien chromosome translocation among 571 self-pollinated progenies. The frequency of translocation was 37.83%, much higher than previous reports. Moreover, various alien translocation types were identified. The analysis of M2 showed that 62.5% of intergeneric translocation lines grew normally without losing the translocated chromosomes. The paper reported a high efficient technical method for inducing alien translocation between wheat and Agropyroncristatum. Additionally, these translocation lines will be valuable for not only basic research on genetic balance, interaction and expression of different chromosome segments of wheat and alien species, but also wheat breeding programs to utilize superior agronomic traits and good compensation effect from alien chromosomes. PMID:23874966

Song, Liqiang; Jiang, Lili; Han, Haiming; Gao, Ainong; Yang, Xinming; Li, Lihui; Liu, Weihua

2013-01-01

325

Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg-type and other: an update on morphology and treatment.  

PubMed

Primary cutaneous B-cell lymphoma (PCBCL) is an heterogeneous group of lymphoproliferative disorders, which account for 25-30% of all primary cutaneous lymphoma and include three main histotypes: 1) primary cutaneous marginal zone B-cell lymphoma (PCMZL); 2) primary cutaneous follicular center cell lymphoma (PCFCL); 3) primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type (PCDLBCL-LT). PCMZL and PCFCL are indolent lymphomas, with an excellent prognosis despite an high rate of cutaneous recurrences; in contrast, PCDLBCL-LT is clinically more aggressive and usually requires to be treated with multi-agent chemotherapy and anti-CD20 monoclonal antibodies. PCDLBCL-LT histologically consists of large round cells (centroblasts and immunoblasts), is characterized by strong bcl-2 expression, in the absence of t(14;18) translocation, and resembles the activated B-cell type of nodal DLBCL. Recently, the term primary cutaneous DLBCL-other (PCDLBCL-O) has been proposed to include diffuse lymphomas composed of large transformed B-cells that lack the typical features of PCDLBCL-LT and do not conform to the definition of PCFCL. Some clinical studies suggested that such cases have an indolent clinical course and may be treated in a conservative manner; however, data regarding the actual prognosis and clinical behaviour of these peculiar cases are still too limited. The spectrum of primary cutaneous DLBCL also encompasses some rare morphological variants, such as anaplastic or plasmablastic subtypes and T-cell rich B-cell lymphoma, and some recently described, exceedingly rare DLBCL subtypes, such as intravascular large B-cell lymphoma and EBV-associated large B-cell lymphoma of the elderly, which often present in the skin. PMID:23149705

Paulli, M; Lucioni, M; Maffi, A; Croci, G A; Nicola, M; Berti, E

2012-12-01

326

B Cells and Humoral Immunity in Atherosclerosis  

PubMed Central

Insights into the important contribution of inflammation and immune functions in the development and progression of atherosclerosis have greatly improved our understanding of this disease. Although the role of T cells has been extensively studied for decades, only recently has the role of B cells gained more attention. Recent studies have identified differential effects of different B-cell subsets and helped to clarify the still poorly understood mechanisms by which these act. B1 cells have been shown to prevent lesion formation, whereas B2 cells have been suggested to promote it. Natural IgM antibodies, mainly derived from B1 cells, have been shown to mediate atheroprotective effects, but the functional role of other immunoglobulin classes, particularly IgG, still remains elusive. In this review, we will focus on recent insights on the role of B cells and various immunoglobulin classes and how these may mediate their effects in atherosclerotic lesion formation. Moreover, we will highlight potential therapeutic approaches focusing on B-cell depletion that could be used to translate experimental evidence to human disease. PMID:24855199

Tsiantoulas, Dimitrios; Diehl, Cody J.; Witztum, Joseph L.; Binder, Christoph J.

2014-01-01

327

Human peripheral blood B-cell compartments: a crossroad in B-cell traffic.  

PubMed

A relatively high number of different subsets of B-cells are generated through the differentiation of early B-cell precursors into mature B-lymphocytes in the bone marrow (BM) and antigen-triggered maturation of germinal center B-cells into memory B-lymphocytes and plasmablasts in lymphoid tissues. These B-cell subpopulations, which are produced in the BM and lymphoid tissues, recirculate through peripheral blood (PB), into different tissues including mucosa and the BM, where long-living plasma cells produce antibodies. These circulating PB B-cells can be classified according to their maturation stage into i) immature/transitional, ii) naïve, and iii) memory B-lymphocytes, and iv) plasmablasts/plasma cells. Additionally, unique subsets of memory B-lymphocytes and plasmablasts/plasma cells can be identified based on their differential expression of unique Ig-heavy chain isotypes (e.g.: IgM, IgD, IgG, IgA). In the present paper, we review recent data reported in the literature about the distribution, immunophenotypic and functional characteristics of these cell subpopulations, as well as their distribution in PB according to age and seasonal changes. Additional information is also provided in this regard based on the study of a population-based cohort of 600 healthy adults aged from 20 to 80 years, recruited in the Salamanca area in western Spain. Detailed knowledge of the distribution and traffic of B-cell subsets through PB mirrors the immune status of an individual subject and it may also contribute to a better understanding of B-cell disorders related to B-cell biology and homeostasis, such as monoclonal B-cell lymphocytosis (MBL). PMID:20839338

Perez-Andres, M; Paiva, B; Nieto, W G; Caraux, A; Schmitz, A; Almeida, J; Vogt, R F; Marti, G E; Rawstron, A C; Van Zelm, M C; Van Dongen, J J M; Johnsen, H E; Klein, B; Orfao, A

2010-01-01

328

Activation-induced cytidine deaminase in antibody diversification and chromosome translocation.  

PubMed

DNA damage, rearrangement, and mutation of the human genome are the basis of carcinogenesis and thought to be avoided at all costs. An exception is the adaptive immune system where lymphocytes utilize programmed DNA damage to effect antigen receptor diversification. Both B and T lymphocytes diversify their antigen receptors through RAG1/2 mediated recombination, but B cells undergo two additional processes--somatic hypermutation (SHM) and class-switch recombination (CSR), both initiated by activation-induced cytidine deaminase (AID). AID deaminates cytidines in DNA resulting in U:G mismatches that are processed into point mutations in SHM or double-strand breaks in CSR. Although AID activity is focused at Immunoglobulin (Ig) gene loci, it also targets a wide array of non-Ig genes including oncogenes associated with lymphomas. Here, we review the molecular basis of AID regulation, targeting, and initiation of CSR and SHM, as well as AID's role in generating chromosome translocations that contribute to lymphomagenesis. PMID:22429855

Gazumyan, Anna; Bothmer, Anne; Klein, Isaac A; Nussenzweig, Michel C; McBride, Kevin M

2012-01-01

329

Protein Translocation Across Biological Membranes  

NSDL National Science Digital Library

This article provides a review of progress made in the study of protein translocation. Subcellular compartments have unique protein compositions, yet protein synthesis only occurs in the cytosol and in mitochondria and chloroplasts. How do proteins get where they need to go? The first steps are targeting to an organelle and efficient translocation across its limiting membrane. Given that most transport systems are exquisitely substrate specific, how are diverse protein sequences recognized for translocation? Are they translocated as linear polypeptide chains or after folding? During translocation, how are diverse amino acyl side chains accommodated? What are the proteins and the lipid environment that catalyze transport and couple it to energy? How is translocation coordinated with protein synthesis and folding, and how are partially translocated transmembrane proteins released into the lipid bilayer? We review here the marked progress of the past 35 years and salient questions for future work.

William Wickner (Dartmouth Medical School; Department of Biological Chemistry)

2005-12-02

330

Pre-B Cell Receptor Signaling Induces Immunoglobulin ? Locus Accessibility by Functional Redistribution of Enhancer-Mediated Chromatin Interactions  

PubMed Central

During B cell development, the precursor B cell receptor (pre-BCR) checkpoint is thought to increase immunoglobulin ? light chain (Ig?) locus accessibility to the V(D)J recombinase. Accordingly, pre-B cells lacking the pre-BCR signaling molecules Btk or Slp65 showed reduced germline V? transcription. To investigate whether pre-BCR signaling modulates V? accessibility through enhancer-mediated Ig? locus topology, we performed chromosome conformation capture and sequencing analyses. These revealed that already in pro-B cells the ? enhancers robustly interact with the ?3.2 Mb V? region and its flanking sequences. Analyses in wild-type, Btk, and Slp65 single- and double-deficient pre-B cells demonstrated that pre-BCR signaling reduces interactions of both enhancers with Ig? locus flanking sequences and increases interactions of the 3?? enhancer with V? genes. Remarkably, pre-BCR signaling does not significantly affect interactions between the intronic enhancer and V? genes, which are already robust in pro-B cells. Both enhancers interact most frequently with highly used V? genes, which are often marked by transcription factor E2a. We conclude that the ? enhancers interact with the V? region already in pro-B cells and that pre-BCR signaling induces accessibility through a functional redistribution of long-range chromatin interactions within the V? region, whereby the two enhancers play distinct roles. PMID:24558349

Stadhouders, Ralph; de Bruijn, Marjolein J. W.; Rother, Magdalena B.; Yuvaraj, Saravanan; de Almeida, Claudia Ribeiro; Kolovos, Petros; Van Zelm, Menno C.; van Ijcken, Wilfred; Grosveld, Frank; Soler, Eric; Hendriks, Rudi W.

2014-01-01

331

Allelic differences in the V{sub H}Ox-1 gene explain the absence of a B cell clonal dominance in the primary response of C57BL/6 mice to phthalate  

SciTech Connect

A highly conserved Id (CRI{sub Xmp-1}) associated with the murine (BALB/c) humoral immune response to the hapten phthalate (Xmp) is conspicuously absent in C57BL/6 mice. The absence of this Id in C57BL/6 mice is shown here to be due to the absence of the appropriate V{sub H} gene (V{sub H}Ox-1) usage in the Xmp response. To determine whether the failure to utilize this V{sub H} was due to an active suppression or to the lack of the requisite V{sub H} gene in the available repertoire, V{sub H}Ox-1 gene-specific primers were used to amplify the germ-line V{sub H}Ox-1 gene from genomic DNA from BALB/c and C57BL/6 mice. The germ-line coding sequence of the C57BL/6 allele of the V{sub H}Ox-1 gene is 99% similar to the germ-line coding sequence of the BALB/c allele. Amplification of cDNA made from splenic RNA from C57BL/6 mice confirmed that this gene is expressed. There are four nucleotide differences that lead to three amino acid changes in the predicted protein sequence. Each change is either in or immediately adjacent to a complementarity-determining region (CDR). Two of these changes are unique to the C57BL/6 allele and are not shared with CRI{sub Xmp-1}-expressing strains. These two changes are predicted to alter the Xmp binding capabilities of the C57BL/6 allelic form of this V{sub H} gene, thereby explaining the absence of the Xmp-1 clonotype, which is dominant in the primary Xmp immune response of most other strains of mice. 31 refs., 2 figs., 2 tabs.

Winter, D.B.; Diamond, M.E.; Abu-hadid, M. [Roswell Park Cancer Institute, Buffalo, NY (United States)] [and others

1995-09-01

332

B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies  

PubMed Central

B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities. PMID:24497559

Vaqué, José P.; Martínez, Nerea; Batlle-López, Ana; Pérez, Cristina; Montes-Moreno, Santiago; Sánchez-Beato, Margarita; Piris, Miguel A.

2014-01-01

333

The Transcription Factor Fli-1 Modulates Marginal Zone and Follicular B Cell Development in Mice1  

PubMed Central

Fli-1 belongs to the Ets transcription factor family and is expressed primarily in hematopoietic cells, including most cells active in immunity. To assess the role of Fli-1 in lymphocyte development in vivo, we generated mice that express a truncated Fli-1 protein, lacking the carboxy-terminal transcriptional activation domain (Fli-1?CTA). Fli-1?CTA/Fli-1?CTA mice had significantly fewer splenic follicular B cells, and an increased number of transitional and marginal zone B cells, compared to wild-type controls. Bone marrow reconstitution studies demonstrated that this phenotype is the result of lymphocyte intrinsic effects. Expression of Ig? and other genes implicated in B cell development, including Pax-5, E2A and Egr-1, are reduced, while Id1 and Id2 are increased in Fli-1?CTA/Fli-1?CTA mice. Proliferation of B cell from Fli-1?CTA/Fli-1?CTA mice was diminished, although intracellular Ca2+ flux in B cells from Fli-1?CTA/Fli-1?CTA mice was similar to that of wild-type controls after anti-IgM stimulation. Immune responses and in vitro class switch recombination were also altered in Fli-1?CTA/Fli-1?CTA mice. Thus, Fli-1 modulates B cell development both centrally and peripherally, resulting in a significant impact on the in vivo immune response. PMID:18641300

Zhang, Xian K.; Moussa, Omar; LaRue, Amanda; Bradshaw, Sarah; Molano, Ivan; Spyropoulos, Demetri D.; Gilkeson, Gary S.; Watson, Dennis K.

2008-01-01

334

Familial cryptic translocation in Angelman syndrome  

SciTech Connect

The majority of patients with Angelman syndrome have been shown to have a cytogenetic or molecular deletion on the maternally derived chromosome 15. We report on a case of Angelman syndrome in which this deletion occurs as an unbalanced cryptic translocation involving chromosomes 14 and 15. The proband was diagnosed clinically as having Angelman syndrome. Multiple cytogenetic studies were done without detecting any deletion. When DNA probes (Oncor) specific for the Prader Willi/Angelman locus became available, the patient was restudied and found to be deleted for {open_quotes}region A{close_quotes} (D15S11) but not for {open_quotes}region B{close_quotes} (GABRB3). No other abnormality was detected. The proband`s mother was then studied. The chromosome 15 marker probe and D15S11 were detected on different chromosomes. Using alpha-satellite probes, a cryptic 14;15 translocation was uncovered. This balanced translocation was also found to be carried by the sister of the proband. This case, along with a case presented at the 1993 ASHG meeting, illustrates the need for using acrocentric probes when studying Angelman syndrome patients. The proband was studied using additional probes specific for this region and found to be deleted for SNRPN but not for D15S10. The breakpoint of the translocation in this patient delineates the smallest deletion of the Angelman syndrome region reported to date and therefore may represent the specific gene involved.

Weyerts, L.K.; Wiley, J.E.; Loud, K.M. [ECU School of Medicine, Greenville, NC (United States)] [and others

1994-09-01

335

Analysis of somatic mutation in five B cell subsets of human tonsil.  

PubMed

Using a series of phenotypic markers that include immunoglobulin (Ig)D, IgM, IgG, CD23, CD44, Bcl-2, CD38, CD10, CD77, and Ki67, human tonsillar B cells were separated into five fractions representing different stages of B cell differentiation that included sIgD+ (Bm1 and Bm2), germinal center (Bm3 and Bm4), and memory (Bm5) B cells. To establish whether the initiation of somatic mutation correlated with this phenotypic characterization, we performed polymerase chain reaction and subsequent sequence analysis of the Ig heavy chain variable region genes from each of the B cell subsets. We studied the genes from the smallest VH families (VH4, VH5, and VH6) in order to facilitate the mutational analysis. In agreement with previous reports, we found that the somatic mutation machinery is activated only after B cells reach the germinal center and become centroblasts (Bm3). Whereas 47 independently rearranged IgM transcripts from the Bm1 and Bm2 subsets were nearly germline encoded, 57 Bm3-, and Bm4-, and Bm5-derived IgM transcripts had accumulated an average of 5.7 point mutations within the VH gene segment. gamma transcripts corresponding to the same VH gene families were isolated from subsets Bm3, Bm4, and Bm5, and had accumulated an average of 9.5 somatic mutations. We conclude that the molecular events underlying the process of somatic mutation takes place during the transition from IgD+, CD23+ B cells (Bm2) to the IgD-, CD23-, germinal center centroblast (Bm3). Furthermore, the analysis of Ig variable region transcripts from the different subpopulations confirms that the pathway of B cell differentiation from virgin B cell throughout the germinal center up to the memory compartment can be traced with phenotypic markers. The availability of these subpopulations should permit the identification of the functional molecules relevant to each stage of B cell differentiation. PMID:8006591

Pascual, V; Liu, Y J; Magalski, A; de Bouteiller, O; Banchereau, J; Capra, J D

1994-07-01

336

The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis.  

PubMed

Bromodomain-containing transcriptional regulators represent new epigenetic targets in different hematologic malignancies. However, bromodomain-mediated mechanisms that couple histone acetylation to transcription in lymphopoiesis and govern mature lymphocyte mitogenesis are poorly understood. Brd2, a transcriptional coregulator that contains dual bromodomains and an extraterminal domain (the BET family), couples chromatin to cell-cycle progression. We reported previously the first functional characterization of a BET protein as an effector of mammalian mitogenic signal transduction: E?-Brd2 Tg mice develop "activated B cell" diffuse large B cell lymphoma. No other animal models exist for genetic or lentiviral expression of BET proteins, hampering testing of novel anti-BET anticancer drugs, such as JQ1. We transduced HSCs with Brd2 lentivirus and reconstituted recipient mice to test the hypothesis that Brd2 regulates hematopoiesis in BM and mitogenesis in the periphery. Forced expression of Brd2 provides an expansion advantage to the donor-derived B cell compartment in BM and increases mature B cell mitogenic responsiveness in vitro. Brd2 binds the cyclin A promoter in B cells, shown by ChIP, and increases cyclin A mRNA and protein levels, and S-phase progression in vitro in mitogen-stimulated primary B cells, but not T cells, reinforcing results from E?-Brd2 mice. The small molecule BET inhibitor JQ1 reduces B cell mitogenesis, consistent with the interpretation that BET inhibitors are antiproliferative. Brd2-specific knockdown experiments show that Brd2 is also required for hematopoiesis. We conclude that Brd2 plays a critical, independent role in regulation of mitogenic response genes, particularly cyclin A, in B cells. PMID:24319289

Belkina, Anna C; Blanton, Wanda P; Nikolajczyk, Barbara S; Denis, Gerald V

2014-03-01

337

Germinal center B cells and mixed leukocyte reactions  

SciTech Connect

The present study was undertaken to determine if germinal center (GC) B cells are sufficiently activated to stimulate mixed leukocyte reactions (MLR). Percoll density fractionation and a panning technique with peanut agglutinin (PNA) were used to isolate GC B cells from the lymph nodes of immune mice. The GC B cells were treated with mitomycin C or irradiation and used to stimulate allogeneic or syngeneic splenic T cells in the MLR. Controls included high-density (HD) B cells prepared from spleens of the same mice and HD B cells activated with lipopolysaccharide (LPS) and dextran sulfate. GC B cells bound high amount sof PNA (i.e., PNAhi). Similarly, the LPS-dextran sulfate-activated B cells were PNAhi. Treatment with neuraminidase rendered the PNAlo HD B cells PNAhi. GC B cells and the LPS-dextran sulfate-activated HD B cells stimulated a potent MLR, while the untreated HD B cells did not. However, following neuraminidase treatment, the resulting PNAhi HD B cell population was able to induce an MLR. The PNA marker appeared to be an indicator of stimulatory activity, but incubating the cells with PNA to bind the cell surface ligand did not interfere with the MLR. GC B cells were also capable of stimulating a syngeneic MLR in most experiments although this was not consistently obtained. It appears that germinal centers represent a unique in vivo microenvironment that provides the necessary signals for B cells to become highly effective antigen-presenting cells.

Monfalcone, A.P.; Kosco, M.H.; Szakal, A.K.; Tew, J.G. (Virginia Commonwealth Univ., Richmond (USA))

1989-09-01

338

A role for IRF8 in B cell anergy  

PubMed Central

B cell central tolerance is a process through which self-reactive B cells are removed from the B cell repertoire. Self-reactive B cells are generally removed by receptor editing in the bone marrow and by anergy induction in the periphery. Interferon regulatory factor 8 (IRF8) is a critical transcriptional regulator of immune system development and function. A recent study has shown that marginal zone B cells and B1 B cells population are dramatically increased in the IRF8 deficient mice, indicating that there are B cell developmental defects in the absence of IRF8. Here, we report that mice deficient for IRF8 produced anti-dsDNA antibodies. Using hen egg lysozyme double transgenic model, we further demonstrate that B cell anergy was breached in the IRF8 deficient mice. While anergic B cells in the IRF8 proficient background were blocked at the transitional stage of development, anergic B cells in the IRF8 deficient background were able to further mature which allow them to regain responses to antigen stimulation. Interestingly, our results show that IRF8 deficient B cells were more sensitive to antigen stimulation and were resistant to antigen induced cell death. Moreover, our results show that IRF8 was expressed at a high level in the anergic B cells and elevated level of IRF8 promoted apoptosis in the transitional B cells. Thus, our findings presented here reveal a previously unrecognized function of IRF8 in B cell anergy induction. PMID:24218455

Pathak, Simanta; Ma, Shibin; Shukla, Vipul; Lu, Runqing

2013-01-01

339

Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses.  

PubMed

Humoral immunity depends on both rapid and long-term antibody production against invading pathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated. Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses. PMID:19615922

Gatto, Dominique; Paus, Didrik; Basten, Antony; Mackay, Charles R; Brink, Robert

2009-08-21

340

B cell signature during inactive systemic lupus is heterogeneous: toward a biological dissection of lupus.  

PubMed

Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomas of quiescent lupus patients to normal B cell transcriptomas. When the statistical analysis is performed on the entire group of patients, the differences between patients and controls appear quite weak with only 14 mRNA genes having a false discovery rate ranging between 11 and 17%, with 6 underexpressed genes (PMEPA1, TLR10, TRAF3IP2, LDOC1L, CD1C and EGR1). However, unforced hierarchical clustering of the microarrays reveals a subgroup of lupus patients distinct from both the controls and the other lupus patients. This subgroup has no detectable clinical or immunological phenotypic peculiarity compared to the other patients, but is characterized by 1/an IL-4 signature and 2/the abnormal expression of a large set of genes with an extremely low false discovery rate, mainly pointing to the biological function of the endoplasmic reticulum, and more precisely to genes implicated in the Unfolded Protein Response, suggesting that B cells entered an incomplete BLIMP1 dependent plasmacytic differentiation which was undetectable by immunophenotyping. Thus, this microarray analysis of B cells during quiescent lupus suggests that, despite a similar lupus phenotype, different biological roads can lead to human lupus. PMID:21886837

Garaud, Jean-Claude; Schickel, Jean-Nicolas; Blaison, Gilles; Knapp, Anne-Marie; Dembele, Doulaye; Ruer-Laventie, Julie; Korganow, Anne-Sophie; Martin, Thierry; Soulas-Sprauel, Pauline; Pasquali, Jean-Louis

2011-01-01

341

B Cell Signature during Inactive Systemic Lupus Is Heterogeneous: Toward a Biological Dissection of Lupus  

PubMed Central

Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomas of quiescent lupus patients to normal B cell transcriptomas. When the statistical analysis is performed on the entire group of patients, the differences between patients and controls appear quite weak with only 14 mRNA genes having a false discovery rate ranging between 11 and 17%, with 6 underexpressed genes (PMEPA1, TLR10, TRAF3IP2, LDOC1L, CD1C and EGR1). However, unforced hierarchical clustering of the microarrays reveals a subgroup of lupus patients distinct from both the controls and the other lupus patients. This subgroup has no detectable clinical or immunological phenotypic peculiarity compared to the other patients, but is characterized by 1/an IL-4 signature and 2/the abnormal expression of a large set of genes with an extremely low false discovery rate, mainly pointing to the biological function of the endoplasmic reticulum, and more precisely to genes implicated in the Unfolded Protein Response, suggesting that B cells entered an incomplete BLIMP1 dependent plasmacytic differentiation which was undetectable by immunophenotyping. Thus, this microarray analysis of B cells during quiescent lupus suggests that, despite a similar lupus phenotype, different biological roads can lead to human lupus. PMID:21886837

Blaison, Gilles; Knapp, Anne-Marie; Dembele, Doulaye; Ruer-Laventie, Julie; Korganow, Anne-Sophie; Martin, Thierry; Soulas-Sprauel, Pauline; Pasquali, Jean-Louis

2011-01-01

342

A {open_quotes}balanced{close_quotes} Y:16 translocation with the Y breakpoint just proximal to the Yq heterochromatin boundary associated with Turner-like neonatal lymphedema suggests the location of a potential anti-Turner gene  

SciTech Connect

A male patient with Turner-like hydrops in the newborn period (Bonnevie-Ullrich syndrome) was studied. The extensive nucchal cystic hygroma and hydrops resolved over several weeks. The karyotype was 46,X,t(Y;16)(q11.2;q24). The paternal karyotype was normal. Chromosome painting with the heterochromatic long arm repeat DYZ2 disclosed that all the hybridization was on the derivative 16. This was confirmed by chromosome painting with DYZ1, the other major Y long arm heterochromatic repeat, and DYZ3, the Y alphoid, centromeric repeat, which showed chromosomal separation of the 2 stained regions. A {open_quotes}FISHing trip{close_quotes} was performed using the Y YAC contig created in Dr. David Page`s laboratory. This disclosed 2 YACs located just proximal to the Y heterochromatin which {open_quotes}jumped{close_quotes} the translocation. The recent discovery of a candidate gene for the azoospermia factor (AZF) in this region suggests the possibility that there are several Y-expressed genes adjacent to the heterochromatin boundary as there are near the pseudoautosomal boundary.

Erickson, R.P.; Hudgins, L. [Univ. of Arizona, Tucson, AZ (United States); Stone, J.F. [Southwest Biomedical Research Institute, Scottsdale, AZ (United States)] [and others

1994-09-01

343

Silencing miR-146a influences B cells and ameliorates experimental autoimmune myasthenia gravis.  

PubMed

MicroRNAs have been shown to be important regulators of immune homeostasis as patients with aberrant microRNA expression appeared to be more susceptible to autoimmune diseases. We recently found that miR-146a was up-regulated in activated B cells in response to rat acetylcholine receptor (AChR) ?-subunit 97-116 peptide, and this up-regulation was significantly attenuated by AntagomiR-146a. Our data also demonstrated that silencing miR-146a with its inhibitor AntagomiR-146a effectively ameliorated clinical myasthenic symptoms in mice with ongoing experimental autoimmune myasthenia gravis. Furthermore, multiple defects were observed after miR-146a was knocked down in B cells, including decreased anti-R97-116 antibody production and class switching, reduced numbers of plasma cells, memory B cells and B-1 cells, and weakened activation of B cells. Previously, miR-146a has been identified as a nuclear factor-?B-dependent gene and predicted to base pair with the tumour necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) genes to regulate the immune response. However, our study proved that miR-146a inhibition had no effect on the expression of TRAF6 and IRAK1 in B cells. This result suggests that the function of miR-146a in B cells does not involve these two target molecules. We conclude that silencing miR-146a exerts its therapeutic effects by influencing the B-cell functions that contribute to the autoimmune pathogenesis of myasthenia gravis. PMID:24962817

Zhang, JunMei; Jia, Ge; Liu, Qun; Hu, Jue; Yan, Mei; Yang, BaiFeng; Yang, Huan; Zhou, WenBin; Li, Jing

2015-01-01

344

Retinoic acid and ?-galactosylceramide regulate the expression of costimulatory receptors and transcription factors responsible for B cell activation and differentiation.  

PubMed

Mature naïve B cells possess a number of BCR coreceptors and other antigen receptors, including the MHC class I-like molecule CD1d, but little is known of the response of B cells to stimulation by the CD1d ligand, ?-galactosylceramide (?GalCer). Previously, we showed that all-trans-retinoic acid (RA) increases the expression of CD1d and the magnitude of CD1d-mediated antibody production in vivo. Potential mechanisms could include changes in the expression of costimulatory molecules and transcription factors that regulate plasma cell formation. In the present study, we have used isolated purified B cells and in vivo studies to demonstrate that ?GalCer and RA initiate a regulated expression of several genes essential for B cell activation and differentiation, such as Pax-5, Blimp-1, IRF-4 and activation-induced cytidine deaminase (Aid). Moreover, whereas ?GalCer mainly increased the expression of Pax-5, CD40 and CD86 that are critical for B cell activation, RA predominantly increased CD138? and Fas?-PNA? B cells, which represent more advanced B cell differentiation. It is also noteworthy that ?GalCer enriched a CD19hi subset of B cells, which represent B cells with more differentiated phenotype and higher potential for antibody production. In vivo, treatment with ?GalCer enriched the CD19hi population, which, after sorting, produced more anti-TT IgG by ELISPOT assay. Together, our data demonstrate that RA and ?GalCer can regulate B cell activation and differentiation at multiple levels in a complementary manner, facilitating the progress of B cells towards antibody secreting cells. PMID:23816303

Chen, Qiuyan; Mosovsky, Kara L; Ross, A Catharine

2013-12-01

345

B cell repopulation after alemtuzumab induction-transient increase in transitional B cells and long-term dominance of naïve B cells.  

PubMed

In organ transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naïve and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to decreased allograft survival. Alemtuzumab induction therapy effectively depletes B cells, but is followed by rapid repopulation up to levels exceeding base line. The characteristics of the repopulating B cells are currently unknown. We studied the phenotypic and functional characteristics of B cells longitudinally in 19 kidney transplant recipients, before and at 6, 9 and 12 months after alemtuzumab induction therapy. A transient increase in transitional B cells and cells with phenotypic characteristics of regulatory B cells, as well as a long-term dominance in naïve B cells was found in alemtuzumab-treated kidney transplant recipients, which was not influenced by conversion from tacrolimus to sirolimus. At all time-points after treatment, B cells showed unaltered proliferative and IgM-producing capacity as compared to pretransplant samples, whereas the ability to produce IgG was inhibited long-term. In conclusion, induction therapy with alemtuzumab results in a long-term shift toward naïve B cells with altered phenotypic and functional characteristics. PMID:22420490

Heidt, S; Hester, J; Shankar, S; Friend, P J; Wood, K J

2012-07-01

346

Congenital B cell lymphocytosis explained by novel germline CARD11 mutations  

PubMed Central

Nuclear factor-?B (NF-?B) controls genes involved in normal lymphocyte functions, but constitutive NF-?B activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)–induced NF-?B activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-?B activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis. PMID:23129749

Xiao, Wenming; Stinson, Jeffrey R.; Lu, Wei; Chaigne-Delalande, Benjamin; Zheng, Lixin; Pittaluga, Stefania; Matthews, Helen F.; Schmitz, Roland; Jhavar, Sameer; Kuchen, Stefan; Kardava, Lela; Wang, Wei; Lamborn, Ian T.; Jing, Huie; Raffeld, Mark; Moir, Susan; Fleisher, Thomas A.; Staudt, Louis M.; Su, Helen C.

2012-01-01

347

BANK1 and BLK Act through Phospholipase C Gamma 2 in B-Cell Signaling  

PubMed Central

The B cell adaptor protein with ankyrin repeats (BANK1) and the B lymphoid tyrosine kinase (BLK) have been genetically associated with autoimmunity. The proteins of these genes interact physically and work in concert during B-cell signaling. Little is know about their interactions with other B-cell signaling molecules or their role in the process. Using yeast two hybrid (Y2H) we sought for factors that interact with BANK1. We found that the molecular switch PLCg2 interacts with BANK1 and that the interaction is promoted by B-cell receptor (BCR) stimulation. We found further that the kinase activity of BLK enhanced BANK1- PLCg2 binding and that the interaction was suppressed upon BLK depletion. Immunoprecipitation and mutational analysis demonstrated that the interaction between BANK1 and PLCg2 was dependent on specific tyrosine and proline residues on the adaptor protein. Our results provide new information important to understand the role of these two genes in basic B-cell physiology and immune-related diseases. PMID:23555801

Bernal-Quirós, Manuel; Wu, Ying-Yu

2013-01-01

348

Pi, a pre-B-cell-specific enhancer element in the immunoglobulin heavy-chain enhancer.  

PubMed Central

We have identified a new immunoglobulin heavy-chain enhancer element, designated pi, between the microE2 and microE3 elements. The pi enhancer element is transcriptionally active primarily during early stages of B-cell development but becomes virtually inactive during B-cell maturation at about the stage of immunoglobulin kappa light-chain gene rearrangement. Mutational analysis suggests that the pi element is crucial for immunoglobulin heavy-chain enhancer activity at the pre-B-cell stage but is almost irrelevant for enhancer activity at the mature B-cell or plasma-cell stage. The activity of the pi enhancer element correlates with the presence of an apparently pre-B-cell-specific protein-DNA complex. The similarity of the pi site to recognition sequences for members of the ets gene family suggests that the protein(s) interacting with the pi site most likely are ets-related transcription factors. Images PMID:8413200

Libermann, T A; Baltimore, D

1993-01-01

349

Splenic marginal zone B cells in humans: where do they mutate their Ig receptor? Sandra Weller, Claude-Agns Reynaud and Jean-Claude Weill  

E-print Network

1 Splenic marginal zone B cells in humans: where do they mutate their Ig receptor? Sandra Weller.200535446 #12;2 Summary Human IgM+ IgD+ CD27+ B cells have mutated Ig genes and harbor a splenic marginal they contained 30-40% of memory B cells displaying the CD27 marker at their surface and a mutated Ig receptor [1

Paris-Sud XI, Université de

350

Clinical significance of translocation.  

PubMed Central

The gastrointestinal tract, besides being the organ responsible for nutrient absorption, is also a metabolic and immunological system, functioning as an effective barrier against endotoxin and bacteria in the intestinal lumen. The passage of viable bacteria from the gastrointestinal tract through the epithelial mucosa is called bacterial translocation. Equally important may be the passage of bacterial endotoxin through the mucosal barrier. This article reviews the evidence that translocation of both endotoxin and bacteria is of clinical significance. It summarises recent published works indicating that translocation of endotoxin in minute amounts is a physiological important phenomenon to boost the reticuloendothelial system (RES), especially the Kupffer cells, in the liver. Breakdown of both the mucosal barrier and the RES capacity results in systemic endotoxaemia. Systemic endotoxaemia results in organ dysfunction, impairs the mucosal barrier, the clotting system, the immune system, and depresses Kupffer cell function. If natural defence mechanisms such as lipopolysaccharide binding protein, high density lipoprotein, in combination with the RES, do not respond properly, dysfunction of the gut barrier results in bacterial translocation. Extensive work on bacterial translocation has been performed in animal models and occurs notably in haemorrhagic shock, thermal injury, protein malnutrition, endotoxaemia, trauma, and intestinal obstruction. It is difficult to extrapolate these results to humans and its clinical significance is not clear. The available data show that the resultant infection remains important in the development of sepsis, especially in the critically ill patient. Uncontrolled infection is, however, neither necessary nor sufficient to account for the development of multiple organ failure. A more plausible sequelae is that bacterial translocation is a later phenomenon of multiple organ failure, and not its initiator. It is hypothesized that multiple organ failure is more probably triggered by the combination of tissue damage and systemic endotoxaemia. Endotoxaemia, as seen in trauma patients especially during the first 24 hours, in combination with tissue elicits a systemic inflammation, called Schwartzmann reaction. Interferon gamma, a T cell produced cytokine, is thought to play a pivotal part in the pathogenesis of this reaction. This reaction might occur only if the endotoxin induced cytokines like tumour necrosis factor and interleukin 1, act on target cells prepared by interferon gamma. After exposure to interferon gamma target cells become more sensitive to stimuli like endotoxin, thus boosting the inflammatory cycle. Clearly, following this line of reasoning, minor tissue damage or retroperitoneal haematoma combined with systemic endotoxaemia could elicit this reaction. The clinically observed failure of multiple organ systems might thus be explained by the interaction of tissue necrosis and high concentrations of endotoxin because of translocation. Future therapeutic strategies could therefore focus more on binding endotoxin in the gut before the triggering event, for example before major surgery. Such a strategy could be combined with the start of early enteral feeding, which has been shown in animal studies to have a beneficial effect on intestinal mucosal barrier function and in traumatized patients to reduce the incidence of septic complications. PMID:8125386

Van Leeuwen, P A; Boermeester, M A; Houdijk, A P; Ferwerda, C C; Cuesta, M A; Meyer, S; Wesdorp, R I

1994-01-01

351

Calcium ultracytochemistry in pancreatic B-cells.  

PubMed

Ultracytochemical studies in B-cells using the pyroantimonate technique in combination with x-ray microanalysis demonstrated calcium deposits in association with structures of functional importance. In a series of experiments precipitate distribution has been shown to depend on the functional state of the B-cell. Increased calcium precipitation during stimulation of insulin secretion occurred at the cell membranes, in the ground plasma and the halos of the secretory granules. If these data bear functional relevance and are not only concomitant effects of the activated secretory apparatus on pyroantimonate precipitation, they may point to a direct involvement of calcium in some early steps of exocytosis and in granule transport mechanisms. PMID:7005053

Klöppel, G; Bommer, G; Lenzen, S

1980-01-01

352

B cells in HIV infection and disease  

PubMed Central

In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4+ T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction. PMID:19319142

Moir, Susan; Fauci, Anthony S.

2009-01-01

353

Primary mediastinal B-cell lymphoma.  

PubMed

Primary mediastinal B-cell lymphoma is a discrete clinicopathologic entity. Molecular analysis reveals it to be distinct from other types of large B-cell lymphoma, and retrospective analysis suggests that it may respond better to multi-agent chemotherapy regimens than to the more commonly used CHOP. The addition of rituximab may mitigate such differences, and may also diminish the role of consolidation radiotherapy, which is often used to treat residual mediastinal masses. For the future the role of FDG-PET scanning requires prospective examination, and it is hoped that this may allow the de-escalation of treatment if it can be shown to yield reliable prognostic information. The relative rarity of this type of lymphoma necessitates international collaboration in clinical trials, with a prospective clinicopathologic study, IELSG 26, already underway. PMID:19074109

Johnson, Peter W M; Davies, Andrew J

2008-01-01

354

Identification of a sub-population of B cells that proliferates after infection with epstein-barr virus  

PubMed Central

Background Epstein-Barr virus (EBV)-driven B cell proliferation is critical to its subsequent persistence in the host and is a key event in the development of EBV-associated B cell diseases. Thus, inquiry into early cellular events that precede EBV-driven proliferation of B cells is essential for understanding the processes that can lead to EBV-associated B cell diseases. Methods Infection with high titers of EBV of mixed, primary B cells in different stages of differentiation occurs during primary EBV infection and in the setting of T cell-immunocompromise that predisposes to development of EBV-lymphoproliferative diseases. Using an ex vivo system that recapitulates these conditions of infection, we correlated expression of selected B cell-surface markers and intracellular cytokines with expression of EBV latency genes and cell proliferation. Results We identified CD23, CD58, and IL6, as molecules expressed at early times after EBV-infection. EBV differentially infected B cells into two distinct sub-populations of latently infected CD23+ cells: one fraction, marked as CD23hiCD58+IL6- by day 3, subsequently proliferated; another fraction, marked as CD23loCD58+, expressed IL6, a B cell growth factor, but failed to proliferate. High levels of LMP1, a critical viral oncoprotein, were expressed in individual CD23hiCD58+ and CD23loCD58+ cells, demonstrating that reduced levels of LMP1 did not explain the lack of proliferation of CD23loCD58+ cells. Differentiation stage of B cells did not appear to govern this dichotomy in outcome either. Memory or naïve B cells did not exclusively give rise to either CD23hi or IL6-expressing cells; rather memory B cells gave rise to both sub-populations of cells. Conclusions B cells are differentially susceptible to EBV-mediated proliferation despite expression of viral gene products known to be critical for continuous B cell growth. Cellular events, in addition to viral gene expression, likely play a critical role in determining the outcome of EBV infection. By indentifying cells predicted to undergo EBV-mediated proliferation, our study provides new avenues of investigation into EBV pathogenesis. PMID:21352549

2011-01-01

355

Hepatitis C and B-cell lymphoma  

Microsoft Academic Search

The association between the hepatitis C virus and B-cell non-Hodgkin's lymphomas is controversial. We review the epidemiological evidence behind the association, and look at the reasons behind the variation in study findings. There is increasing evidence of the pathogenesis of hepatitis C-associated lymphoma. Treatment of the hepatitis C virus with antiviral therapy may lead to the regression of some low-grade

N. C. Turner; G. Dusheiko; A. Jones

2003-01-01

356

NKT Cell Responses to B Cell Lymphoma  

PubMed Central

Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, ?-galactosylceramide (?-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from ?-GalCer treated mice produced IFN-? following ?-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma. PMID:24955247

Li, Junxin; Sun, Wenji; Subrahmanyam, Priyanka B.; Page, Carly; Younger, Kenisha M.; Tiper, Irina V.; Frieman, Matthew; Kimball, Amy S.; Webb, Tonya J.

2014-01-01

357

Foliar Absorption and Phloem Translocation  

NSDL National Science Digital Library

Herbicides must be absorbed into plants in order to be effective. Herbicide absorption can occur through leaves, roots or both. The process by which herbicides kill weeds, called mode of action, requires herbicide absorption and may also require herbicide movement or translocation within the plant. Translocation means that the herbicide moves from the site of absorption to some other plant part. Foliar applied herbicides that have the necessary characteristics to move in the phloem will translocate to areas of the plant that are actively growing; however, not all foliar-applied herbicides move from the leaves that intercepted the spray solution. Herbicides that are absorbed but not translocated are calledcontact herbicides, while herbicides that translocate to shoot or root meristems are called systemic herbicides. Absorption and translocation of xylem mobile herbicides will be discussed in another lesson.

358

De Novo microdeletion on an inherited Robertsonian translocation chromosome: A cause for dysmorphism in the apparently balanced translocation carrier  

SciTech Connect

Robertsonian translocations are usually ascertained through abnormal children, making proposed phenotypic effects of apparently balanced translocations difficult to study in an unbiased way. From molecular genetic studies, though, some apparently balanced rearrangments are now known to be associated with phenotypic abnormalities resulting from uniparental disomy. Molecular explanations for other cases in which abnormality is seen in a balanced translocation carrier are being sought. In the present paper, an infant is described who has retarded growth, developmental delay, gross muscular hypotonia, slender habitus, frontal bossing, micrognathia, hooked nose, abundant wispy hair, and blue sclerae. Cytogenetically, she appeared to be a carrier of a balanced, paternally derived 14;21 Robertsonian translocation. Analysis of DNA polymorphisms showed that she had no paternal allele at the D14S13 locus (14q32). Study of additional DNA markers within 14q32 revealed that her previously undescribed phenotype results from an interstitial microdeletion within 14q32. Fluorescent in situ hybridization was used to show that this microdeletion had occurred de novo on the Robertsonian translocation chromosome. These observations may reactivate old suspicions of a causal association between Robertsonian translocations and de novo rearrangements in offspring; a systematic search for similar subcytogentic rearrangements in other families, in which there are phenotypically abnormal children with apparently balanced translocations, may be fruitful. The clinical and molecular genetic data presented also define a new contiguous gene syndrome due to interstitial 14q32 deletion. 42 refs., 4 figs., 1 tab.

Bonthron, D.T.; Smith, S.J.L.; Fantes, J.; Gosden, C.M.

1993-09-01

359

Transfer of Small Resting B Cells into Immunodeficient Hosts Results in the Selection of a Self-renewing Activated B Cell Population  

Microsoft Academic Search

Summary We studied the role of bone marrow B cell production in the renewal of peripheral B cells and the feedback mechanisms that control the entry of newly formed B cells into the peripheral B cell pools. When resting lymph node B cells are injected into B cell-deficient hosts, a fraction of the transferred cells expands and constitutes a highly

Fabien Agenès; António A. Freitas

360