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1

Oncogenic human papillomaviruses block expression of the B-cell translocation gene-2 tumor suppressor gene.  

PubMed

Human papillomavirus (HPV)-induced carcinogenesis is critically dependent on the activities of the viral E6 and E7 oncogenes. Here, we demonstrate that expression of the putative tumor suppressor gene B-cell translocation gene-2 (BTG2) is reinduced in HPV16- and HPV18-positive cancer cells on silencing of viral oncogene expression, indicating that BTG2 is repressed by oncogenic HPVs. Inhibition of BTG2 expression was mediated by the HPV E6 oncogene and occurred in a p53-dependent manner. Luciferase reporter gene analyses revealed that BTG2 repression takes place at the transcriptional level and is dependent on the integrity of the major p53-response element within the BTG2 promoter. Ectopic expression of BTG2 acted antiproliferative in cervical cancer cells. Tissue specimens commonly exhibited reduced BTG2 protein levels in HPV-positive high-grade lesions (CIN2/3) and cervical carcinomas, when compared with normal cervical epithelium. These findings identify the antiproliferative BTG2 gene as a novel cellular target blocked by the HPV E6 oncoprotein. PMID:19551855

Cullmann, Claire; Hoppe-Seyler, Karin; Dymalla, Susanne; Lohrey, Claudia; Scheffner, Martin; Dürst, Matthias; Hoppe-Seyler, Felix

2009-11-01

2

Antiproliferative B cell translocation gene 2 protein is down- regulated post-transcriptionally as an early event in prostate carcinogenesis  

Microsoft Academic Search

B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in ~50% of basal cells in benign glands from the

Michael A. Ficazzola; Mitchell Fraiman; Jordan Gitlin; Kenneth Woo; Jonathan Melamed; Mark A. Rubin; Paul D. Walden

3

1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma.  

PubMed

Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence that a distinct category of chromosomal translocations observed in human tumours--those targeting 1q12 satellite DNA--can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localized to the nuclear periphery and to arise as a consequence of long range 'pairing' between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms. PMID:20432501

Fournier, Alexandra; McLeer-Florin, Anne; Lefebvre, Christine; Duley, Samuel; Barki, Leila; Ribeyron, Juliana; Alboukadel, Kassambara; Hamaidia, Sieme; Granjon, Aurélie; Gressin, Rémy; Lajmanovich, Alicia; Bonnefoix, Thierry; Chauvelier, Stéphanie; Debernardi, Alexandra; Rousseaux, Sophie; de Fraipont, Florence; Figeac, Martin; Kerckaert, Jean-Pierre; De Vos, John; Usson, Yves; Delaval, Katia; Grichine, Alexei; Vourc'h, Claire; Khochbin, Saadi; Feil, Robert; Leroux, Dominique; Callanan, Mary B

2010-05-01

4

1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma  

PubMed Central

Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence that a distinct category of chromosomal translocations observed in human tumours—those targeting 1q12 satellite DNA—can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localized to the nuclear periphery and to arise as a consequence of long range ‘pairing’ between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms.

Fournier, Alexandra; McLeer-Florin, Anne; Lefebvre, Christine; Duley, Samuel; Barki, Leila; Ribeyron, Juliana; Kassambara, Alboukadel; Hamaidia, Sieme; Granjon, Aurelie; Gressin, Remy; Lajmanovich, Alicia; Bonnefoix, Thierry; Chauvelier, Stephanie; Debernardi, Alexandra; Rousseaux, Sophie; de Fraipont, Florence; Figeac, Martin; Kerckaert, Jean-Pierre; De Vos, John; Usson, Yves; Delaval, Katia; Grichine, Alexei; Vourc'h, Claire; Khochbin, Saadi; Feil, Robert; Leroux, Dominique; Callanan, Mary B

2010-01-01

5

Expression of the follicular lymphoma variant translocation 1 gene in diffuse large B-cell lymphoma correlates with subtype and clinical outcome.  

PubMed

Sphingolipids serve an important role as effector molecules in signaling pathways bearing on apoptosis and cell survival. The balance between proapoptotic ceramide and prosurvival sphingosine-1-phosphate, sometimes termed the "sphingolipid rheostat," has received particular attention. Less well studied is the role of the follicular lymphoma variant translocation 1 (FVT1) gene, which was identified through its involvement in an atypical follicular lymphoma translocation and which encodes an enzyme in the synthetic pathway of ceramide. We investigated the expression of FVT1 in a variety of B-cell non-Hodgkin lymphomas and found that FVT1 is significantly underexpressed by germinal center-type diffuse large B-cell lymphoma (DLBCL) when compared with non-germinal center-type DLBCL, follicular lymphoma, and normal tonsil control samples. Increased expression of FVT1 correlated with decreased survival, suggesting that changes in the expression of FVT1 and in the concentrations of bioactive sphingolipids may be important in the pathogenesis and treatment of some types of DLBCL. PMID:19019774

Czuchlewski, David R; Csernus, Balazs; Bubman, Darya; Hyjek, Elizabeth; Martin, Peter; Chadburn, Amy; Knowles, Daniel M; Cesarman, Ethel

2008-12-01

6

Expression of the Follicular Lymphoma Variant Translocation 1 Gene in Diffuse Large B-Cell Lymphoma Correlates With Subtype and Clinical Outcome  

PubMed Central

Sphingolipids serve an important role as effector molecules in signaling pathways bearing on apoptosis and cell survival. The balance between proapoptotic ceramide and prosurvival sphingosine-1-phosphate, sometimes termed the “sphingolipid rheostat,” has received particular attention. Less well studied is the role of the follicular lymphoma variant translocation 1 (FVT1) gene, which was identified through its involvement in an atypical follicular lymphoma translocation and which encodes an enzyme in the synthetic pathway of ceramide. We investigated the expression of FVT1 in a variety of B-cell non-Hodgkin lymphomas and found that FVT1 is significantly underexpressed by germinal center–type diffuse large B-cell lymphoma (DLBCL) when compared with non–germinal center–type DLBCL, follicular lymphoma, and normal tonsil control samples. Increased expression of FVT1 correlated with decreased survival, suggesting that changes in the expression of FVT1 and in the concentrations of bioactive sphingolipids may be important in the pathogenesis and treatment of some types of DLBCL.

Czuchlewski, David R.; Csernus, Balazs; Bubman, Darya; Hyjek, Elizabeth; Martin, Peter; Chadburn, Amy; Knowles, Daniel M.; Cesarman, Ethel

2013-01-01

7

L-Mimosine blocks cell proliferation via upregulation of B-cell translocation gene 2 and N-myc downstream regulated gene 1 in prostate carcinoma cells.  

PubMed

L-Mimosine, an iron chelator and a prolyl 4-hydroxylase inhibitor, blocks many cancer cells at the late G1 phase. B-cell translocation gene 2 (Btg2) regulates the G1/S transition phases of the cell cycle. N-myc downstream regulated gene 1 (Ndrg1) is a differentiation-inducing gene upregulated by hypoxia. We evaluated the molecular mechanisms of L-mimosine on cell cycle modulation in PC-3 and LNCaP prostate carcinoma cells. The effect of L-mimosine on cell proliferation of prostate carcinoma cells was determined by the [3H]thymidine incorporation and flow cytometry assays. L-Mimosine arrested the cell cycle at the G1 phase in PC-3 cells and at the S phase in LNCaP cells, thus attenuating cell proliferation. Immunoblot assays indicated that hypoxia and L-mimosine stabilized hypoxia-inducible factor-1? (HIF-1?) and induced Btg2 and Ndrg1 protein expression, but downregulated protein levels of cyclin A in both PC-3 and LNCaP cells. L-Mimosine treatment decreased cyclin D1 protein in PC-3 cells, but not in LNCaP cells. Dimethyloxalylglycine, a pan-prolyl hydroxylase inhibitor, also induced Btg2 and Ndrg1 protein expression in LNCaP cells. The transient gene expression assay revealed that L-mimosine treatment or cotransfection with HIF-1? expression vector enhanced the promoter activities of Btg2 and Ndrg1 genes. Knockdown of HIF-1? attenuated the increasing protein levels of both Btg2 and Ndrg1 by hypoxia or L-mimosine in LNCaP cells. Our results indicated that hypoxia and L-mimosine modulated Btg2 and Ndrg1 at the transcriptional level, which is dependent on HIF-1?. L-Mimosine enhanced expression of Btg2 and Ndrg1, which attenuated cell proliferation of the PC-3 and LNCaP prostate carcinoma cells. PMID:22116304

Chung, Li-Chuan; Tsui, Ke-Hung; Feng, Tsui-Hsia; Lee, Shiow-Ling; Chang, Phei-Lang; Juang, Horng-Heng

2011-11-23

8

B-cell translocation gene 2 positively regulates GLP-1-stimulated insulin secretion via induction of PDX-1 in pancreatic ?-cells.  

PubMed

Glucagon-like peptide-1 (GLP-1) is a potent glucoincretin hormone and an important agent for the treatment of type 2 diabetes. Here we demonstrate that B-cell translocation gene 2 (BTG2) is a crucial regulator in GLP-1-induced insulin gene expression and insulin secretion via upregulation of pancreatic duodenal homeobox-1 (PDX-1) in pancreatic ?-cells. GLP-1 treatment significantly increased BTG2, PDX-1 and insulin gene expression in pancreatic ?-cells. Notably, adenovirus-mediated overexpression of BTG2 significantly elevated insulin secretion, as well as insulin and PDX-1 gene expression. Physical interaction studies showed that BTG2 is associated with increased PDX-1 occupancy on the insulin gene promoter via a direct interaction with PDX-1. Exendin-4 (Ex-4), a GLP-1 agonist, and GLP-1 in pancreatic ?-cells increased insulin secretion through the BTG2-PDX-1-insulin pathway, which was blocked by endogenous BTG2 knockdown using a BTG2 small interfering RNA knockdown system. Finally, we revealed that Ex-4 and GLP-1 significantly elevated insulin secretion via upregulation of the BTG2-PDX-1 axis in pancreatic islets, and this phenomenon was abolished by endogenous BTG2 knockdown. Collectively, our current study provides a novel molecular mechanism by which GLP-1 positively regulates insulin gene expression via BTG2, suggesting that BTG2 has a key function in insulin secretion in pancreatic ?-cells. PMID:23703573

Hwang, Seung-Lark; Kwon, Okyun; Kim, Sun-Gyun; Lee, In-Kyu; Kim, Yong Deuk

2013-05-24

9

t(14;19)(q32;q13): A recurrent translocation in B-cell precursor acute lymphoblastic leukemia  

Microsoft Academic Search

The recurrent t(14;19)(q32;q13) translocation associated with chronic B-cell lymphoproliferative disorders, such as atypical chronic lymphocytic leukemia, results in the juxtaposition of the IGH@ and BCL3 genes and subsequent overexpression of BCL3. We report six patients with B-cell precursor acute lymphoblastic leukemia who have a cytogenetically identical translocation with different breakpoints at the molecular level. Fluorescence in situ hybridization with locus-specific

Hazel M. Robinson; Kerry E. Taylor; G. Reza Jalali; Kan Luk Cheung; Christine J. Harrison; Anthony V. Moorman

2004-01-01

10

Precursor B-Cell Acute Lymphoblastic Leukemia/Lymphoma with L3 Morphology, Philadelphia Chromosome, MYC Gene Translocation, and Coexpression of TdT and Surface Light Chains: A Case Report  

PubMed Central

Acute lymphoblastic leukemia is predominantly found in children. It is a neoplasm of precursor cells or lymphoblasts committed to either a B- or T-cell lineage. The immature cells in B-acute lymphoblastic leukemia/lymphoma can be small or medium sized with scant or moderate cytoplasm and typically express B-cell markers such as CD19, cytoplasmic CD79a, and TdT without surface light chains. These markers, along with cytogenetic studies, are vital to the diagnosis, classification, and treatment of these neoplasms. We present an unusual case of a precursor B-cell ALL, in an 82-year-old woman, who presented with pancytopenia and widespread lymphadenopathy. The cells show L3 morphology (Burkitt-like lymphoma) with coexpression of TdT and surface light chains in addition to an MYC gene translocation and Philadelphia chromosome.

Hirzel, Alicia C.; Gasparini, Robert; Sriganeshan, Vathany

2013-01-01

11

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

Microsoft Academic Search

Translocations involving an immunoglobulin (IG) locus are a recurring theme in B cell neoplasia. The rearrangements lead to the joining of an IG gene with a (proto)oncogene, whereby the latter comes under the influence of transcription-stimulating sequences in the constitutively\\u000a active IG locus resulting in deregulation of the oncogene and neoplastic growth. We present here three cases of B cell

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

2007-01-01

12

Microbial Translocation and B Cell Dysfunction in Human Immunodeficiency Virus Disease  

PubMed Central

The gut mucosal barrier disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Lipo Polys Accharide (LPS). The association of enhanced microbial translocation and B cell dysfunction in HIV disease is not fully understood. High dose and short term exposure of microbial Toll-Like Receptor (TLR) agonists were used as vaccine adjuvants, however, low dose and long term exposure of TLR agonists could be harmful. The characteristics of B cell dysfunction in HIV disease included B cell, especially memory B cell depletion, enhanced levels of autoimmune antibodies and impaired vaccine or antigen responsiveness. This review discusses and explores the possibility of the effect of microbial translocation on memory B cell depletion and impaired vaccine responses in HIV infection. By determining the mechanisms of B cell depletion and perturbations in HIV disease, it may be possible to design interventions that can improve immune responses to vaccines, reduce selected opportunistic infections and perhaps slow disease progression.

Jiang, Wei

2013-01-01

13

Pathogenetic and clinical implications of non-immunoglobulin ; BCL6 translocations in B-cell non-Hodgkin's lymphoma.  

PubMed

Chromosomal translocations affecting band 3q27, where BCL6 gene is located, are among the most common genetic abnormalities in non-Hodgkin's lymphoma of B-cell type (B-NHL). The BCL6 gene encodes a BTB/POZ zinc finger transcription factor, which exerts repressive activity by recruiting corepressor molecules. The 3q27/BCL6 translocation is unique in that it can involve not only immunoglobulin (Ig) genes but also non-Ig chromosomal loci as a partner. To date, around 20 non-Ig partner genes have been identified. As a result of non-Ig ; BCL6 translocations, many types of regulatory sequences of each partner gene substitute for the 5' untranslated region of BCL6, and the rearranged BCL6 comes under the control of the replaced promoter. The introduction of non-Ig ; BCL6 constructs into transformed cells led to high-level Bcl-6 protein expression in the nucleus, while BCL6 mRNA levels in clinical materials of diffuse large B-cell lymphoma (DLBCL) with non-Ig ; BCL6 translocations were unexpectedly low. A comparative study suggested that non-Ig ; BCL6 translocation and a low level of BCL6 mRNA expression are concordant indicators of a poor clinical outcome in cases of DLBCL. The coexistence of a non-Ig ; BCL6 translocation with t(14 ; 18)(q32 ; q21) in a single clone did not significantly affect the clinical features of follicular lymphoma. The pathogenetic and clinical implications of non-Ig ; BCL6 translocations in B-NHL subtypes may not be identical to those of Ig ; BCL6. PMID:17142954

Ohno, Hitoshi

2006-11-01

14

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

15

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

PubMed Central

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

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

2004-01-01

16

B cell delivered gene therapy for tolerance induction: role of autoantigen-specific B cells  

PubMed Central

Antigen-specific tolerance induction using autologous B-cell gene therapy is a potential treatment to eliminate undesirable immune responses. For example, we have shown that experimental autoimmune encephalomyelitis (EAE) and type 1 diabetes in NOD mice can be ameliorated using antigen-Ig fusion protein transduced B cells. However, it is well established that autoreactive antigen-specific B cells are activated in many autoimmune diseases and can contribute to pathogenesis. While syngeneic B cells from immunized or autoimmune mice can serve as tolerogenic antigen-presenting cells (APC), this observation begs the question of whether the antigen-specific B cells per se can be transduced as tolerogenic APC. To test this, we employed two model systems employing B cell receptor (BCR) transgenic or wild type (wt) mice as B cell donors. While adoptively transferred MOG-Ig transduced wt C57Bl/6 B cells were highly tolerogenic and ameliorated EAE, MOG-Ig transduced anti-MOG B cells from BCR transgenic mice were not. This phenomenon was reproduced in the NOD diabetes model in which pro-insulin-Ig transduced polyclonal wt NOD B cells were protective, whereas similarly transduced anti-insulin BCR B cells were not. Since the frequency of antigen-specific B cells in an immunized animal is quite low, we wished to determine the threshold numbers of BCR transgenic B cells that could be present in an effective transduced population. Therefore, we “spiked” polyclonal wt C57Bl/6 B cells with different numbers of anti-MOG BCR transgenic B cells. In the EAE model, we found protection when BCR B cells were present at 1%, but they prevented tolerance induction at 10%. Antigen-specific B cells expressed normal levels of co-stimulatory molecules and were tolerogenic when transduced with an irrelevant antigen (OVA). Thus, the presence of a BCR specific for the target autoantigen may interfere with the tolerogenic process to that antigen, but BCR-specific B cells are not intrinsically defective as tolerogenic APC. Taken together, these data suggest that antigen-specific tolerance induction can be achieved in the presence of a limited number of antigen-specific B cells, but higher numbers of pathogenic B cells may mask this induction. This observation should guide future development of therapies using autologous B cells to treat patients with autoimmune diseases.

Zhang, Ai-Hong; Li, Xin; Onabajo, Olusegun O.; Su, Yan; Skupsky, Jonathan; Thomas, James W.; Scott, David W.

2010-01-01

17

Distinctive growth requirements and gene expression patterns distinguish progenitor B cells from pre-B cells  

PubMed Central

Long-term bone marrow cultures have been useful in determining gene expression patterns in pre-B cells and in the identification of cytokines such as interleukin 7 (IL-7). We have developed a culture system to selectively grow populations of B lineage restricted progenitors (pro-B cells) from murine bone marrow. Pro-B cells do not grow in response to IL-7, Steel locus factor (SLF), or a combination of the two. c-kit, the SLF receptor, and the IL-7 receptor are both expressed by pro-B cells, indicating that the lack of response is not simply due to the absence of receptors. Furthermore, SLF is not necessary for the growth of pro-B cells since they could be expanded on a stromal line derived from Steel mice that produces no SLF. IL-7 responsiveness in pre-B cells is associated with an increase in n-myc expression and is correlated with immunoglobulin (Ig) gene rearrangements. Although members of the ets family of transcription factors and the Pim-1 kinase are expressed by pro-B cells, n-myc is not expressed. Pro-B cells maintain Ig genes in the germline configuration, which is correlated with a low level of recombination activating genes 1 and 2 (Rag-1 and 2) mRNA expression, but high expression of sterile mu and terminal deoxynucleotidyl transferase. Pro-B cells are unable to grow separated from the stromal layer by a porous membrane, indicating that stromal contact is required for growth. These results suggest that pro-B cells are dependent on alternative growth signals derived from bone marrow stroma and can be distinguished from pre-B cells by specific patterns of gene expression.

1993-01-01

18

HCV-associated B cell clonalities in the liver do not carry the t(14;18) chromosomal translocation.  

PubMed

Infection with HCV can be associated with B-cell non-Hodgkin lymphoma. Polymerase chain reaction (PCR) amplification assays for Bcl-2/IgH rearrangement were performed on nucleic acids extracted from portal tract inflammatory infiltrates, isolated with laser capture microdissection (LCM), from liver biopsy sections of 16 hepatitis C virus (HCV)-infected patients with and without extrahepatic B cell-related disorders. Results were compared with total DNA extracted from core liver biopsy specimens and from peripheral blood mononuclear cells (PBMCs). We failed to demonstrate specific Bcl-2/IgH amplicons either in liver tissue or in PBMCs in all patients of the current series. Multiple PCR assays for variable diversity joining (VDJ) IgH gene rearrangements were also performed in the liver compartment. Selective amplification compatible with mono or oligoclonal B cell clonotypes was demonstrated in 80% (6/8) and 25% (2/8) of patients with and without clinical evidence of B-cell disorders. V(H)1 and V(H)3 were the most represented V(H) families. In situ expression of Bcl-2 protein was carried out by immunohistochemistry on liver biopsy sections. Bcl-2 protein was detected in 2 (12.5%) patients who did not associate extrahepatic disorders. In conclusion, current data support the concept that production of IgH gene rearrangements is not associated with Bcl-2/IgH chromosomal translocation in hepatic compartment. Liver overexpression of Bcl-2 protein may occur in at least a minor proportion of HCV-infected patients. PMID:16231354

Sansonno, Domenico; Tucci, Felicia Anna; De Re, Valli; Lauletta, Gianfranco; Montrone, Michele; Libra, Massimo; Dammacco, Franco

2005-11-01

19

Nuclear translocation of B-cell-specific transcription factor, BACH2, modulates ROS mediated cytotoxic responses in mantle cell lymphoma.  

PubMed

BACH2, a B-cell specific transcription factor, plays a critical role in oxidative stress-mediated apoptosis. Bortezomib (Velcade(TM)) is widely used to treat relapsed mantle cell lymphoma (MCL) patients despite varying clinical outcomes. As one of the potential mechanisms of action, bortezomib was reported to elicit endoplasmic reticulum (ER) stress which triggers reactive oxygen species (ROS). In the present study, we investigated the redox-sensitive intracellular mechanism that might play a critical role in bortezomib response in MCL cells. We demonstrated that in MCL cells that are sensitive to bortezomib treatments, BACH2 was translocated to the nucleus in response to bortezomib and induced apoptotic responses through the modulation of anti-oxidative and anti-apoptotic genes. On the other hand, in bortezomib resistant cells, BACH2 expression was confined in the cytoplasm and no suppression of antiapoptotic or antioxidative genes, Nrf2, Gss, CAT, HO-1 and MCL1, was detected. Importantly, levels of BACH2 were significantly higher in bortezomib sensitive MCL patient cells, indicating that BACH2 levels could be an indicator for clinical bortezomib responses. BACH2 translocation to the cytoplasm after phosphorylation was inhibited by PI3K inhibitors and combinatory regimens of bortezomib and PI3K inhibitors sensitized MCL cells to bortezomib. These data suggest that cellular distribution of BACH2 in response to ROS determines the threshold for the induction of apoptosis. Therapies that inhibit BACH2 phosphorylation could be the key for increasing bortezomib cytotoxic response in patients. PMID:23936317

Chen, Zheng; Pittman, Eric F; Romaguera, Jorge; Fayad, Luis; Wang, Michael; Neelapu, Sattva S; McLaughlin, Peter; Kwak, Larry; McCarty, Nami

2013-08-02

20

Transitional B cells Exhibit a BCR-specific Nuclear Defect In Gene Transcription  

PubMed Central

The signaling programs that enforce negative selection in early transitional (T1) B cells in response to B cell receptor (BCR) engagement remain poorly defined. We carried out a comprehensive comparison of BCR signaling in T1 vs. follicular mature (FM) splenic B cells. T1, in contrast to FM B cells, failed to express key NF-?B target genes in response to BCR engagement; and exhibited a striking defect in assembly of an active transcriptional complex at the promoter of the survival and proliferative genes, A1 and c-Myc. Surprisingly, and contrary to previous models, classical PKC and IKK activation, NF-?B nuclear translocation and DNA binding were intact in T1 B cells. Further, despite a marked reduction in NFAT1 expression, differential NFAT or AP-1 activation cannot explain this transcriptional defect. Our combined findings demonstrate that T1 B cells are programmed for signal- and stage-specific ‘nuclear non-responsiveness’ upon encounter with self-antigens.

Andrews, Sarah F; Rawlings, David J

2009-01-01

21

Translocations among Antibody Genes in Human Cancer  

Microsoft Academic Search

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

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

1983-01-01

22

Altered subcellular localization of c-Myc protein identifies aggressive B-cell lymphomas harboring a c-MYC translocation.  

PubMed

Nearly 100% of Burkitt lymphomas (BLs) and 5% to 8% of diffuse large B-cell lymphomas (DLBCLs) harbor a balanced translocation involving c-MYC. Although characteristic morphologic and immunophenotypic features can identify BL in most cases, tumors with atypical features are often encountered in clinical practice. Furthermore, no morphologic or immunophenotypic finding can predict an underlying c-MYC translocation in DLBCL with certainty. Here we report on a novel monoclonal antibody recognizing the c-myc protein in formalin-fixed, paraffin-embedded tissue which we used to evaluate a spectrum of aggressive B-cell lymphomas by standard immunohistochemistry. Cases consisted of 17 BLs (15 cases with confirmed c-MYC translocation), 19 DLBCLs without a c-MYC translocation, 5 DLBCLs with a c-MYC translocation, and 2 B-cell lymphomas, unclassifiable, with features intermediate between DLBCL and BL (intermediate DBLCL/BL, one case with c-MYC translocation and one case without a c-MYC translocation). The intensity and subcellular localization of tumor-specific staining for c-myc protein was determined independently by 2 pathologists and in a blinded fashion for each case. We observed c-myc expression in the tumor cells of all cases regardless of c-MYC status. Among BLs, c-myc protein primarily localized to the nucleus of tumor cells in 15 of 17 cases (88%) and equally localized to the nucleus and cytoplasm of tumor cells in 2 of 17 cases (12%). In no case did c-myc protein primarily localize to the cytoplasm. In contrast, among DLBCLs lacking a c-MYC translocation the c-myc protein primarily localized to the cytoplasm of the tumor cells in 18 of 19 cases (95%) and equally localized to the nucleus and cytoplasm in the tumor cells in 1 of 19 cases (5%). In no case did c-myc protein primarily localize to the nucleus. Among DLBCLs with a c-MYC translocation and intermediate DBLCL/BLs, the c-myc protein primarily localized to the nucleus, or equally localized to the nucleus and cytoplasm of the tumor cells in 4 of 5 cases (80%) and 2 of 2 cases (100%), respectively. Taken together, we find that a primarily nuclear or mixed nuclear and cytoplasmic staining pattern for c-myc in an aggressive B-cell lymphoma is highly predictive of a c-MYC translocation (positive-predictive value=0.92, negative-predictive value=0.95, P<0.0001). We further show that the subcellular localization of c-myc can be determined with good interobserver agreement among pathologists (kappa statistic=0.90). Thus this novel immunohistochemsitry test is a useful tool for identifying aggressive B-cell lymphomas likely to harbor a c-MYC rearrangement and thus warrant genetic testing. PMID:20442643

Ruzinova, Marianna B; Caron, Tyler; Rodig, Scott J

2010-06-01

23

Testing gene function early in the B cell lineage in mb1-cre mice  

Microsoft Academic Search

The mb1 gene encodes the Ig- signaling subunit of the B cell antigen receptor and is expressed exclusively in B cells beginning at the very early pro-B cell stage in the bone marrow. We examine here the efficacy of the mb1 gene as a host locus for cre recombinase expression in B cells. We show that by integrating a humanized

E. Hobeika; S. Thiemann; B. Storch; H. Jumaa; P. J. Nielsen; R. Pelanda; M. Reth

2006-01-01

24

Gene Translocations in Musculoskeletal Neoplasms  

PubMed Central

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

Krishnan, Balaji; Khanna, Gaurav

2008-01-01

25

The 3q27 and 18q21 translocations for follicular lymphoma and diffuse large B-cell lymphoma in the rituximab era.  

PubMed

The 3q27 and 18q21 chromosomal translocations are major hallmarks in B-cell lymphoma. We aimed to determine the frequencies of these translocations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and to evaluate their prognostic impact in the rituximab era. This study included 98 FL and 93 DLBCL patients whose abnormal karyotypes had been detected using G-banding. Patients uniformly underwent R-CHOP therapy : doxorubicin, cyclophosphamide, vincristine, prednisolone, and rituximab ; survivors were followed up for 29 months (median). The 3q27 and 18q21 translocations were detected in 14 and 77 FL patients and 14 and 22 DLBCL patients, respectively. Overall survival (OS) and progression-free survival (PFS) did not differ significantly between the groups with 3q27, 18q21, concurrent 3q27 and 18q21 translocations, and other chromosomal abnormalities for FL and DLBCL. There were no significant differences in OS and PFS between patients with 3q27 translocation-positive FL and those with 3q27 translocation-positive DLBCL or between the patients with 18q21 translocation-positive FL and those with 18q21 translocation-positive DLBCL. The presence of 3q27 and 18q21 translocations did not correlate with the clinical outcomes of FL or DLBCL patients following R-CHOP treatment. PMID:23995106

Watanabe, Reina; Tomita, Naoto; Matsumoto, Chihiro; Hattori, Yukako; Matsuura, Shiro; Takasaki, Hirotaka; Hashimoto, Chizuko; Fujita, Hiroyuki; Fujisawa, Shin; Ishigatsubo, Yoshiaki

2013-01-01

26

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

2013-06-20

27

Chromosomal location targets different MYC family gene members for oncogenic translocations  

PubMed Central

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

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

2009-01-01

28

Fluorescence in situ hybridization assessment of the telomeric regions of jumping translocations in a case of aggressive B-cell non-Hodgkin lymphoma  

Microsoft Academic Search

We report a jumping translocation involving a donor chromosome 1 long arm in a case of aggressive B-cell non-Hodgkin lymphoma (NHL). Conventional cytogenetic banding studies demonstrated a breakpoint distal to the heterochromatic region of the donor 1q chromosome. Characterization by fluorescence in situ hybridization (FISH) of the jumping translocation demonstrated an apparent telomeric sequence loss of the recipient chromosomes. Additional

Brian A. Gray; Angela Bent-Williams; Julie Wadsworth; Russell L. Maiese; Andres Bhatia; Robert T. Zori

1997-01-01

29

B-Cell Gene Therapy for Tolerance Induction: Host but Not Donor B-Cell Derived IL-10 is Necessary for Tolerance  

PubMed Central

Genetically modified B cells are excellent tolerogenic antigen-presenting cells (APCs) in multiple models of autoimmunity. However, the mechanisms of action are still not completely understood. In our models, we generate antigen-specific tolerogenic B cells by transducing naïve or primed B cells with an antigen–immunoglobulin G (peptide–IgG) construct. In order to be transduced, B cells require activation with mitogens such as LPS. We and others have found that LPS stimulation of B cells upregulates the production of IL-10, a key cytokine for maintaining immune tolerance. In the current study, we defined the role of B-cell produced IL-10 in tolerance induction by using IL-10 deficient B cells as donor APCs. We found that peptide–IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model. Moreover, we demonstrated that the tolerogenic effect of peptide–IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients. Taken together, our results suggest that tolerance induced by peptide–IgG B-cell gene therapy requires IL-10 from the host but not donor B cells. These data shed important insights into the mechanisms of tolerance induction mediated by B-cell gene therapy.

Su, Yan; Zhang, Ai-Hong; Noben-Trauth, Nancy; Scott, David W.

2011-01-01

30

Immunoglobulin light chain gene translocations in non-Hodgkin's lymphoma as assessed by fluorescence in situ hybridisation.  

PubMed

In non-Hodgkin's lymphoma (NHL), the majority of translocations involve the immunoglobulin heavy chain gene (IGH) locus, while a few involve the immunoglobulin light chain gene (IGL) locus, consisting of the kappa light chain gene (IGkappa) and the lambda light chain gene (IGlambda). Although many reports have dealt with the translocation and/or amplification of IGH in NHL, only a few have identified IGL translocations. To identify cytogenetic abnormalities and the partner chromosomes of IGL translocations in NHL, we performed dual-colour fluorescence in situ hybridisation (DC-FISH) and spectral karyotyping (SKY) in seven NHL cell lines and 40 patients with NHL. We detected IGL translocations in two cell lines and nine patients: four patients with diffuse large B-cell lymphoma, three with follicular lymphoma, one with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue and one with mantle cell lymphoma. Five distinct partners of IGlambda translocation were identified by SKY analysis: 3q27 in three patients, and 1p13, 6p25, 17p11.2 and 17q21 in one patient each. Three cases featured double translocations of IGH and IGL. These findings warrant the identification of novel genes 1p13, 6p25, 17p11.2 and 17q21. PMID:18005388

Fujimoto, Yoshiko; Nomura, Kenichi; Fukada, Shuji; Shimizu, Daisuke; Shimura, Kazuho; Matsumoto, Yosuke; Horiike, Shigeo; Nishida, Kazuhiro; Shimazaki, Chihiro; Abe, Masafumi; Taniwaki, Masafumi

2008-01-01

31

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.

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

2009-01-01

32

B-cell-specific demethylation of BTK , the defective gene in X-linked agammaglobulinemia  

Microsoft Academic Search

BTK, the gene that is defective in X-linked agammaglobulinemia, encodes a cytoplasmic tyrosine kinase that is critical for B-cell proliferation, or survival. To identify regulatory elements that control the expression of BTK we evaluated the methylation pattern of this gene in cell lines and in freshly isolated cells. An Hpa II site that was specifically demethylated in mature B cells

Ornella Parolini; Jurg Rohrer; Linda H. Shapiro; Mary Ellen Conley

1995-01-01

33

The IL-12R?2 gene functions as a tumor suppressor in human B cell malignancies  

PubMed Central

The IL-12R?2 gene is expressed in human mature B cell subsets but not in transformed B cell lines. Silencing of this gene may be advantageous to neoplastic B cells. Our objective was to investigate the mechanism(s) and the functional consequence(s) of IL-12R?2 gene silencing in primary B cell tumors and transformed B cell lines. Purified tumor cells from 41 patients with different chronic B cell lymphoproliferative disorders, representing the counterparts of the major mature human B cell subsets, tested negative for IL-12R?2 gene expression. Hypermethylation of a CpG island in the noncoding exon 1 was associated with silencing of this gene in malignant B cells. Treatment with the DNA methyltransferase inhibitor 5-Aza-2?-deoxycytidine restored IL-12R?2 mRNA expression in primary neoplastic B cells that underwent apoptosis following exposure to human recombinant IL-12 (hrIL-12). hrIL-12 inhibited proliferation and increased the apoptotic rate of IL-12R?2–transfected B cell lines in vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12R?2–transfected Burkitt lymphoma RAJI cells in SCID-NOD mice through antiproliferative and proapoptotic effects, coupled with neoangiogenesis inhibition related to human IFN-?–independent induction of hMig/CXCL9. The IL-12R?2 gene acts as tumor suppressor in chronic B cell malignancies, and IL-12 exerts direct antitumor effects on IL-12R?2–expressing neoplastic B cells.

Airoldi, Irma; Di Carlo, Emma; Banelli, Barbara; Moserle, Lidia; Cocco, Claudia; Pezzolo, Annalisa; Sorrentino, Carlo; Rossi, Edoardo; Romani, Massimo; Amadori, Alberto; Pistoia, Vito

2004-01-01

34

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.  

PubMed

Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions. PMID:22622038

Sauer, Aisha V; Morbach, Henner; Brigida, Immacolata; Ng, Yen-Shing; Aiuti, Alessandro; Meffre, Eric

2012-05-24

35

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy  

PubMed Central

Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions.

Sauer, Aisha V.; Morbach, Henner; Brigida, Immacolata; Ng, Yen-Shing; Aiuti, Alessandro; Meffre, Eric

2012-01-01

36

Systematic comparison of gene expression between murine memory and naive B cells demonstrates that memory B cells have unique signaling capabilities.  

PubMed

Memory B cells play essential roles in the maintenance of long-term immunity and may be important in the pathogenesis of autoimmune disease, but how these cells are distinguished from their naive precursors is poorly understood. To address this, it would be important to understand how gene expression differs between memory and naive B cells to elucidate memory-specific functions. Using model systems that help overcome the lack of murine memory-specific markers and the low frequency of Ag-specific memory and naive cells, we undertook a global comparison of gene expression between memory B cells and their naive precursors. We identified genes with differential expression and confirmed the differential expression of many of these by quantitative RT-PCR and of some of these at the protein level. Our initial analysis revealed differential expression patterns of genes that regulate signaling. Memory B cells have increased expression of genes important in regulating adenosine signaling and in modulating cAMP responses. Furthermore, memory B cells up-regulate receptors that are essential for embryonic stem cell self-renewal. We further demonstrate that one of these, leukemia inhibitory factor receptor, can initiate functional signaling in memory B cells whereas it does not in naive B cells. Thus, memory and naive B cells are intrinsically wired to signal differently from one another and express a functional signaling pathway that is known to maintain stem cells in other lineages. PMID:18566367

Tomayko, Mary M; Anderson, Shannon M; Brayton, Catherine E; Sadanand, Saheli; Steinel, Natalie C; Behrens, Timothy W; Shlomchik, Mark J

2008-07-01

37

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

PubMed Central

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

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

2012-01-01

38

Early growth response genes regulate B cell development, proliferation and immune response  

PubMed Central

SUMMARY Egr-1 (Early growth response gene-1) is an immediate early gene encoding a zinc finger motif containing transcription factor. Upon cross-linking of B cell receptor (BCR), mature B cells undergo proliferation with an increase in Egr-1. Immature B lymphoma cells that express Egr-1 constitutively are growth inhibited when Egr-1 is downregulated by negative signals from BCR or by antisense oligonucelotides. To test the hypothesis that Egr-1 is important for B-cell development, we examined B cells from primary and secondary lymphoid organs in Egr-1-/- mice. Marginal zone B cell development was arrested in these mice while the B cells in all other compartments were increased. To test the hypothesis that Egr-1 function may be partially compensated by other Egr family members, we developed transgenic mice expressing a dominant negative form of Egr-1, which lacks the transactivation domain but retains the DNA binding domain, in a B cell specific manner. There was a decrease in B lymphopioesis in the bone marrow accompanied by a reduction in splenic immature and mature B cells as well as marginal zone B cells in the transgenic mice. Moreover, transgenic mice respond poorly to BCR cross-linking in vitro and T-independent and T-dependent antigens in vivo.

Gururajan, Murali; Simmons, Alan; Dasu, Trivikram; Spear, Brett T.; Calulot, Chris; Robertson, Darrell A.; Wiest, David L.; Monroe, John G.; Bondada, Subbarao

2008-01-01

39

In Vivo Ablation of Surface Immunoglobulin on Mature B Cells by Inducible Gene Targeting Results in Rapid Cell Death  

Microsoft Academic Search

Gene targeting experiments have demonstrated that the expression of immunoglobulin heavy chain in the pre-B cell receptor (pBCR) and of heavy and light chains in the B cell antigen receptor (BCR) marks checkpoints in early B cell development that the cells have to pass to survive. To investigate whether the persistence of mature B cells in the peripheral immune system

Kong-Peng Lam; Ralf Kühn; Klaus Rajewsky

1997-01-01

40

Activated Notch1 Modulates Gene Expression in B Cells Similarly to Epstein-Barr Viral Nuclear Antigen 2  

PubMed Central

Both Epstein-Barr viral nuclear antigen 2 (EBNA2) and activated Notch transactivate genes by interacting with the transcription factor RBP-J?. The viral protein EBNA2 may hence be regarded as a functional equivalent of an activated Notch receptor. Until now, nothing has been known about the physiological role of Notch signaling in B cells. Here we investigated whether activated Notch can induce the same phenotypic changes as EBNA2 in Burkitt's lymphoma cells. An estrogen receptor fusion protein of the intracellular part of mouse Notch 1 (mNotch1-IC), mimicking in the presence of estrogen a constitutively active Notch receptor, was stably transfected into the Burkitt's lymphoma cell lines BL41-P3HR1 and HH514. Northern blot analysis revealed that the LMP2A gene is induced by Notch-IC in the presence of estrogen, whereas increased expression of LMP1 could be detected only if cycloheximide was simultaneously added. Concerning the cellular genes regulated by EBNA2, Notch-IC was able to upregulate CD21 but not CD23 expression. Immunoglobulin ? (Ig?) expression, which is downregulated by EBNA2, was also negatively regulated by Notch-IC. Similarly to EBNA2, Notch-IC was able to repress c-myc expression, which is under the control of the immunoglobulin heavy-chain locus in Burkitt's lymphoma cells with a t(8;14) translocation. The data show that Notch-IC is able to participate in gene regulation in B cells.

Strobl, Lothar J.; Hofelmayr, Heike; Marschall, Gabriele; Brielmeier, Markus; Bornkamm, Georg W.; Zimber-Strobl, Ursula

2000-01-01

41

B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia.  

PubMed

The immunodeficiency disorder, X-linked agammaglobulinemia (XLA), results from mutations in the gene encoding Bruton tyrosine kinase (Btk). Btk is required for pre-B cell clonal expansion and B-cell antigen receptor signaling. XLA patients lack mature B cells and immunoglobulin and experience recurrent bacterial infections only partially mitigated by life-long antibody replacement therapy. In pursuit of definitive therapy for XLA, we tested ex vivo gene therapy using a lentiviral vector (LV) containing the immunoglobulin enhancer (Emu) and Igbeta (B29) minimal promoter to drive B lineage-specific human Btk expression in Btk/Tec(-/-) mice, a strain that reproduces the features of human XLA. After transplantation of EmuB29-Btk-LV-transduced stem cells, treated mice showed significant, albeit incomplete, rescue of mature B cells in the bone marrow, peripheral blood, spleen, and peritoneal cavity, and improved responses to T-independent and T-dependent antigens. LV-treated B cells exhibited enhanced B-cell antigen receptor signaling and an in vivo selective advantage in the peripheral versus central B-cell compartment. Secondary transplantation showed sustained Btk expression, viral integration, and partial functional responses, consistent with long-term stem cell marking; and serial transplantation revealed no evidence for cellular or systemic toxicity. These findings strongly support pursuit of B lineage-targeted LV gene therapy in human XLA. PMID:20093406

Kerns, Hannah M; Ryu, Byoung Y; Stirling, Brigid V; Sather, Blythe D; Astrakhan, Alexander; Humblet-Baron, Stephanie; Liggitt, Denny; Rawlings, David J

2010-01-21

42

Decreased expression of B cell related genes in leukocytes of women with Parkinson's disease  

PubMed Central

Background Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations. Results Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status. Conclusions Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD.

2011-01-01

43

Fucoidan prevents C? germline transcription and NF?B p52 translocation for IgE production in B cells  

Microsoft Academic Search

Fucoidan, a dietary fiber contained in seaweed, reduces the increase of antigen-specific IgE in mice exposed to ovalbumin. In this study, we investigated the effect of fucoidan on IgE production and intracellular events in B cells in vitro. Fucoidan inhibited the production of IgE and C? germline transcription in murine B cells induced by IL-4 (100ng\\/ml) and anti-CD40 antibodies (10?g\\/ml),

Souichi Oomizu; Yuhki Yanase; Hidenori Suzuki; Yoshikazu Kameyoshi; Michihiro. Hide

2006-01-01

44

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

PubMed Central

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

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

2007-01-01

45

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

46

Most Marginal Zone B Cells in Rat Express Germline Encoded Ig VH Genes and Are Ligand Selected  

Microsoft Academic Search

The present study was performed to analyze whether marginal zone B (MZ-B) cells in nondeliberately immunized adult rats are selected on basis of the specificity of their B cell receptor, and to determine to what extent memory B cells contribute to the MZ-B cell subset. To this end, the Ig PC7183 VH gene repertoire was studied among VHDJH-m transcripts expressed

Peter M. Dammers; Annie Visser; Eliane R. Popa; Paul Nieuwenhuis; Frans G. M. Kroese

2000-01-01

47

Loss of an Ig? gene enhancer in mature B cells results in rapid gene silencing and partial reversible dedifferentiation.  

PubMed

We address here whether there is cellular memory of a transcriptional enhancer once it has served its purpose to establish an active chromatin state. We have previously shown that the mouse Ig? gene's downstream enhancers, E3' and Ed, are essential but play redundant roles for establishing transcriptional activity in the locus during B cell development. To determine whether these enhancers are also necessary for the maintenance of transcriptional activity, we conditionally deleted E3' in mature B cells that possessed Ed(-/-) alleles. Upon E3' deletion, the locus became rapidly silenced and lost positive histone epigenetic marks, and the mature B cells partially dedifferentiated, induced RAG-1 and -2 along with certain other pro-B cell makers, and then redifferentiated after triggering Ig? gene rearrangements. We conclude that the Ig? gene's downstream enhancers are essential for both the establishment and maintenance of transcriptional activity and that there is no cellular memory of previous transcriptional activity in this locus. Furthermore, upon enhancer loss, the mature B cells unexpectedly underwent reversible retrograde differentiation. This result establishes that receptor editing can occur in mature B cells and raises the possibility that this may provide a tolerance mechanism for eliminating autoreactive B cells in the periphery. PMID:23508106

Zhou, Xiaorong; Xiang, Yougui; Ding, Xiaoling; Garrard, William T

2013-03-18

48

Fucoidan prevents C{epsilon} germline transcription and NF{kappa}B p52 translocation for IgE production in B cells  

SciTech Connect

Fucoidan, a dietary fiber contained in seaweed, reduces the increase of antigen-specific IgE in mice exposed to ovalbumin. In this study, we investigated the effect of fucoidan on IgE production and intracellular events in B cells in vitro. Fucoidan inhibited the production of IgE and C{epsilon} germline transcription in murine B cells induced by IL-4 (100 ng/ml) and anti-CD40 antibodies (10 {mu}g/ml), whereas it stimulated cell proliferation. A significant effect of fucoidan on IgE production was observed when B cells were stimulated with a higher dose (5 {mu}g/ml) of anti-CD40 antibodies, but not when stimulated with lower doses (1.25, 2.5 {mu}g/ml), regardless of the IL-4 concentrations. Moreover, nuclear translocation of NF{kappa}B p52, but neither that of NF{kappa}B p65, nor the phosphorylation of JAK1 and STAT6 was reduced by fucoidan. These results suggest that fucoidan inhibited IgE production by preventing the NF{kappa}B p52-mediated pathways activated by CD40.

Oomizu, Souichi [Hiroshima Prefectural Institute of Industrial Science and Technology, Higashi-Hiroshima (Japan); Yanase, Yuhki [Hiroshima Prefectural Institute of Industrial Science and Technology, Higashi-Hiroshima (Japan); Department of Dermatology, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima (Japan); Suzuki, Hidenori [Department of Dermatology, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima (Japan); Kameyoshi, Yoshikazu [Department of Dermatology, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima (Japan); Hide, Michihiro [Department of Dermatology, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima (Japan)]. E-mail: mhide@hiroshima-u.ac.jp

2006-11-24

49

Organizational structure and the periphery of the gene regulatory network in B-cell lymphoma  

PubMed Central

Background The physical periphery of a biological cell is mainly described by signaling pathways which are triggered by transmembrane proteins and receptors that are sentinels to control the whole gene regulatory network of a cell. However, our current knowledge about the gene regulatory mechanisms that are governed by extracellular signals is severely limited. Results The purpose of this paper is three fold. First, we infer a gene regulatory network from a large-scale B-cell lymphoma expression data set using the C3NET algorithm. Second, we provide a functional and structural analysis of the largest connected component of this network, revealing that this network component corresponds to the peripheral region of a cell. Third, we analyze the hierarchical organization of network components of the whole inferred B-cell gene regulatory network by introducing a new approach which exploits the variability within the data as well as the inferential characteristics of C3NET. As a result, we find a functional bisection of the network corresponding to different cellular components. Conclusions Overall, our study allows to highlight the peripheral gene regulatory network of B-cells and shows that it is centered around hub transmembrane proteins located at the physical periphery of the cell. In addition, we identify a variety of novel pathological transmembrane proteins such as ion channel complexes and signaling receptors in B-cell lymphoma.

2012-01-01

50

Evaluating Translocation Gene Fusions by SNP Array Data  

PubMed Central

Somatic cell genetic alterations are a hallmark of tumor development and progression. Although various technologies have been developed and utilized to identify genetic aberrations, identifying genetic translocations at the chromosomal level is still a challenging task. High density SNP microarrays are useful to measure DNA copy number variation (CNV) across the genome. Utilizing SNP array data of cancer cell lines and patient samples, we evaluated the CNV and copy number breakpoints for several known fusion genes implicated in tumorigenesis. This analysis demonstrated the potential utility of SNP array data for the prediction of genetic aberrations via translocations based on identifying copy number breakpoints within the target genes. Genome-wide analysis was also performed to identify genes harboring copy number breakpoints across 820 cancer cell lines. Candidate oncogenes were identified that are linked to potential translocations in specific cancer cell lines.

Liu, Hong; Zilberstein, Asher; Pannier, Pascal; Fleche, Frederic; Arendt, Christopher; Lengauer, Christoph; Hahn, Chang S.

2012-01-01

51

Correlation of gene expression and genome mutation in single B-cells.  

PubMed

High-throughput measurement of gene-expression and immune receptor repertoires have recently become powerful tools in the study of adaptive immune response. However, despite their now-widespread use, both tend to discard cell identity by treating cell populations in bulk, and therefore lose the correlation between genetic variability and gene-expression at the single cell level. In order to recover this information, we developed a method to simultaneously measure gene expression profiles and genome mutations in single cells. We applied this method by quantifying the relationships between gene expression and antibody mutation in ensembles of individual B-cells from immunized mice. The results reveal correlations reflecting the manner in which information propagates between a B-cell's antigen receptors, its gene expression, and its mutagenic machinery, and demonstrate the power of this approach to illuminate both heterogeneity and physiology in cell populations. PMID:23840752

Weinstein, Joshua A; Zeng, Xun; Chien, Yueh-Hsiu; Quake, Stephen R

2013-06-28

52

Correlation of Gene Expression and Genome Mutation in Single B-Cells  

PubMed Central

High-throughput measurement of gene-expression and immune receptor repertoires have recently become powerful tools in the study of adaptive immune response. However, despite their now-widespread use, both tend to discard cell identity by treating cell populations in bulk, and therefore lose the correlation between genetic variability and gene-expression at the single cell level. In order to recover this information, we developed a method to simultaneously measure gene expression profiles and genome mutations in single cells. We applied this method by quantifying the relationships between gene expression and antibody mutation in ensembles of individual B-cells from immunized mice. The results reveal correlations reflecting the manner in which information propagates between a B-cell’s antigen receptors, its gene expression, and its mutagenic machinery, and demonstrate the power of this approach to illuminate both heterogeneity and physiology in cell populations.

Weinstein, Joshua A.; Zeng, Xun; Chien, Yueh-Hsiu; Quake, Stephen R.

2013-01-01

53

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

PubMed Central

The MLL gene, on human chromosome 11q23, undergoes chromosomal translocation in acute leukemias, resulting in gene fusion with AF4 (chromosome 4) and ENL (chromosome 19). We report here translocation of MLL with nine different chromosomes and two paracentric chromosome 11 deletions in early B cell, B- or T-cell lineage, or nonlymphocytic acute leukemias. The mRNA translocation junction from 22 t(4;11) patients, including six adult leukemias, and nine t(11;19) tumors reveals a remarkable conservation of breakpoints within MLL, AF4, or ENL genes, irrespective of tumor phenotype. Typically, the breakpoints are upstream of the zinc-finger region of MLL, and deletion of this region can accompany translocation, supporting the der(11) chromosome as the important component in leukemogenesis. Partial sequence of a fusion between MLL and the AFX1 gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA. These data suggest that the heterogeneous 11q23 abnormalities might cause attachment of Ser/Pro-rich segments to the NH2 terminus of MLL, lacking the zinc-finger region, and that translocations occur in early hematopoietic cells, before commitment to distinct lineages. Images Fig. 1

Corral, J; Forster, A; Thompson, S; Lampert, F; Kaneko, Y; Slater, R; Kroes, W G; van der Schoot, C E; Ludwig, W D; Karpas, A

1993-01-01

54

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

SciTech Connect

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

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

1993-09-15

55

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

56

Immunoglobulin heavy chain variable region gene utilization by B cell hybridomas derived from rheumatoid synovial tissue.  

PubMed Central

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects synovial joints. Activated B lymphocytes and plasma cells are present in the synovial tissue and are thought to contribute to the immunopathology of the rheumatoid joint. To investigate rheumatoid synovial B lymphocytes, we have generated B cell hybridomas from synovial tissue of an RA patient. Here we describe the immunoglobulin VH gene repertoire of eight IgM- and 10 IgG-secreting synovial-derived hybridomas. The VH4 gene family is highly represented (38.5%) in this panel of hybridomas compared with the frequency of VH4 gene expression in circulating B lymphocytes reported previously (19-22%) and with the VH4 gene frequency we observed in a panel of hybridomas derived in the same manner from the spleen and tonsil of normal individuals (19%). The increased frequency of VH4 gene expression was not due to the expansion of a single B cell clone in vivo as none of these hybridomas was clonally related. Two synovial-derived hybridomas secreted autoantibodies; one (VH3+) secreted an IgM-rheumatoid factor (RF) and the other (VH4+) secreted IgM with polyreactive binding to cytoskeletal proteins and cardiolipin. The antibodies secreted by the remaining synovial-derived hybridomas were not reactive with the autoantigens tested. The VH gene usage in a proportion (5/17) of synovial-derived hybridomas that expressed CD5 antigen provided preliminary evidence that CD5+ B cells in RA synovium have a similar increase of VH4 gene expression reported for CD5+ B cells from normal individuals and patients with chronic lymphocytic leukaemia.

Brown, C M; Longhurst, C; Haynes, G; Plater-Zyberk, C; Malcolm, A; Maini, R N

1992-01-01

57

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

PubMed Central

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

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

2008-01-01

58

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

PubMed Central

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

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

2011-01-01

59

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

SciTech Connect

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

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

1987-10-01

60

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

PubMed

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

2013-08-15

61

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.

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

2013-01-01

62

Gene expression-based risk score in diffuse large B-cell lymphoma  

PubMed Central

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and displays heterogeneous clinical and molecular characteristics. In this study, high throughput gene expression profiling of DLBCL tumor samples was used to design a 12-gene expression–based risk score (GERS) predictive for patient's overall survival. GERS allowed identifying a high-risk group comprising 46,4% of the DLBCL patients in two independent cohorts (n=414 and n=69). GERS was shown to be an independent predictor of survival when compared to the previously published prognostic factors, including the International Prognostic Index (IPI). GERS displayed a prognostic value in germinal-center B-cell–like subgroup (GCB) and activated B cell–like (ABC) molecular subgroups of patients as well as in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or Rituximab-CHOP (R-CHOP) regimens. Combination of GERS and IPI lead to a potent prognostic classification of DLBCL patients. Finally, a genomic instability gene signature was highlighted in gene expression profiles of patients belonging to the high-risk GERS-defined group.

Bret, Caroline; Klein, Bernard; Moreaux, Jerome

2012-01-01

63

Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma  

Microsoft Academic Search

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappaB transcription complex. However, except for a small fraction of cases,

Mara Compagno; Wei Keat Lim; Adina Grunn; Subhadra V. Nandula; Manisha Brahmachary; Qiong Shen; Francesco Bertoni; Maurilio Ponzoni; Marta Scandurra; Andrea Califano; Govind Bhagat; Amy Chadburn; Riccardo Dalla-Favera; Laura Pasqualucci

2009-01-01

64

Aberrant Expression of ID2, a Suppressor of B-Cell-Specific Gene Expression, in Hodgkin's Lymphoma  

PubMed Central

The global loss of B-cell-specific gene expression is a distinctive feature of the Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin’s lymphoma (HL). The reasons for this loss remained largely unknown as transcription factors with pleiotropic effects on B-cell-specific gene expression, namely E2A, EBF, and PAX5, are present in primary HRS cells. We show here that ID2, which can inactivate E2A and perhaps PAX5, is not detectable in normal B cells but is strongly and uniformly expressed in HRS cells of all cases of classical HL. Recurrent chromosomal gains of the ID2 gene might contribute to this aberrant expression. Co-immunoprecipitation of E2A with ID2 from HRS-derived cell lines together with the high amount of ID2 relative to the B-cell transcription factors E2A and PAX5 in HRS-derived cell lines and primary HRS cells indicated that aberrant ID2 expression contributes significantly to the loss of the B-cell-specific gene expression in HRS cells. ID2 was also expressed in lymphocyte-predominance HL, mediastinal large B-cell, diffuse large B-cell, and Burkitt’s lymphoma, where lower amounts of ID2 relative to E2A and PAX5 compared with HRS cells might prevent a global down-regulation of B-cell-specific genes and ID2 may contribute to lymphomagenesis in other ways.

Renne, Christoph; Martin-Subero, Jose Ignacio; Eickernjager, Maren; Hansmann, Martin-Leo; Kuppers, Ralf; Siebert, Reiner; Brauninger, Andreas

2006-01-01

65

Novel ORC4L gene mutation in B-cell lymphoproliferative disorders.  

PubMed

B-cell lymphoproliferative disorders are characterized by marked genetic, morphological, and clinical heterogeneity. The identification of prognostic markers could help to develop risk-adapted treatment strategies. Because proliferation of cells is essential for tumor growth, analysis of the cell cycle might give additional information on tumor progression and clinical behavior. Because initiation of DNA replication represents a significant step in cell division, it is worthwhile to focus the attention to the origin recognition complex (ORC), protein complex essential for initiation of DNA replication. Studies have already shown that ORC-associated factors give a more accurate assessment of cell proliferation than previous markers for many types of malignancies, but so far there have been no studies of eventual role of ORC4L in B-cell lymphoproliferative disorders. Here, we describe 3 patients with B-cell lymphoproliferative disorders (2 with non-Hodgkin lymphoma and 1 with nonsecretory multiple myeloma) carrying a novel A286V mutation within ORC4L gene. All 3 patients were in the advanced stage of disease, but their response to the chemotherapy treatment was good and they achieved complete clinical remission in a relatively short period. Although the functional relevance of this mutation has not yet been elucidated, our observation raises a possibility that A286V mutation, which is constitutively present in these patients, might represent a favorable prognostic marker in B-cell lymphoproliferative disorders. PMID:20010161

Radojkovic, Milica; Ristic, Slobodan; Divac, Aleksandra; Tomic, Branko; Nestorovic, Aleksandra; Radojkovic, Dragica

2009-12-01

66

The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma.  

PubMed

The BCL6 gene is frequently disrupted at its 5' noncoding region by 3q27 chromosomal translocations in B-cell lymphoma. As a result of translocation, BCL6 is juxtaposed to reciprocal partners, such as the immunoglobulin (Ig) gene family. Besides the Ig loci, multiple non-Ig partners of the BCL6 translocation have been reported. Here we describe the identification of the GAS5 (growth arrest-specific transcript 5) gene as a novel partner of the BCL6 in a patient with diffuse large B-cell lymphoma, harboring the t(1;3)(q25;q27). In this case, the chromosome 1 breakpoint was located within the intronic small nucleolar RNA (snoRNA) sequence of GAS5 and the chromosome 3 breakpoint at 4 kb upstream of BCL6 exon 1a. As the result of chromosomal translocation, the GAS5-BCL6 chimeric transcripts were expressed, in which the 5'-terminal oligopyrimidine (5'TOP) sequence of GAS5 was fused to the whole coding sequence of BCL6. The GAS5 gene on chromosome 1q25 is the second BCL6 partner, to the SNHG5 on 6q15, which is classified as a non-protein-coding multiple snoRNA host and 5'-TOP class gene. PMID:18406879

Nakamura, Yuichi; Takahashi, Naoki; Kakegawa, Emi; Yoshida, Katsuhiko; Ito, Yoshihiro; Kayano, Hidekazu; Niitsu, Nozomi; Jinnai, Itsuro; Bessho, Masami

2008-04-15

67

Impaired Immune Responses and B-Cell Proliferation in Mice Lacking the Id3 Gene  

PubMed Central

B-lymphocyte activation and proliferation induced by the B-cell receptor (BCR) signals are important steps in the initiation of humoral immune responses. How the BCR signals are translated by nuclear transcription factors into cell cycle progression is poorly understood. Id3 is an immediate-early gene responding to growth and mitogenic signals in many cell types including B cells. The primary function of the Id3 protein has been defined as that of inhibitor of basic-helix-loop-helix (bHLH) transcription factors. The interaction between Id3 and bHLH proteins, many of which are essential for cellular differentiation, has been proposed as a key regulatory event leading to cellular proliferation instead of differentiation. To further investigate the role of Id3 in tissue and embryo development and the mechanism of Id3-mediated growth regulation, we generated and analyzed Id3-deficient mice. While these mice display no overt abnormality in tissue and embryo development, their humoral immunity is compromised. The amounts of immunoglobulins produced in Id3-deficient mice immunized with a T-cell-dependent antigen and a type 2 T-cell-independent antigen are attenuated and severely impaired, respectively. Further analysis of lymphocytes isolated from Id3-deficient mice reveals a B-cell defect in their proliferation response to BCR cross-linking but not to lipopolysaccharide or a combination of BCR cross-linking and interleukin-4. Analyses of cultured lymphocytes also suggest involvement of Id3 in cytokine production in T cells and isotype switching in B cells. Finally, the proliferation defect in Id3-deficient B cells can be rescued by ectopic expression of Id1, a homologue of Id3. Taken together, these results define a necessary and specific role for Id3 in mediating signals from BCR to cell cycle progression during humoral immune responses.

Pan, Lihua; Sato, Shinichi; Frederick, Joshua P.; Sun, Xiao-Hong; Zhuang, Yuan

1999-01-01

68

Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells.  

PubMed

The transcription factor Pax5 represses lineage-inappropriate genes and activates B cell-specific genes in B lymphocytes. By identifying 110 Pax5-repressed genes, we now demonstrate that Pax5 downregulates diverse biological activities including receptor signaling, cell adhesion, migration, transcriptional control, and cellular metabolism at B cell commitment. The T lymphoid or myeloid expression of these genes demonstrates that Pax5(-/-) pro-B cells and common lymphoid progenitors display lymphoid and myeloid promiscuity of gene expression. These lineage-inappropriate genes require continuous Pax5 activity for their repression, as they are reactivated in committed pro-B cells and mature B cells following conditional Pax5 deletion. Pax5-repressed genes are also reexpressed in plasma cells, which depend for normal function on Cd28 and Ccr2 reactivation. The loss of Pax5 during terminal differentiation thus contributes to the plasma cell transcription program. Finally, ectopic expression of the Pax5-repressed chemokine gene Ccl3 in B cells results in increased osteoclast formation and bone loss, demonstrating that Pax5-mediated gene repression is essential for normal homeostasis of hematopoietic development. PMID:16546096

Delogu, Alessio; Schebesta, Alexandra; Sun, Qiong; Aschenbrenner, Katharina; Perlot, Thomas; Busslinger, Meinrad

2006-03-01

69

The BRG1 Chromatin Remodeler Regulates Widespread Changes in Gene Expression and Cell Proliferation During B Cell Activation.  

PubMed

Widespread changes in gene expression underlie B cell development and activation, yet our knowledge of which chromatin-remodeling factors are essential is limited. Here, we demonstrate that the BRG1 catalytic subunit of SWI/SNF complexes was dispensable for murine B cell development but played an important, albeit selective, role during activation. Although BRG1 was dispensable for CD69 induction and differentiation into plasma cells based on the ability of mutant B cells to undergo hypertrophy and secrete IgM antibodies, it was required for robust cell proliferation in response to activation. Accordingly, BRG1 was required for only ?100 genes to be expressed at normal levels in naïve B cells but >1,000 genes during their activation. BRG1 upregulated fivefold more genes than it downregulated, and the toll-like receptor pathway and JAK/STAT cytokine-signaling pathways were particularly dependent on BRG1. The importance of BRG1 in B cell activation was underscored by the occurrence of opportunistic Pasteurella infections in conditionally mutant mice. B cell activation has long served as a model of inducible gene expression, and the results presented here identify BRG1 as a chromatin-remodeling factor that upregulates the transcriptome of B cells during their activation to promote rapid cell proliferation and to mount an effective immune response. J. Cell. Physiol. 229: 44-52, 2014. © 2013 Wiley Periodicals, Inc. PMID:23757284

Holley, Darcy W; Groh, Beezly S; Wozniak, Glenn; Donohoe, Dallas R; Sun, Wei; Godfrey, Virginia; Bultman, Scott J

2014-01-01

70

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

PubMed Central

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

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

2011-01-01

71

SNP-based large-scale identification of allele-specific gene expression in human B cells.  

PubMed

Polymorphism and variations in gene expression provide the genetic basis for human variation. Allelic variation of gene expression, in particular, may play a crucial role in phenotypic variation and disease susceptibility. To identify genes with allelic expression in human cells, we genotyped genomic DNA and cDNA isolated from 31 immortalized B cell lines from three Centre d'Etude du Polymorphisme Humain (CEPH) families using high-density single-nucleotide polymorphism (SNP) chips containing 13,900 exonic SNPs. We identified seven SNPs in five genes with monoallelic expression, 146 SNPs in 125 genes with allelic imbalance in expression with preferentially higher expression of one allele in a heterozygous individual. The monoallelically expressed genes (ERAP2, MDGA1, LOC644422, SDCCAG3P1 and CLTCL1) were regulated by cis-acting, non-imprinted differential allelic control. In addition, all monoallelic gene expression patterns and allelic imbalances in gene expression in B cells were transmitted from parents to offspring in the pedigree, indicating genetic transmission of allelic gene expression. Furthermore, frequent allele substitution, probably due to RNA editing, was also observed in 21 genes in 23 SNPs as well as in 48 SNPs located in regions containing no known genes. In this study, we demonstrated that allelic gene expression is frequently observed in human B cells, and SNP chips are very useful tools for detecting allelic gene expression. Overall, our data provide a valuable framework for better understanding allelic gene expression in human B cells. PMID:22178530

Song, Min-Young; Kim, Hye-Eun; Kim, Sun; Choi, Ick-Hwa; Lee, Jong-Keuk

2011-12-08

72

Burkitt lymphoma arising from lymphoplasmacytic lymphoma following acquisition of MYC translocation and loss of the ETV6 tumor suppressor gene.  

PubMed

Lymphoplasmacytic lymphoma is a mature B-cell lymphoma with variable plasmacytic differentiation that displays an indolent clinical course. Its transformation to a high-grade B-cell lymphoma may occur uncommonly. Although acquisition of a MYC translocation could result in transformation of a low-grade lymphoma into diffuse large B-cell lymphoma, Burkitt lymphoma, or B-lymphoblastic leukemia, to our knowledge the latter 2 transformations have not been well documented in lymphoplasmacytic lymphoma. We report the case of a 70-year-old woman with a 9-year history of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia who presented with rapid enlargement of a left neck mass and pancytopenia, which was diagnosed as Burkitt lymphoma with extensive bone marrow involvement. A series of histopathologic, molecular, and cytogenetic evaluations proved a cytogenetic evolution including t(8;14)(q24;q32)/MYC-IgH and identical clonal B-cell gene rearrangements from the 2 distinct lymphomas, confirming stage 4 aggressive Burkitt lymphoma arising from lymphoplasmacytic lymphoma. PMID:23276184

Peker, Deniz; Quigley, Brian; Qin, Dahui; Papenhausen, Peter; Zhang, Ling

2013-01-01

73

Multiorgan infiltration by CD8+ T cells and 1p;16p translocation in a patient with hypogammaglobulinemia and a reduced number of B cells.  

PubMed

Common variable immunodeficiency (CVID) disorders are the most common form of clinically significant primary immunodeficiencies found in adults. There is now clear evidence that CVID includes a group of clinically and genetically heterogeneous conditions. In addition to recurrent infections, some patients are highly prone to granulomatous lesions. Rarely, CVID may be characterized by an increased number of circulating CD8+ T cells with tissue infiltration. We report a unique case of CVID associated with a sarcoidosis-like disease and polyclonal CD8+ T cell expansion with multiple tissue infiltration occurring in a subject with the chromosome translocation t(1;16). No sequence variant in TACI, APRIL, BAFF, ICOS or BTK genes was discovered. Cytometric analysis showed that the chemokine receptors expressed on peripheral and tissue CD8+ T cells are responsible for the tissue homing of the cells. Moreover, CD8+ T cells produced high amounts of IFN-?, but not IL-4 and IL-17, with regular expression of the transcription factor Vav1. Genes coding for IL-32 and FRAP1, both involved in the regulation of memory T cell differentiation, are located in the translocation breakpoint. This suggests that a chromosomal abnormality plays a role in the clinical features of this phenotypic variant of CVID. PMID:22286841

Vultaggio, Alessandra; Matucci, Andrea; D'Elios, Mario Milco; Andreucci, Elena; Giglio, Sabrina; Annunziato, Francesco; Zupo, Simonetta; Maggi, Enrico

2012-01-26

74

Continuing rearrangement but absence of somatic hypermutation in immunoglobulin genes of human B cell precursor leukemia  

PubMed Central

Southern blot analyses revealed that cells from nearly 30% of childhood B cell precursor acute lymphoblastic leukemias (ALLs) contained more than two rearranged, nongermline bands for Ig heavy chain genes. DNA corresponding to these bands was molecularly cloned from two cases which showed three and seven rearranged bands, respectively. Nucleotide sequence analysis of the cloned DNA demonstrated that each band represented different VDJ or DJ rearrangements. While the same DJ joints were shared by several rearrangements, different DJ joints were found in the majority of rearrangements, precluding V region substitution as an explanation for the multiplicity of heavy chain rearrangements in these leukemias. Most of the V region segments involved in these rearrangements were restricted to VH region families that have been shown previously to be preferentially rearranged in human fetal B lineage cells. Sequence analysis of multiple copies of the same VDJ rearrangements from different cells revealed no somatic mutation, a mechanism responsible for detection of extra rearranged Ig DNA bands in certain other B lineage tumors. The data suggest that in some cases of ALL Ig heavy chain genes begin and continue to rearrange de novo within the neoplastic B cell precursor populations derived from an original malignant cell transformed at a stem cell stage of differentiation.

1988-01-01

75

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

Microsoft Academic Search

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

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

2003-01-01

76

Rearrangement and expression of immunoglobulin light chain genes can precede heavy chain expression during normal B cell development in mice  

Microsoft Academic Search

Summary In mouse mutants incapable of expressing m chains, V k J k joints are detected in the CD43 1 B cell progenitors. In agreement with these earlier results, we show by a molecular single cell analysis that 4-7% of CD43 1 B cell progenitors in wild-type mice rearrange immunoglobulin (Ig) k genes before the assembly of a productive V

Tatiana I. Novobrantseva; Verena M. Martin; Roberta Pelanda; W. Muller; Klaus Rajewsky

2010-01-01

77

Regulatory elements of the mb-1 gene encoding the Ig-? component of the human B-cell antigen receptor  

Microsoft Academic Search

The mb-1 gene encodes the Ig-? component of the B-cell antigen receptor. It is specifically expressed in pre-B and mature B cells but not in plasma cells losing membrane Ig (mIg) expression. We looked for transcriptional regulatory elements within a 12 kb genomic fragment. A strong promoter activity was found in a 591 bp fragment harboring consensus binding sites for

Isabelle Leduc; Michel Cogne

1996-01-01

78

Lack of extensive mutations in the VH5 genes used in common B cell chronic lymphocytic leukemia  

PubMed Central

B cell chronic lymphocytic leukemia (CLL) is a malignancy of the CD5+ B cells. Prior studies indicated that CLL B cells generally express immunoglobulin (Ig) VH and VL genes with little or no somatic mutations. However, a recent report indicated that VH251, one of three VH genes belonging to the VH5 subgroup (e.g., VH251, VH32, and VH15), not only is frequently rearranged in this disease, but also has extensive and selective mutations when expressed by CLL B cells. The extent and nature of these mutations contrasts markedly from the low level of mutations noted in VH5 genes used by normal B cells or other Ig V genes found expressed in CLL. To determine whether this difference reflects a unique property of VH251 or a previously unrecognized subgroup of CLL, we examined for VH5 Ig gene rearrangements in leukemia cells from 68 patients that satisfied clinical and diagnostic criteria for CD5+ B cell CLL. Southern blot hybridization studies with probes for VH251 and the JH locus revealed that only 7 (10%) of the 68 monoclonal CLL cell populations had undergone Ig gene rearrangement involving VH5 genes. Two (3%) were found to have functionally rearranged VH5 genes that shared > or = 98% sequence homology with 5- 2R1, a VH251 gene isolated from a pre-B cell acute lymphocytic leukemia. The other five CLL (7%) had functionally rearranged VH5 genes that each shared > or = 99% nucleic acid sequence homology with a germline VH32 isolated from human sperm DNA. These data indicate that VH251 or VH32 also may be expressed by CD5+ CLL B cells with little or no somatic mutation. These findings contrast with a recently published study on VH5 gene expression in B CLL and contest the hypothesis that extensive somatic mutation is a common property of the VH5 genes used in this disease. Further work to define the clinical and/or phenotypic characteristics of patients with leukemia cells that express mutated versus nonmutated Ig V genes may reveal subsets of CLL that possibly differ in their cytogenesis, etiopathogenesis, and/or clinical behavior.

1993-01-01

79

Duplication and suppression of chloroplast protein translocation genes in maize.  

PubMed Central

The HCF106 (high chlorophyll fluorescence) gene of maize encodes a chloroplast membrane protein required for translocation of a subset of proteins across the thylakoid membrane. Mutations in HCF106 caused by the insertion of Robertson's Mutator transposable elements have been mapped to chromosome 2S. Here we show that there is a closely related homolog of HCF106 encoded elsewhere in the maize genome (HCF106c) that can partially compensate for these mutations. This homolog maps on chromosome 10L and is part of the most recent set of segmental duplications in the maize genome. Triple mutants that are disrupted in both the HCF106 and Sec-dependent protein translocation pathways provide evidence that they act independently. The HCF106c gene accounts for a previously reported exception to the correlation between epigenetic suppression of hcf106 and methylation of Mutator transposons. We also demonstrate that insertions of Robertson's Mutator elements into either introns or promoters can lead to mutations whose phenotypes are suppressed in the absence of Mu activity, while alleles with insertions in both positions are not suppressed. The implications of these observations are discussed.

Settles, A M; Baron, A; Barkan, A; Martienssen, R A

2001-01-01

80

Genomic structure of the bovine mb-1 gene encoding the Ig-? subunit of the B cell antigen receptor complex  

Microsoft Academic Search

The B cell antigen receptor (BCR) comprises surface immunoglobulin and disulfide-bonded heterodimer of Ig-? and Ig-? chains, which are the products of the mb-1 and B29 genes, respectively. In this study, we describe the isolation and analysis of a 6.2-kb genomic DNA clone containing bovine mb-1 gene encoding Ig-?. Sequence data revealed that the bovine mb-1 gene is composed of

Hwa-Young Youn; Kyu-Woan Cho; Yoshiaki Nishimura; Ryo Goitsuka; Toshihiro Watari; Hajime Tsujimoto; Atsuhiko Hasegawa

1997-01-01

81

Increased Expression of Several Mitochondrial Genes in Human and Monkey B-Cell Non-Hodgkin Lymphomas  

Microsoft Academic Search

Mitochondrial genes overexpressed in human and monkey B-cell non-Hodgkin lymphomas (B-NHLs) were sought via subtraction hybridization, cloning, and differential screening of the resulting cDNA libraries. The cDNAs of mitochondrial genes constituted an appreciable proportion of all lymphoma-specific cDNAs. Lymphomogenesis was associated with upregulation of a set of mitochondrial genes, which varied with lymphoma type but always included NADHIV. A possible

A. I. Nikolaev; A. V. Martynenko; B. B. Kalmyrzaev; L. I. Inozemtseva; V. I. Dubovaya; G. Hunsmann; B. Bodemer; V. Z. Tarantul

2001-01-01

82

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

83

B Cells in Chronically Hepatitis C Virus-Infected Individuals Lack a Virus-Induced Mutation Signature in the TP53, CTNNB1, and BCL6 Genes  

PubMed Central

Hepatitis C virus (HCV) is considered to have a causative role in B-cell lymphoproliferative diseases, including B-cell lymphomas, in chronic virus carriers. Previous data from in vitro HCV-infected B-cell lines and peripheral blood mononuclear cells from HCV-positive individuals suggested that HCV might have a direct mutagenic effect on B cells, inducing mutations in the tumor suppressor gene TP53 and the proto-oncogenes BCL6 and CTNNB1 (?-catenin). To clarify whether HCV indeed has a mutagenic effect on B cells in vivo, we analyzed naive and memory B cells from the peripheral blood of four chronic HCV carriers and intrahepatic B cells from the livers of two HCV-positive patients for mutations in the three reported target genes. However, no mutations were found in the TP53 and CTNNB1 genes. For BCL6, which is a physiological target of the somatic hypermutation process in germinal-center B cells, the mutation levels identified were not higher than those reported in the respective B-cell subsets in healthy individuals. Hence, we conclude that in chronic HCV carriers, the virus does not generally induce mutations in the cancer-related genes TP53, CTNNB1, and BCL6 in B cells. Based on these findings, new targets have to be investigated as potential mediators of HCV-associated B-cell lymphomagenesis.

Tucci, Felicia Anna; Broering, Ruth; Johansson, Patricia; Schlaak, Joerg F.

2013-01-01

84

Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma  

Microsoft Academic Search

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and\\/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression.

J Iqbal; T C Greiner; K Patel; B J Dave; L Smith; J Ji; G Wright; W G Sanger; D L Pickering; S Jain; D E Horsman; Y Shen; K Fu; D D Weisenburger; C P Hans; E Campo; R D Gascoyne; A Rosenwald; E S Jaffe; J Delabie; L Rimsza; G Ott; H K Müller-Hermelink; J M Connors; J M Vose; T McKeithan; L M Staudt; W C Chan

2007-01-01

85

Patients with activated B-cell like diffuse large B-cell lymphoma in high and low infectious disease areas have different inflammatory gene signatures.  

PubMed

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with an association with inflammation and viral infections. We hypothesize that environmental factors may be involved in the pathogenesis of DLBCL. In this study, we compared gene expression profiles of lymph node tissues from patients with DLBCL from two different geographical areas with diverse environmental exposures. Specimens from Egyptian and Swedish patients with DLBCL as well as controls were studied. Gene expression analysis using microarray and quantitative polymerase chain reaction demonstrated significantly higher expression of signal transducer and activator of transcription 3 (STAT3) in Swedish as compared to Egyptian patients and control materials from both countries. This was confirmed at protein level using confocal microscopy. The receptor tyrosine kinase ROR1, a "survival factor" for malignant cells, was overexpressed and significantly related to the STAT3 expression pattern. The difference in the expression of genes involved in inflammatory responses and in the tumorigenic process of DLBCL might relate to infectious agents and/or other environmental exposures. PMID:23046110

Högfeldt, Therese; Bahnassy, Abeer A; Kwiecinska, Anna; Osterborg, Anders; Tamm, Katja Pokrovskaja; Porwit, Anna; Zekri, Abdel-Rahman N; Lundahl, Joachim; Khaled, Hussein M; Mellstedt, Håkan; Moshfegh, Ali

2012-11-08

86

Rearrangement and Expression of Endogenous Immunoglobulin Genes Occur in Many Murine B Cells Expressing Transgenic Membrane IgM.  

National Technical Information Service (NTIS)

In studies presented here, we reopen the question of whether the presence of a functionally rearranged mu heavy chain transgene ('mu transgene') is sufficient to block endogenous IgM gene rearrangement during B-cell development. Using anti-IgM allotypic r...

A. M. Stall D. G. Sieckmann F. G. Kroese F. T. Gadus L. A. Herzenberg

1988-01-01

87

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

Microsoft Academic Search

Immunoglobulin genotyping of Epstein- Barr virus (EBV)-positive posttransplan- tation 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 in- vestigate whether EBV can rescue cells that are failed products of the somatic hypermutation process occurring in ger- minal centers (GCs), we isolated GC cells from

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

2005-01-01

88

Genetic and Physical Interaction of the B-Cell SLE-Associated Genes BANK1 and BLK  

PubMed Central

Objectives Altered signaling in B-cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signaling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterize the role of BANK1 and BLK in SLE, we performed a genetic interaction analysis hypothesizing that genetic interactions could reveal functional pathways relevant to disease pathogenesis. Methods We Used the method GPAT16 to analyze the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localization, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK. Results Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from Northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, we tested the possibility that BANK1 and BLK could also show a protein-protein interaction. We demonstrated co-immunoprecipitation and co-localization of BLK and BANK1. In a Daudi cell line and primary naïve B-cells the endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies. Conclusions Here, we show a genetic interaction between BANK1 and BLK, and demonstrate that these molecules interact physically. Our results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signaling pathway.

Castillejo-Lopez, Casimiro; Delgado-Vega, Angelica M.; Wojcik, Jerome; Kozyrev, Sergey V.; Thavathiru, Elangovan; Wu, Ying-Yu; Sanchez, Elena; Pollmann, David; Lopez-Egido, Juan R.; Fineschi, Serena; Dominguez, Nicolas; Lu, Rufei; James, Judith A.; Merrill, Joan T.; Kelly, Jennifer A.; Kaufman, Kenneth M.; Moser, Kathy; Gilkeson, Gary; Frostegard, Johan; Pons-Estel, Bernardo A.; D'Alfonso, Sandra; Witte, Torsten; Callejas, Jose Luis; Harley, John B.; Gaffney, Patrick; Martin, Javier; Guthridge, Joel M.; Alarcon-Riquelme, Marta E.

2012-01-01

89

Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations  

PubMed Central

Follicular lymphoma (FL) is genetically characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation in approximately 90% of cases. In contrast to FL carrying the t(14;18), their t(14;18)-negative counterparts are less well studied about their immunohistochemical, genetic, molecular, and clinical features. Within a previously published series of 184 FLs grades 1 to 3A with available gene expression data, we identified 17 FLs lacking the t(14;18). Comparative genomic hybridization and high-resolution single nucleotide polymorphism (SNP) array profiling showed that gains/amplifications of the BCL2 gene locus in 18q were restricted to the t(14;18)-positive FL subgroup. A comparison of gene expression profiles showed an enrichment of germinal center B cell–associated signatures in t(14;18)-positive FL, whereas activated B cell–like, NF?B, proliferation, and bystander cell signatures were enriched in t(14;18)-negative FL. These findings were confirmed by immunohistochemistry in an independent validation series of 84 FLs, in which 32% of t(14;18)-negative FLs showed weak or absent CD10 expression and 91% an increased Ki67 proliferation rate. Although overall survival did not differ between FL with and without t(14;18), our findings suggest distinct molecular features of t(14;18)-negative FL.

Leich, Ellen; Salaverria, Itziar; Bea, Silvia; Zettl, Andreas; Wright, George; Moreno, Victor; Gascoyne, Randy D.; Chan, Wing-Chung; Braziel, Rita M.; Rimsza, Lisa M.; Weisenburger, Dennis D.; Delabie, Jan; Jaffe, Elaine S.; Lister, Andrew; Fitzgibbon, Jude; Staudt, Louis M.; Hartmann, Elena M.; Mueller-Hermelink, Hans-Konrad; Campo, Elias; Ott, German

2009-01-01

90

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

Microsoft Academic Search

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

Toru Uchiyama; Satoru. Kumaki; Yoshinori Ishikawa; Masafumi Onodera; Miki Sato; Wei Du; Yoji Sasahara; Nobuyuki Tanaka; Kazuo Sugamura; Shigeru Tsuchiya

2006-01-01

91

DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status  

PubMed Central

In an initial epigenetic characterization of diffuse large B-cell lymphoma (DLBCL), we evaluated the DNA methylation levels of over 500 CpG islands. Twelve CpG islands (AR, CDKN1C, DLC1, DRD2, GATA4, GDNF, GRIN2B, MTHFR, MYOD1, NEUROD1, ONECUT2, and TFAP2A) showed significant methylation in over 85% of tumors. Interestingly, the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B-cell-like (ABC-DLBCL) and germinal center B-cell-like (GCB-DLBCL) subtypes. In addition, we compared the methylation and expression status of sixty-seven genes proximal (within 500-bp) to the methylation assays. We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors. However, many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated. Nevertheless, the proportional reductions in BNIP3, MGMT, RBP1, GATA4, IGSF4, CRABP1, and FLJ21062 expression with increasing methylation suggests that epigenetic processes strongly influence these genes. Lastly, the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing. Overall, further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted.

Pike, Brian L.; Greiner, Timothy C.; Wang, Xiaoming; Weisenburger, Dennis D.; Hsu, Ya-Hsuan; Renaud, Gabriel; Wolfsberg, Tyra G.; Kim, Myungjin; Weisenberger, Daniel J.; Siegmund, Kimberly D.; Ye, Wei; Groshen, Susan; Mehrian-Shai, Ruty; Delabie, Jan; Chan, Wing C.; Laird, Peter W.; Hacia, Joseph G.

2009-01-01

92

Multiplex PCR and Genescan analysis to detect immunoglobulin heavy chain gene rearrangement in feline B-cell neoplasms.  

PubMed

Lymphoid neoplasms are usually diagnosed on the basis of cytological and histopathological findings. However, in some cases, discrimination of lymphoid neoplasms from reactive lymphoid proliferation is difficult. PCR amplification of complementarity-determining region 3 (CDR3) of the immunoglobulin heavy-chain variable region (IGHV) gene can be used to assess clonality of B-cell populations as a supportive diagnostic tool for B-cell neoplasms. Because of the sequence variation and possible somatic hypermutation of the IGHV gene, sensitivity of the PCR-based assay to detect clonal IGHV gene rearrangement largely depends on the sequences and numbers of primer sets. Prior to the development of an efficient assay, we cloned and sequenced 97 IGHV complementary DNAs (48 IGHV-1 and 49 IGHV-3 clones) from normal cat spleens. On the basis of these sequences, we designed 6 forward primers at the variable region and 5 reverse primers at the joining region. Using each of 6 forward primers and a mixture of 5 reverse primers, we amplified CDR3 of IGHV genes and analyzed the PCR products by conventional PAGE and Genescan analyses using fluorescence-labeled primers. Twenty-six feline B-cell neoplasms diagnosed by histopathological and immunohistochemical examinations were subjected to the newly developed analysis of IGHV gene rearrangement. Clonal IGHV gene rearrangement was detected in 22 of 26 (84%) samples by both PAGE and Genescan analyses. To reduce the number of PCR reactions, we constructed a multiplex PCR analysis system using a mixture of IGHV-1- and IGHV-3-specific primers as forward primers and a mixture of 5 joining region reverse primers. Results of the multiplex PCR were 100% concordant with those obtained by each of the singleplex PCRs. The multiplex PCR-based assay and Genescan analysis developed in the present study would be useful and practical tools to detect clonal IGHV gene rearrangement in feline B-cell neoplasms. PMID:21703693

Mochizuki, Hiroyuki; Nakamura, Kenji; Sato, Hirofumi; Goto-Koshino, Yuko; Sato, Masahiko; Takahashi, Masashi; Fujino, Yasuhito; Ohno, Koichi; Uchida, Kazuyuki; Nakayama, Hiroyuki; Tsujimoto, Hajime

2011-06-23

93

B-cell-specific and interferon-gamma-inducible regulation of the HLA-DR alpha gene.  

PubMed Central

We investigated the cis-acting sequences that function in the B-cell-specific and interferon-gamma-inducible expression of the HLA-DR alpha gene, a human class II major histocompatibility complex gene. The effects of 5' deletions on the activity of the DR alpha promoter and the influence of upstream DR alpha promoter elements on the activity of the herpes simplex virus thymidine kinase promoter were examined by a transient transfection assay in human B-, T-, and fibroblast cell lines. We show that the DR alpha gene is regulated by positive and negative cis-acting sequences between positions -1300 and +31 from the site of initiation of transcription. We also demonstrate that the DR alpha promoter sequences from positions -116 to -92 and from -136 to -80 are the minimal sequences required for conferring B-cell specificity and interferon-gamma inducibility upon the Herpes simplex virus thymidine kinase promoter, respectively.

Tsang, S Y; Nakanishi, M; Peterlin, B M

1988-01-01

94

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

Microsoft Academic Search

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

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

1991-01-01

95

Profiling of apoptosis genes identifies distinct types of primary cutaneous large B cell lymphoma  

Microsoft Academic Search

Two distinct primary cutaneous large B cell lymphomas are recognized: primary cutaneous follicle centre lymphoma (PCFCL), characterized by an excellent prognosis, and primary cutaneous large B cell lymphoma, leg-type (PCLBCL leg-type), with an unfavourable prognosis. To determine whether inhibition of the apoptosis pathways may underlie the difference in clinical outcome between PCFCL and PCLBCL leg-type, we investigated the expression of

J. C. van Galen; J. J. Hoefnagel; M. H. Vermeer; R. Willemze; R. Dijkman; C. P. Tensen; WPH de Boer; C. J. W. Meijer; J. J. Oudejans

2008-01-01

96

Prognostic impact of chromosomal alteration of 3q27 on nodal B-cell lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 329 consecutive patients.  

PubMed

Rearrangements involving the BCL6 gene are found in 30% of diffuse large B-cell lymphomas (DLBCLs). We evaluated the clinical characteristics and prognoses of patients with B-cell lymphoma carrying 3q27 translocations. Among the 59 patients having 3q27 translocation, 10.9% had follicular lymphoma (FL) and 23.1% had DLBCL. It is of interest that the prognostic significance was not found between FL and DLBCL with 3q27 translocations. Progression-free survival (PFS) rate was significantly higher in the FL patients with 3q27 translocation than in those with 18q21 translocation. PFS rate was significantly higher in the DLBCL patients with 3q27 translocation than in those with 18q21 translocation. These findings suggest that the presence of 3q27 translocation is a significant prognostic factor in DLBCL. PMID:17197022

Niitsu, Nozomi; Okamoto, Masataka; Nakamura, Naoya; Nakamine, Hirokazu; Aoki, Sadao; Hirano, Masami; Miura, Ikuo

2007-01-02

97

Transgenic mice bearing the human c-myc gene activated by an immunoglobulin enhancer: A pre-B-cell lymphoma model  

SciTech Connect

Transgenic mice carrying a fusion gene in which the mouse immunoglobulin enhancer has been inserted into an otherwise normal human c-myc gene develop a narrow spectrum of pre-B-cell lymphomas. Tumor occurrence is correlated with expression of the transgene in organs in which large numbers of pre-B cells predominate. These tumors, which arise stochastically, are virtually all lymphoblastic lymphomas of the pre-B-cell type. Evidently the isolated enhancer targets oncogene expression and tumorigenesis to the early B-cell population in preference to more mature B-cell populations. The transgene also confers enhanced in vitro growth properties on nontransformed pre-B cells as observed in bone marrow cultures derived from transgenic animals. These cultured cells represent a population in which the activating function of c-myc can be uncoupled from secondary oncogenic events occurring in vivo.

Schmidt, E.V.; Pattengale, P.K.; Weir, L.; Leder, P. (Harvard Medical School, Boston, MA (USA))

1988-08-01

98

ALVAC-mediated gene transfer is efficient in lymphoid malignancies of T-and early B-cell origin, but not in tumors arising from mature B-cells.  

PubMed

Natural attenuation of ALVAC virus in mammals makes it an attractive vector for cancer vaccine therapy of immunocompromised hosts, such as patients with lymphoid malignancies. However, the transduction efficiency of ALVAC constructs in lymphoid tumors has not yet been characterized. We studied a wide spectrum of human T- and B-cell leukemia and lymphomas and found significant heterogeneity of the ALVAC-mediated gene product expression in these tumors. While ALVAC-B7.1, ALVAC-B7.2, or ALVAC-luciferase vectors effectively expressed recombinant genes in malignancies arising from T- or early B-cell precursors, negative or low expression of ALVAC recombinant genes occurred in tumors arising from mature B-cells. We showed that ALVAC-encoded B7.1 or B7.2 was continuously expressed on the infected, and subsequently irradiated, leukemia cells, and only cells with ALVAC-mediated expression of costimulatory molecules (but not unmodified leukemia cells or those infected with the ALVAC-parental vector) induced significant proliferation and IFN-gamma production by alloreactive T-cells. These data provide the rationale for clinical studies using the ALVAC vector system for gene transfer into lymphoid tumors of T- and early B-cell origin to render them more immunogenic, while alternative strategies should be considered for immunotherapy of mature B-cell malignancies. PMID:11676394

Gitelson, E; Ghose, A; Buckstein, R; Imrie, K; Lim, M S; Reis, M; Spaner, D; Tartaglia, J; Berinstein, N L

2001-09-01

99

T(14;18)(q32;q21) involving MALT1 and IGH genes occurs in extranodal diffuse large B-cell lymphomas of the breast and testis.  

PubMed

Primary B-cell lymphoma of the testis, breast and thyroid are rare and data concerning cytogenetic aberrations at these extranodal sites are scarce. We examined the presence of extranodal marginal zone lymphoma-associated translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(p14.1;q32) and numerical aberrations of chromosomes 1, 3, 12 and 18 by fluorescence in situ hybridization in 6 extranodal marginal zone lymphomas and 24 diffuse large B-cell lymphomas with (n=9) or without (n=15) marginal zone lymphoma components, with primary localizations in the breast (n=15), testis (n=9) and thyroid (n=6). We found t(14;18)(q32;q21), with breakpoints in IGH and MALT1, in one testicular diffuse large B-cell lymphoma and in two diffuse large B-cell lymphomas of the breast. No other translocations, amplifications or deletions involving IGH, BCL-10, BCL-2, MALT1 and IAP2 were detected. Numerical aberrations occurred in 67% of the lymphomas, 67% of extranodal marginal zone lymphomas, 56% of diffuse large B-cell lymphomas with marginal zone lymphoma components and in 73% of 'de novo' diffuse large B-cell lymphomas. These included 78% of testis, 67% of thyroid and 60% of breast lymphomas, and included mainly trisomy 18 (n=16), trisomy 3 (n=8) and trisomy 1 (n=3). One testicular diffuse large B-cell lymphoma harbored both t(14;18)(q32;q21) and trisomy 3. Our results indicate that at least a few cases of diffuse large B-cell lymphoma of the testis and the breast belong to the spectrum of extranodal marginal zone lymphoma. PMID:23018871

Kuper-Hommel, Marion J J; Schreuder, Max I; Gemmink, Anita H; van Krieken, J Han J M

2012-09-28

100

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

Microsoft Academic Search

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

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

1986-01-01

101

Regulation of VH gene repertoire and somatic mutation in germinal centre B cells by passively administered antibody  

PubMed Central

Immunization with T-dependent antigens induces a rapid differentiation of B cells to plasmacytes that produce the primary immunoglobulin M (IgM) and IgG antibodies with low affinities for the immunogen. It is proposed that the IgG antibody forms immune complexes with the residual antigen which provide an important stimulus for the formation of germinal centres (GC) and the activation of somatic mutation. This hypothesis was tested by passive administration of hapten-specific antibody into mice shortly after the immunization with nitrophenyl (NP) coupled to chicken gamma globulin (NP-CGG) in an environment of limited T-cell help. Athymic mice that received normal T helper cells at 72 hr after the administration of antigen produced low levels of anti-NP antibody and the splenic GC formation was delayed until day 12 after the antigen administration. The analysis of VDJ segments from NP-reactive GC B cells showed very few mutations in the VH genes. Passive injection of anti-NP IgG1 monoclonal antibody – but, not IgM – stimulated the GC formation up to normal levels and the somatic mutation activity in the GC B cells was fully restored. In addition, GC B cells in the recipients of IgG1 antibody demonstrated a change in the usage of germline-encoded VH genes which was not apparent among the primary antibody-forming cells. These results suggest the existence of a specific feedback mechanism whereby the IgG antibody regulates the GC formation, clonotypic repertoire and somatic mutation in GC B cells.

Song, H; Nie, X; Basu, S; Singh, M; Cerny, J

1999-01-01

102

A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network  

PubMed Central

The epigenetic changes during B-cell development relevant to both normal function and hematologic malignancy are incompletely understood. We examined DNA methylation and RNA expression status during early B-cell development by sorting multiple replicates of four separate stages of pre-B cells derived from normal human fetal bone marrow and applied high-dimension DNA methylation scanning and expression arrays. Features of promoter and gene body DNA methylation were strongly correlated with RNA expression in multipotent progenitors (MPPs) both in a static state and throughout differentiation. As MPPs commit to pre-B cells, a predominantly demethylating phenotype ensues, with 79% of the 2966 differentially methylated regions observed involving demethylation. Demethylation events were more often gene body associated rather than promoter associated; predominantly located outside of CpG islands; and closely associated with EBF1, E2F, PAX5 and other functional transcription factor (TF) sites related to B-cell development. Such demethylation events were accompanied by TF occupancy. After commitment, DNA methylation changes appeared to play a smaller role in B-cell development. We identified a distinct development-dependent demethylation signature which has gene expression regulatory properties for pre-B cells, and provide a catalog reference for the epigenetic changes that occur in pre-B-cell leukemia and other B-cell-related diseases.

Lee, Seung-Tae; Xiao, Yuanyuan; Muench, Marcus O.; Xiao, Jianqiao; Fomin, Marina E.; Wiencke, John K.; Zheng, Shichun; Dou, Xiaoqin; de Smith, Adam; Chokkalingam, Anand; Buffler, Patricia; Ma, Xiaomei; Wiemels, Joseph L.

2012-01-01

103

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

Microsoft Academic Search

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

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

1993-01-01

104

Germline translocations in mice: unique tools for analyzing gene function and long-distance regulatory mechanisms.  

PubMed

Translocations have provided invaluable tools for identifying both cancer-linked genes and loci associated with heritable human diseases, but heritable human translocations are rare and few mouse models exist. Here we report progress on analysis of a collection of heritable translocations generated by treatment of mice with specific chemicals or radiation during late spermatogenic stages. The translocation mutants exhibit a range of visible phenotypes reflecting the disruption of coding sequences or the separation of genes from essential regulatory elements. The breakpoints of both radiation-induced and chemically induced mutations in these mice are remarkably clean, with very short deletions, duplications, or inversions in some cases, and ligation mediated by microhomology, suggesting nonhomologous end joining as the major path of repair. These mutations provide new tools for the discovery of novel genes and regulatory elements linked to human developmental disorders and new clues to the molecular basis of human genetic disease. PMID:18648012

Elso, Colleen; Lu, Xiaochen; Morrison, Stephanie; Tarver, Angela; Thompson, Heather; Thurkow, Hillary; Yamada, N Alice; Stubbs, Lisa

2008-01-01

105

Immunization and Infection Change the Number of Recombination Activating Gene (RAG)-expressing B Cells in the Periphery by Altering Immature Lymphocyte Production  

Microsoft Academic Search

Recombination activating gene ( RAG ) expression in peripheral B cells increases after immuni- zation with (4-hydroxy-3-nitrophenyl) acetyl coupled to chicken gamma globulin (NP-CGG) in alum. This increase could result from reinduction of RAG expression or, alternatively, from accumulation of RAG -expressing immature B cells in the periphery. We have used mice that carry a green fluorescent protein (GFP) RAG

Hitoshi Nagaoka; Gloria Gonzalez-Aseguinolaza; Moriya Tsuji; Michel C. Nussenzweig

106

Selection of Antigen-Specific, Idiotype-Positive B Cells in Transgenic Mice Expressing a Rearranged M167-mu Heavy Chain Gene. (Reannouncement with New Availability Information).  

National Technical Information Service (NTIS)

Flow cytometric analysis of antigen specific, idiotype-positive B cell development in transgenic mice expressing a rearranged M167-micron gene shows that large numbers of phosphocholine (PC)-specific, M167-id+ B cells develop in the spleen and bone marrow...

J. J. Kenny C. O'Connell D. G. Sieckmann R. T. Fischer D. L. Longo

1991-01-01

107

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

108

Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features.  

PubMed

In childhood B-cell precursor acute lymphoblastic leukemia, cytogenetics is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment. Little is known of the relationship between different cytogenetic subtypes in B-cell precursor acute lymphoblastic leukemia and the recently reported copy number abnormalities affecting significant leukemia associated genes. In a consecutive series of 1427 childhood B-cell precursor acute lymphoblastic leukemia patients, we have determined the incidence and type of copy number abnormalities using multiplex ligation-dependent probe amplification. We have shown strong links between certain deletions and cytogenetic subtypes, including the novel association between RB1 deletions and intrachromosomal amplification of chromosome 21. In this study, we characterized the different copy number abnormalities and show heterogeneity of PAX5 and IKZF1 deletions and the recurrent nature of RB1 deletions. Whole gene losses are often indicative of larger deletions, visible by conventional cytogenetics. An increased number of copy number abnormalities is associated with NCI high risk, specifically deletions of IKZF1 and CDKN2A/B, which occur more frequently among these patients. IKZF1 deletions and rearrangements of CRLF2 among patients with undefined karyotypes may point to the poor risk BCR-ABL1-like group. In conclusion, this study has demonstrated in a large representative cohort of children with B-cell precursor acute lymphoblastic leukemia that the pattern of copy number abnormalities is highly variable according to the primary genetic abnormality. PMID:23508010

Schwab, Claire J; Chilton, Lucy; Morrison, Heather; Jones, Lisa; Al-Shehhi, Halima; Erhorn, Amy; Russell, Lisa J; Moorman, Anthony V; Harrison, Christine J

2013-03-18

109

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.

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

2003-01-01

110

Abnormalities in DNA rearrangements of immunoglobulin gene loci in precursor B cells derived from X-linked agammaglobulinemia patient and a severe combined immunodeficiency patient  

Microsoft Academic Search

In an attempt to characterize the genes that cause immunodeficiencies such as X-linked agammaglobulinemia (XLA) and severe combined immunodeficiency (SCID) we established precursor B-cell lines by transforming the patients' bone marrow cells with Epstein-Barr viruses. DNA rearrangements of immunoglobulin JH gene loci were observed on both chromosomes in pre-B cells derived from an XLA patient. We cloned and characterized both

Yoshikazu Ichihara; Hiroshi Matsuoka; Ikuya Tsuge; Jun-ichi Okada; Shinpei Torii; Hisashi Yasui; Yoshikazu Kurosawa

1988-01-01

111

B-Cell-Delivered Gene Therapy Induces Functional T Regulatory Cells and Leads to a Loss of Antigen-Specific Effector Cells  

Microsoft Academic Search

Previous reports have shown that B-cell-mediated gene therapy can induce tolerance in several animal models for autoimmune diseases and inhibitory antibody formation in hemophilia A mice. We know from our previous work that the induction of tolerance following B-cell therapy is dependent upon CD25+ regulatory T cells (Tregs). To extend these studies and identify the effects of this gene therapy

Jonathan Skupsky; Ai-Hong Zhang; Yan Su; David W Scott

2010-01-01

112

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

PubMed Central

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

1996-01-01

113

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

PubMed

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

Reimold, A M; Ponath, P D; Li, Y S; Hardy, R R; David, C S; Strominger, J L; Glimcher, L H

1996-02-01

114

Effects of glucose refeeding and glibenclamide treatment on glucokinase and GLUT2 gene expression in pancreatic B-cells and liver from rats.  

PubMed Central

The mutual role of glucose and insulin in the regulation of glucokinase and GLUT2 glucose transporter gene expression in pancreatic B-cells and liver has been studied in vivo in the rat. Glucokinase mRNA was quantified by competitive reverse-transcriptase PCR analysis, and GLUT2 mRNA by Northern-blot analysis in total RNA fractions. As in the liver, glucokinase mRNA decreased by 64% in pancreatic B-cells after starvation for 2 days and was induced 3-fold by short-term treatment (1 h) of the rats with oral glucose (4 g/kg body wt.). In contrast the sulphonylurea compound glibenclamide (0.1 mg/kg body wt.) did not significantly stimulate glucokinase gene expression in pancreatic B-cells. But glibenclamide caused a 4-fold increase of glucokinase mRNA in liver which was abolished by concomitant administration of diazoxide, a drug which antagonizes glibenclamide stimulated insulin secretion. GLUT2 gene expression was decreased by 50% in pancreatic B-cells and liver after starvation of the rats for 2 days. Neither short-term treatment (1 h) with glucose nor glibenclamide resulted in a significant increase of GLUT2 gene expression in pancreatic B-cells and liver. The results suggest that it is glucose which stimulates glucokinase gene expression in pancreatic B-cells whereas the transcriptional regulation of the glucokinase gene in liver is directed by insulin. Images Figure 1 Figure 3 Figure 4

Tiedge, M; Lenzen, S

1995-01-01

115

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

116

Analysis of the Plastidic phosphate translocator Gene Family in Arabidopsis and Identification of New phosphate translocator-Homologous Transporters, Classified by Their Putative Substrate-Binding Site1  

PubMed Central

Analysis of the Arabidopsis genome revealed the complete set of plastidic phosphate translocator (pPT) genes. The Arabidopsis genome contains 16 pPT genes: single copies of genes coding for the triose phosphate/phosphate translocator and the xylulose phosphate/phosphate translocator, and two genes coding for each the phosphoenolpyruvate/phosphate translocator and the glucose-6-phosphate/phosphate translocator. A relatively high number of truncated phosphoenolpyruvate/phosphate translocator genes (six) and glucose-6-phosphate/phosphate translocator genes (four) could be detected with almost conserved intron/exon structures as compared with the functional genes. In addition, a variety of PT-homologous (PTh) genes could be identified in Arabidopsis and other organisms. They all belong to the drug/metabolite transporter superfamily showing significant similarities to nucleotide sugar transporters (NSTs). The pPT, PTh, and NST proteins all possess six to eight transmembrane helices. According to the analysis of conserved motifs in these proteins, the PTh proteins can be divided into (a) the lysine (Lys)/arginine group comprising only non-plant proteins, (b) the Lys-valine/alanine/glycine group of Arabidopsis proteins, (c) the Lys/asparagine group of Arabidopsis proteins, and (d) the Lys/threonine group of plant and non-plant proteins. None of these proteins have been characterized so far. The analysis of the putative substrate-binding sites of the pPT, PTh, and NST proteins led to the suggestion that all these proteins share common substrate-binding sites on either side of the membrane each of which contain a conserved Lys residue.

Knappe, Silke; Flugge, Ulf-Ingo; Fischer, Karsten

2003-01-01

117

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

PubMed Central

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

1983-01-01

118

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

PubMed Central

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

2013-01-01

119

Gene expression profiles in acute myeloid leukemia with common translocations using SAGE  

PubMed Central

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15+ myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15+ cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy.

Lee, Sanggyu; Chen, Jianjun; Zhou, Guolin; Shi, Run Zhang; Bouffard, Gerard G.; Kocherginsky, Masha; Ge, Xijin; Sun, Miao; Jayathilaka, Nimanthi; Kim, Yeong Cheol; Emmanuel, Neelmini; Bohlander, Stefan K.; Minden, Mark; Kline, Justin; Ozer, Ozden; Larson, Richard A.; LeBeau, Michelle M.; Green, Eric D.; Trent, Jeffery; Karrison, Theodore; Liu, Piu Paul; Wang, San Ming; Rowley, Janet D.

2006-01-01

120

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

121

BCL8, a novel gene involved in translocations affecting band 15q11-13 in diffuse large-cell lymphoma  

PubMed Central

Translocations affecting the chromosomal region 15q11–13 and various other partners are recurrent in diffuse large-cell lymphomas (DLCL). To identify the putative gene, here named BCL8, involved in these translocations we have cloned the breakpoint region from a DLCL patient with t(14;15)(q32;q11–13) and the corresponding germ-line region from chromosome 15. The genomic locus on chromosome 15 is clonally rearranged in about 4% of DLCL in agreement with the frequency of 15q11–13 translocations. A probe derived from the BCL8 locus on chromosome 15 detected a transcript in human testis and prostate, whereas no expression was found in spleen, thymus, and blood leukocytes. Analysis of the BCL8 cDNA clones isolated from human testis cDNA library showed that the BCL8 gene generates a major transcript of 2.6 kb and a less prominent 4.5-kb species due to differential polyadenylylation. By reverse transcription–PCR analysis of RNA extracted from frozen DLCL samples and lymphoma cell lines, BCL8 expression was detected in all patients carrying 15q11–13 abnormalities and in a fraction of randomly selected DLCL patients. These results suggest that the BCL8 gene is not normally expressed in lymphoid tissues, but its expression can be activated by chromosomal translocation or by other mechanisms in DLCL. Ectopic expression of BCL8 in a significant proportion of DLCL suggests an important role for this gene in the molecular pathogenesis of B cell lymphoma.

Dyomin, Vadim G.; Rao, Pulivarthi H.; Dalla-Favera, Riccardo; Chaganti, R. S. K.

1997-01-01

122

BCL8, a novel gene involved in translocations affecting band 15q11-13 in diffuse large-cell lymphoma.  

PubMed

Translocations affecting the chromosomal region 15q11-13 and various other partners are recurrent in diffuse large-cell lymphomas (DLCL). To identify the putative gene, here named BCL8, involved in these translocations we have cloned the breakpoint region from a DLCL patient with t(14;15)(q32;q11-13) and the corresponding germ-line region from chromosome 15. The genomic locus on chromosome 15 is clonally rearranged in about 4% of DLCL in agreement with the frequency of 15q11-13 translocations. A probe derived from the BCL8 locus on chromosome 15 detected a transcript in human testis and prostate, whereas no expression was found in spleen, thymus, and blood leukocytes. Analysis of the BCL8 cDNA clones isolated from human testis cDNA library showed that the BCL8 gene generates a major transcript of 2.6 kb and a less prominent 4.5-kb species due to differential polyadenylylation. By reverse transcription-PCR analysis of RNA extracted from frozen DLCL samples and lymphoma cell lines, BCL8 expression was detected in all patients carrying 15q11-13 abnormalities and in a fraction of randomly selected DLCL patients. These results suggest that the BCL8 gene is not normally expressed in lymphoid tissues, but its expression can be activated by chromosomal translocation or by other mechanisms in DLCL. Ectopic expression of BCL8 in a significant proportion of DLCL suggests an important role for this gene in the molecular pathogenesis of B cell lymphoma. PMID:9159141

Dyomin, V G; Rao, P H; Dalla-Favera, R; Chaganti, R S

1997-05-27

123

TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma  

PubMed Central

Recently, the landscape of single base mutations in diffuse large B-cell lymphoma (DLBCL) was described. Here we report the discovery of a gene fusion between TBL1XR1 and TP63, the only recurrent somatic novel gene fusion identified in our analysis of transcriptome data from 96 DLBCL cases. Based on this cohort and a further 157 DLBCL cases analyzed by FISH, the incidence in de novo germinal center B cell–like (GCB) DLBCL is 5% (6 of 115). The fusion appears exclusive to GCB and was not seen in 138 non-GCB cases examined (P = .008, Fisher exact test) but was present at low incidence in follicular lymphoma (1 of 81). In all 7 cases identified, the 3? end of the fusion consists of exons 4 and onwards of TP63. The recurrence, subtype enrichment, and the remarkably conserved nature of the TP63 portion of the fusion suggest an important functional role in the lymphomas that harbor this event.

Scott, David W.; Mungall, Karen L.; Ben-Neriah, Susana; Rogic, Sanja; Morin, Ryan D.; Slack, Graham W.; Tan, King L.; Chan, Fong Chun; Lim, Raymond S.; Connors, Joseph M.; Marra, Marco A.; Mungall, Andrew J.; Steidl, Christian

2012-01-01

124

Silencing and Nuclear Repositioning of the ?5 Gene Locus at the Pre-B Cell Stage Requires Aiolos and OBF-1  

PubMed Central

The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes ?5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the ?5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function.

Karnowski, Alexander; Cao, Chun; Matthias, Gabriele; Carotta, Sebastian; Corcoran, Lynn M.; Martensson, Inga-Lill; Skok, Jane A.; Matthias, Patrick

2008-01-01

125

Genomic Hallmarks of Genes Involved in Chromosomal Translocations in Hematological Cancer  

PubMed Central

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

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

2012-01-01

126

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

Microsoft Academic Search

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

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

2006-01-01

127

Polymorphisms in the 3?-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma  

PubMed Central

Background Primary gastric B-cell lymphomas arise from mucosa-associated lymphatic tissue (MALT) in patients with chronic Helicobacter pylori infection. We investigated whether germline variants in the CDH1 gene, coding for E-cadherin, genetically predispose patients to primary gastric B-cell lymphoma. Design and Methods Single marker analyses of the CDH1 gene were conducted in patients with primary gastric B-cell lymphoma (n=144), in patients with primary gastric high-grade lymphoma (n=61), and in healthy blood donors (n=361). Twelve single nucleotide polymorphisms were genotyped by TaqMan® technology. Allelic imbalance was tested by pyrosequencing and clone direct sequencing of heterozygote genomic and cDNA. Mutation detection was conducted around the poly-A signal of the CDH1 3?-untranslated region. The influence of the 3?-untranslated region on protein translation was determined by a luciferase reporter assay. Results Single marker analyses identified two single nucleotide polymorphisms in strong linkage disequilibrium located in the CDH1 3?-untranslated region. One of them was significantly associated with primary gastric diffuse large B-cell lymphomas after correction for multiple testing and this association was confirmed in an independent sample set. Patients homozygous for the rare T allele (rs1801026) had a 4.9-fold increased risk (95% CI: 1.5–15.9) of developing primary gastric diffuse large B-cell lymphoma. Allelic imbalance and reporter gene assays indicated a putative influence on mRNA stability and/or translational efficacy. Conclusions We identified variants in CDH1 as the first potential genetic risk factors for the development of primary gastric diffuse large B-cell lymphomas. One of the potentially causative variants affects allelic CDH1 expression. These findings support the hypothesis that besides somatic alterations of B-cells, germline variants in the CDH1 gene contribute to a predisposition to the development of primary gastric diffuse large B-cell lymphomas.

Jacobs, Gunnar; Hellmig, Stephan; Huse, Klaus; Titz, Andrea; Franke, Andre; Kwiatkowski, Ruta; Ott, Stephan; Kosmahl, Markus; Fischbach, Wolfgang; Lucius, Ralph; Klapper, Wolfram; Folsch, Ulrich R.; Hampe, Jochen; Schreiber, Stefan; Rosenstiel, Philip

2011-01-01

128

Regulation of the pro-B-cell-specific enhancer of the Id1 gene involves the C/EBP family of proteins.  

PubMed Central

The Id1 protein acts as a negative regulator in early-B-cell differentiation by antagonizing the function of the basic helix-loop-helix transcription factors. Expression of the Id1 gene during B-cell development is governed at the transcriptional level primarily by a pro-B-cell-specific enhancer (PBE) located 3 kb downstream of the gene. We report here the identification of CAAT/enhancer binding protein beta (C/EBPbeta) as a component of the two major PBE-binding complexes (PBEC1 and PBEC2) found in pro-B cells by gel mobility shift assays. Formation of the PBECs is abolished when a classic C/EBP binding site is used as a competitor, and binding complexes similar to the PBECs are formed when the classic C/EBP site is used as a probe. We show that CHOP, a negative regulator of C/EBPs, specifically inhibits PBE binding in vitro and its enhancer activity in vivo. In pro-B cells, C/EBPbeta binds to the PBE site not as apparent homodimers but possibly in association with at least one other polypeptide, which might determine the pro-B-cell-specific expression of the Id1 gene. Although isoforms of C/EBPbeta are expressed in various B cells, they bind to DNA only in LyD9 and Ba/F3 pro-B cells. We show that CHOP is expressed in 70Z/3 and WEHI-231 cells. We also demonstrate that CHOP is associated with C/EBPbeta in WEHI-231 cells, which may provide an additional mechanism to control the function of C/EBPbeta and the expression of the Id1 gene.

Saisanit, S; Sun, X H

1997-01-01

129

Overexpression of the Human BCL2 Gene Product Results in Growth Enhancement of Epstein-Barr Virus-Immortalized B Cells  

Microsoft Academic Search

The biological activity of the human BCL-2 gene product was analyzed in an Epstein-Barr virus (EBV)-infected human lymphoblastoid B-cell line transfected with BCL-2 sequences driven by the simian virus 40 promoter and enhancer. Overproduction of the BCL-2 protein conferred a selective growth advantage to the EBV-infected B cells as compared with control transfectants in low-serum medium and also after seeding

Yoshihide Tsujimoto; Yoshihide

1989-01-01

130

A Conserved Transcriptional Enhancer Regulates RAG Gene Expression in Developing B Cells  

Microsoft Academic Search

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.

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

2003-01-01

131

Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL.  

PubMed

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders. PMID:21617698

Lanasa, M C; Allgood, S D; Slager, S L; Dave, S S; Love, C; Marti, G E; Kay, N E; Hanson, C A; Rabe, K G; Achenbach, S J; Goldin, L R; Camp, N J; Goodman, B K; Vachon, C M; Spector, L G; Rassenti, L Z; Leis, J F; Gockerman, J P; Strom, S S; Call, T G; Glenn, M; Cerhan, J R; Levesque, M C; Weinberg, J B; Caporaso, N E

2011-05-27

132

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

PubMed

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

Gleissner, B; Maurer, J; Thiel, E

2000-09-01

133

Acute Leukemias Associated With the 4;11 Chromosome Translocation Have Rearranged Immunoglobulin Heavy Chain Genes  

Microsoft Academic Search

Studies of acute leukemia with the 4;1 1 translocation have yielded conflicting results regarding the lineage of the cell of origin in this disease. To investigate this issue further, we have examined the state of immunoglobulin genes in tumor cells from two affected patients, immunopheno- typed their leukemic cells using a number of monoclonal antibody reagents with specificities for lymphoid

William M. Crist; Michael L. Cleary; Carlo E. Grossi; Edgar F. Prasthofer; Glen D. Heggie; George A. Omura; Andrew J. Carroll; Michael P. Link; Jeffrey Sklar

1985-01-01

134

Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification.  

PubMed

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5(+) B lymphocyte that is thought not to undergo intraclonal diversification. Using V(H)DJ(H) cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1-35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their V(H)DJ(H) genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone. PMID:12208878

Gurrieri, Carmela; McGuire, Peter; Zan, Hong; Yan, Xiao-Jie; Cerutti, Andrea; Albesiano, Emilia; Allen, Steven L; Vinciguerra, Vincent; Rai, Kanti R; Ferrarini, Manlio; Casali, Paolo; Chiorazzi, Nicholas

2002-09-01

135

Comparative RNA-Seq and Microarray Analysis of Gene Expression Changes in B-Cell Lymphomas of Canis familiaris  

PubMed Central

Comparative oncology is a developing research discipline that is being used to assist our understanding of human neoplastic diseases. Companion canines are a preferred animal oncology model due to spontaneous tumor development and similarity to human disease at the pathophysiological level. We use a paired RNA sequencing (RNA-Seq)/microarray analysis of a set of four normal canine lymph nodes and ten canine lymphoma fine needle aspirates to identify technical biases and variation between the technologies and convergence on biological disease pathways. Surrogate Variable Analysis (SVA) provides a formal multivariate analysis of the combined RNA-Seq/microarray data set. Applying SVA to the data allows us to decompose variation into contributions associated with transcript abundance, differences between the technology, and latent variation within each technology. A substantial and highly statistically significant component of the variation reflects transcript abundance, and RNA-Seq appeared more sensitive for detection of transcripts expressed at low levels. Latent random variation among RNA-Seq samples is also distinct in character from that impacting microarray samples. In particular, we observed variation between RNA-Seq samples that reflects transcript GC content. Platform-independent variable decomposition without a priori knowledge of the sources of variation using SVA represents a generalizable method for accomplishing cross-platform data analysis. We identified genes differentially expressed between normal lymph nodes of disease free dogs and a subset of the diseased dogs diagnosed with B-cell lymphoma using each technology. There is statistically significant overlap between the RNA-Seq and microarray sets of differentially expressed genes. Analysis of overlapping genes in the context of biological systems suggests elevated expression and activity of PI3K signaling in B-cell lymphoma biopsies compared with normal biopsies, consistent with literature describing successful use of drugs targeting this pathway in lymphomas.

Monks, Noel; Eugster, Emily; Cherba, David; Berlinski, Pamela; Kamerling, Steve; Marotti, Keith; Simpson, Heather; Rusk, Tony; Tembe, Waibhav; Legendre, Christophe; Benson, Hollie; Liang, Winnie; Webb, Craig Paul

2013-01-01

136

Histone H2AX suppresses translocations in lymphomas of E?-c-Myc transgenic mice that contain a germline amplicon of tumor-promoting genes.  

PubMed

The DNA damage response (DDR) can restrain the ability of oncogenes to cause genomic instability and drive malignant transformation. The gene encoding the histone H2AX DDR factor maps to 11q23, a region frequently altered in human cancers. Since H2ax functions as a haploinsufficient suppressor of B lineage lymphomas with c-Myc amplification and/or translocation, we determined the impact of H2ax expression on the ability of deregulated c-Myc expression to cause genomic instability and drive transformation of B cells. Neither H2ax deficiency nor haploinsufficiency affected the rate of mortality of E?-c-Myc mice from B lineage lymphomas with genomic deletions and amplifications. Yet H2ax functioned in a dosage-dependent manner to prevent unbalanced translocations in E?-c-Myc tumors, demonstrating that H2ax functions in a haploinsufficient manner to suppress allelic imbalances and limit molecular heterogeneity within and among E?-c-Myc lymphomas. Regardless of H2ax copy number, all E?-c-Myc tumors contained identical amplification of chromosome 19 sequences spanning 20 genes. Many of these genes encode proteins with tumor-promoting activities, including Cd274, which encodes the PD-L1 programmed death ligand that induces T cell apoptosis and enables cancer cells to escape immune surveillance. This amplicon was in non-malignant B and T cells and non-lymphoid cells, linked to the E?-c-Myc transgene, and associated with overexpression of PD-L1 on non-malignant B cells. Our data demonstrate that, in addition to deregulated c-Myc expression, non-malignant B lineage lymphocytes of E?-c-Myc transgenic mice may have constitutive amplification and increased expression of other tumor-promoting genes. PMID:23966158

Fusello, Angela; Horowitz, Julie; Yang-Iott, Katherine; Brady, Brenna L; Yin, Bu; Rowh, Marta A W; Rappaport, Eric; Bassing, Craig H

2013-08-08

137

A Nonimmunoglobulin Transgene and the Endogenous Immunoglobulin ? Gene Are Coordinately Regulated by Alternative RNA Processing during B-Cell Maturation  

PubMed Central

The immunoglobulin (Ig) genes have been extensively studied as model systems for developmentally regulated alternative RNA processing. Transcripts from these genes are alternatively processed at their 3? ends to yield a transcript that is either cleaved and polyadenylated at a site within an intron or spliced to remove the poly(A) site and subsequently cleaved and polyadenylated at a downstream site. Results obtained from expressing modified genes in established tissue culture cell lines that represent different stages of B-lymphocyte maturation have suggested that the only requirement for regulation is that a pre-mRNA contain competing cleavage-polyadenylation and splice reactions whose efficiencies are balanced. Since several non-Ig genes modified to have an Ig gene-like structure are regulated in cell lines, Ig-specific sequences are not essential for this control. This strongly implies that changes in the amounts or activities of general RNA processing components mediate the processing regulation. Despite numerous studies in cell lines, this model of Ig gene regulation has never been tested in vivo during normal lymphocyte maturation. We have now introduced a non-Ig gene with an Ig gene-like structure into the mouse germ line and demonstrate that RNA from the transgene is alternatively processed and regulated in murine splenic B cells. This establishes that the balance and arrangement of competing cleavage-polyadenylation reactions are sufficient for RNA processing regulation during normal B-lymphocyte development. These experiments also validate the use of tissue culture cell lines for studies of Ig processing regulation. This is the first transgenic mouse produced to test a specific model for regulated mRNA processing.

Seipelt, Rebecca L.; Spear, Brett T.; Snow, E. Charles; Peterson, Martha L.

1998-01-01

138

Sequence and Analysis of the Human ABL Gene, the BCR Gene, and Regions Involved in the Philadelphia Chromosomal Translocation  

Microsoft Academic Search

The complete human BCR gene (152-141 nt) on chromosome 22 and greater than 80% of the human ABL gene (179-512 nt) on chromosome 9 have been sequenced from mapped cosmid and plasmid clones via a shotgun strategy. Because these two chromosomes are translocated with breakpoints within the BCR and ABL genes in Philadelphia chromosome-positive leukemias, knowledge of these sequences also

Stephanie L. Chissoe; Angelika Bodenteich; Yun-Fang Wang; Ying-Ping Wang; Dennis Burian; Sandra W. Clifton; Judy Crabtree; Alexandra Freeman; Kala Iyer; Li Jian; Yichen Ma; Hei-Jen McLaury; Hua-Qin Pan; Omayma H. Sarhan; Steve Toth; Zhili Wang; Guozhong Zhang; Nora Heisterkamp; John Groffen; Bruce A. Roe

1995-01-01

139

Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas  

Microsoft Academic Search

Approximately 12% of all pleomorphic adenomas of the salivary glands are characterized by chromosome aberrations involving the chromosome segment 12q13–15. Several chromosomes have been found as translocation partners of chromosome 12, and some of these recurrently. Recently, the HMGIC gene was identified as the target gene affected by the 12q13–15 aberrations. Here, we report the identification and characterization of a

Jan MW Geurts; Eric FPM Schoenmakers; Eva Röijer; Anna-Karin Aström; Göran Stenman; Wim JM van de Ven; WJM van de Ven

1998-01-01

140

HDAC7 is a repressor of myeloid genes whose downregulation is required for transdifferentiation of pre-B cells into macrophages.  

PubMed

B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes. PMID:23696748

Barneda-Zahonero, Bruna; Román-González, Lidia; Collazo, Olga; Rafati, Haleh; Islam, Abul B M M K; Bussmann, Lars H; di Tullio, Alessandro; De Andres, Luisa; Graf, Thomas; López-Bigas, Núria; Mahmoudi, Tokameh; Parra, Maribel

2013-05-16

141

HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages  

PubMed Central

B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell–specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes.

Collazo, Olga; Rafati, Haleh; Islam, Abul B. M. M. K.; Bussmann, Lars H.; di Tullio, Alessandro; De Andres, Luisa; Graf, Thomas; Lopez-Bigas, Nuria; Mahmoudi, Tokameh; Parra, Maribel

2013-01-01

142

An update of preimplantation genetic diagnosis in gene diseases, chromosomal translocation, and aneuploidy screening  

PubMed Central

Preimplantation genetic diagnosis (PGD) is gradually widely used in prevention of gene diseases and chromosomal abnormalities. Much improvement has been achieved in biopsy technique and molecular diagnosis. Blastocyst biopsy can increase diagnostic accuracy and reduce allele dropout. It is cost-effective and currently plays an important role. Whole genome amplification permits subsequent individual detection of multiple gene loci and screening all 23 pairs of chromosomes. For PGD of chromosomal translocation, fluorescence in-situ hybridization (FISH) is traditionally used, but with technical difficulty. Array comparative genomic hybridization (CGH) can detect translocation and 23 pairs of chromosomes that may replace FISH. Single nucleotide polymorphisms array with haplotyping can further distinguish between normal chromosomes and balanced translocation. PGD may shorten time to conceive and reduce miscarriage for patients with chromosomal translocation. PGD has a potential value for mitochondrial diseases. Preimplantation genetic haplotyping has been applied for unknown mutation sites of single gene disease. Preimplantation genetic screening (PGS) using limited FISH probes in the cleavage-stage embryo did not increase live birth rates for patients with advanced maternal age, unexplained recurrent abortions, and repeated implantation failure. Polar body and blastocyst biopsy may circumvent the problem of mosaicism. PGS using blastocyst biopsy and array CGH is encouraging and merit further studies. Cryopreservation of biopsied blastocysts instead of fresh transfer permits sufficient time for transportation and genetic analysis. Cryopreservation of embryos may avoid ovarian hyperstimulation syndrome and possible suboptimal endometrium.

Chang, Li-Jung; Chen, Shee-Uan; Tsai, Yi-Yi; Hung, Chia-Cheng; Fang, Mei-Ya

2011-01-01

143

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.

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

2013-01-01

144

ZBTB32 is an early repressor of the class II transactivator and MHC class II gene expression during B cell differentiation to plasma cells1  

PubMed Central

The MHC class II transactivator (CIITA) and MHC class II expression is silenced during the differentiation of B cells to plasma cells. When B cell differentiation is carried out ex vivo, CIITA silencing occurs rapidly but the factors contributing to this event are not known. ZBTB32, also known as repressor of GATA3, was identified as an early repressor of CIITA in an ex vivo plasma cell differentiation model. ZBTB32 activity occurred at a time when Blimp-1, the regulator of plasma cell fate and suppressor of CIITA, was minimally induced. Ectopic expression of ZBTB32 suppressed CIITA and I-A gene expression in B cells. ShRNA depletion of ZBTB32 in a plasma cell line resulted in reexpression of CIITA and I-A. Compared to conditional Blimp-1 knock out and wild-type B cells, B cells from ZBTB32/ROG-knock out mice displayed delayed kinetics in silencing CIITA during ex vivo plasma cell differentiation. ZBTB32 was found to bind to the CIITA gene, suggesting that ZBTB32 directly regulates CIITA. Lastly, ZBTB32 and Blimp-1 coimmunoprecipitated, suggesting that the two repressors may ultimately function together to silence CIITA expression. These results introduce ZBTB32 as a novel regulator of MHC-II gene expression and a potential regulatory partner of Blimp-1 in repressing gene expression.

Yoon, Hyesuk; Scharer, Christopher D.; Majumder, Parimal; Davis, Carl W.; Butler, Royce; Zinzow-Kramer, Wendy; Skountzou, Ioanna; Koutsonanos, Dimitrios G.; Ahmed, Rafi; Boss, Jeremy M.

2012-01-01

145

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

PubMed

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

Hernando, Henar; Shannon-Lowe, Claire; Islam, Abul B; Al-Shahrour, Fatima; Rodríguez-Ubreva, Javier; Rodríguez-Cortez, Virginia C; Javierre, Biola M; Mangas, Cristina; Fernández, Agustín F; Parra, Maribel; Delecluse, Henri-Jacques; Esteller, Manel; López-Granados, Eduardo; Fraga, Mario F; López-Bigas, Nuria; Ballestar, Esteban

2013-01-15

146

Genetic design of an optimized packaging cell line for gene vectors transducing human B cells  

Microsoft Academic Search

Viral gene vectors often rely on packaging cell lines, which provide the necessary factors in trans for the formation of virus-like particles. Previously, we reported on a first-generation packaging cell line for gene vectors, which are based on the B-lymphotropic Epstein–Barr virus (EBV), a human ?-herpesvirus. This 293HEK-derived packaging cell line harbors a helper virus genome with a genetic modification

E Hettich; A Janz; R Zeidler; D Pich; E Hellebrand; B Weissflog; A Moosmann; W Hammerschmidt

2006-01-01

147

Tracking Differential Gene Expression in MRL/MpJ Versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity  

PubMed Central

Background Anergy is a key mechanism controlling expression of autoreactive B cells and a major site for failed regulation in autoimmune diseases. Yet the molecular basis for this differentiated cell state remains poorly understood. The current lack of well-characterized surface or molecular markers hinders the isolation of anergic cells for further study. Global gene profiling recently identified transcripts whose expression differentiates anergic from naïve B cells in model mouse systems. The objective of the current study was to evaluate the molecular and cellular processes that differentiate anergic cells that develop in the healthy C57BL/6 (B6) milieu from those that develop in the autoimmune-prone MRL/MpJ (MRL) background. This approach takes advantage of B6 and MRL mice bearing an anti-laminin Ig transgene with a well characterized anergic B cell phenotype. Results Global gene expression was evaluated in purified transgenic B cells using Operon version 3.0 oligonucleotide microarray assaying >31,000 oligoprobes. Genes with a 2-fold expression difference in B6 as compared to MRL anergic B cells were identified. Expression of selected genes was confirmed using quantitative RT-PCR. This approach identified 43 probes corresponding to 37 characterized genes, including Ptpn22, CD74, Birc1f/Naip, and Ctla4, as differentially expressed in anergic B cells in the two strains. Gene Ontology classification identified differentiation, cell cycle, proliferation, development, apoptosis, and cell death as prominently represented ontology groups. Ingenuity Pathway Analysis identified two major networks incorporating 27 qualifying genes. Network 1 centers on beta-estradiol and TP53, and Network 2 encompasses RB1, p38 MAPK, and NFkB cell growth, proliferation, and cell cycle signaling pathways. Conclusion Using microarray analysis we identified 37 characterized genes and two functional pathways engaged in maintenance of B cell anergy for which expression is distorted by underlying autoimmune genetic susceptibility. This approach identifes a new biological role for multiple genes and potential new therapeutic targets in autoimmunity.

Clark, Amy G.; Mackin, Katherine M.; Foster, Mary H.

2008-01-01

148

Tracking Differential Gene Expression in MRL/MpJ Versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity.  

PubMed

BACKGROUND: Anergy is a key mechanism controlling expression of autoreactive B cells and a major site for failed regulation in autoimmune diseases. Yet the molecular basis for this differentiated cell state remains poorly understood. The current lack of well-characterized surface or molecular markers hinders the isolation of anergic cells for further study. Global gene profiling recently identified transcripts whose expression differentiates anergic from naïve B cells in model mouse systems. The objective of the current study was to evaluate the molecular and cellular processes that differentiate anergic cells that develop in the healthy C57BL/6 (B6) milieu from those that develop in the autoimmune-prone MRL/MpJ (MRL) background. This approach takes advantage of B6 and MRL mice bearing an anti-laminin Ig transgene with a well characterized anergic B cell phenotype. RESULTS: Global gene expression was evaluated in purified transgenic B cells using Operon version 3.0 oligonucleotide microarray assaying >31,000 oligoprobes. Genes with a 2-fold expression difference in B6 as compared to MRL anergic B cells were identified. Expression of selected genes was confirmed using quantitative RT-PCR. This approach identified 43 probes corresponding to 37 characterized genes, including Ptpn22, CD74, Birc1f/Naip, and Ctla4, as differentially expressed in anergic B cells in the two strains. Gene Ontology classification identified differentiation, cell cycle, proliferation, development, apoptosis, and cell death as prominently represented ontology groups. Ingenuity Pathway Analysis identified two major networks incorporating 27 qualifying genes. Network 1 centers on beta-estradiol and TP53, and Network 2 encompasses RB1, p38 MAPK, and NFkB cell growth, proliferation, and cell cycle signaling pathways. CONCLUSION: Using microarray analysis we identified 37 characterized genes and two functional pathways engaged in maintenance of B cell anergy for which expression is distorted by underlying autoimmune genetic susceptibility. This approach identifes a new biological role for multiple genes and potential new therapeutic targets in autoimmunity. PMID:19578517

Clark, Amy G; Mackin, Katherine M; Foster, Mary H

2008-06-10

149

Components of the antigen processing and presentation pathway revealed by gene expression microarray analysis following B cell antigen receptor (BCR) stimulation  

PubMed Central

Background Activation of naïve B lymphocytes by extracellular ligands, e.g. antigen, lipopolysaccharide (LPS) and CD40 ligand, induces a combination of common and ligand-specific phenotypic changes through complex signal transduction pathways. For example, although all three of these ligands induce proliferation, only stimulation through the B cell antigen receptor (BCR) induces apoptosis in resting splenic B cells. In order to define the common and unique biological responses to ligand stimulation, we compared the gene expression changes induced in normal primary B cells by a panel of ligands using cDNA microarrays and a statistical approach, CLASSIFI (Cluster Assignment for Biological Inference), which identifies significant co-clustering of genes with similar Gene Ontology™ annotation. Results CLASSIFI analysis revealed an overrepresentation of genes involved in ion and vesicle transport, including multiple components of the proton pump, in the BCR-specific gene cluster, suggesting that activation of antigen processing and presentation pathways is a major biological response to antigen receptor stimulation. Proton pump components that were not included in the initial microarray data set were also upregulated in response to BCR stimulation in follow up experiments. MHC Class II expression was found to be maintained specifically in response to BCR stimulation. Furthermore, ligand-specific internalization of the BCR, a first step in B cell antigen processing and presentation, was demonstrated. Conclusion These observations provide experimental validation of the computational approach implemented in CLASSIFI, demonstrating that CLASSIFI-based gene expression cluster analysis is an effective data mining tool to identify biological processes that correlate with the experimental conditional variables. Furthermore, this analysis has identified at least thirty-eight candidate components of the B cell antigen processing and presentation pathway and sets the stage for future studies focused on a better understanding of the components involved in and unique to B cell antigen processing and presentation.

Lee, Jamie A; Sinkovits, Robert S; Mock, Dennis; Rab, Eva L; Cai, Jennifer; Yang, Peng; Saunders, Brian; Hsueh, Robert C; Choi, Sangdun; Subramaniam, Shankar; Scheuermann, Richard H

2006-01-01

150

Non-synonymous variants in Pre B-cell leukemia homeobox (PBX) genes are associated with congenital heart defects  

PubMed Central

Congenital cardiac malformations are one of the most common birth defects and most are believed to be multigenic/multifactorial in nature. Recently mice lacking Pre-B cell leukemia transcription homeobox (PBX) genes were created and found to have a range of ventricular outflow tract (OFT) malformations. Therefore, we screened 95 patients with congenital heart defects, including OFT malformations, for variants in genes encoding PBX proteins, as well as interacting proteins. The coding exons of PBX1-4, PKNOX1, PKNOX2, MEIS1-3, and PBXIP1 were amplified by polymerase chain reaction and the products analyzed on a Lightscanner. Samples with abnormal melting profiles were analyzed by DNA sequencing. Seven non-synonymous variants (6 novel and 1 SNP) were identified in 5 proteins (Pbx3, Pbx4, Meis1, Meis3 and Pknox1). One Pbx3 variant, p.A136V, is located in a highly conserved polyalanine tract and predicted to be deleterious. This variant was present in 5.2% of heart defect patients compared with 1.3% of 380 race- and ethnicity-matched controls (P<0.05). None of the other variants were predicted to be damaging. In conclusion, our results support the Pbx3 Ala136Val variant as a modifier or risk allele for congenital heart defects and implicate PBX-related genes as candidates for CHD, especially those affecting the cardiac outflow tract.

Arrington, Cammon B.; Dowse, Benjamin R.; Bleyl, Steven B.; Bowles, Neil E.

2012-01-01

151

Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell hybridoma.  

PubMed Central

The events in interleukin-6 (IL-6) signal transduction leading to primary response gene activation were analyzed in murine B-cell hybridoma and plasmacytoma cells which require IL-6 for growth. IL-6 stimulation of IL-6-deprived cells resulted in the rapid and transient tyrosine phosphorylation of a 160-kDa cellular protein (p160). This was followed by the highly selective induction of two primary response genes, junB/AP-1 transcription factor and TIS11. junB and TIS11 inductions were unaffected by cycloheximide, suggesting that posttranslational modifications accounted for their activation. Activation of junB and TIS11 transcription required rapid tyrosine kinase activity as well as a different protein kinase activity sensitive to the potent kinase inhibitor, H7, and activated following p160 tyrosine phosphorylation. This H7-sensitive kinase appears to be distinct from any well-characterized protein kinase-second messenger system. On the basis of these findings, we propose that IL-6-induced signal transduction proceeds through a novel protein kinase cascade which activates junB and TIS11 gene transcription. Images

Nakajima, K; Wall, R

1991-01-01

152

A Large Gene Network in Immature Erythroid Cells Is Controlled by the Myeloid and B Cell Transcriptional Regulator PU.1  

PubMed Central

PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages.

Will, Britta; Shi, Minyi; Raha, Debasish; Mahajan, Milind C.; Weissman, Sherman; Snyder, Michael; Steidl, Ulrich; Zheng, Deyou; Skoultchi, Arthur I.

2011-01-01

153

Marginal-zone B cells.  

PubMed

Recent advances in genomics and proteomics, combined with the facilitated generation and analysis of transgenic and gene-knockout animals, have revealed new complexities in classical biological systems, including the B-cell compartment. Studies on an 'old', but poorly characterized, B-cell subset--the naive, marginal-zone (MZ) B-cell subset--over the past two years have spawned an avalanche of data that encompass the generation and function of these cells. Now that the initial 'infatuation' is over, it is time to reconsider these data and generate some conclusions that can be incorporated into a working model of the B-cell system. PMID:12033738

Martin, Flavius; Kearney, John F

2002-05-01

154

CD5+ Diffuse Large B-Cell Lymphoma Consists of Germline Cases and Hypermutated Cases in the Immunoglobulin Heavy Chain Gene Variable Region  

Microsoft Academic Search

CD5+ diffuse large B-cell lymphoma (DLBCL) has recently been identified as a subgroup with different clinical characteristics\\u000a from CD5- DLBCL and as having a poorer outcome than CD5- DLBCL. Data regarding differences in gene alteration between CD5+\\u000a and CD5- DLBCL have accumulated. In this article, we report an analysis of the immunoglobulin heavy-chain gene variable region\\u000a (VH) gene in 35

Naoya Nakamura; Shigeo Nakamura; Motoko Yamaguchi; Ryo Ichinohasama; Tadashi Yoshino; Tetsuo Kuze; Yoshikazu Sasaki; Sachiko Yoshida; Masafumi Abe

2005-01-01

155

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development  

PubMed Central

We studied a man with distal hypospadias, partial anomalous pulmonary venous return, mild limb-length inequality and a balanced translocation involving chromosomes 9 and 13. To gain insight into the etiology of his birth defects, we mapped the translocation breakpoints by high-resolution comparative genomic hybridization (CGH), using chromosome 9- and 13-specific tiling arrays to analyze genetic material from a spontaneously aborted fetus with unbalanced segregation of the translocation. The chromosome 13 breakpoint was ?400?kb away from the nearest gene, but the chromosome 9 breakpoint fell within an intron of Basonuclin 2 (BNC2), a gene that encodes an evolutionarily conserved nuclear zinc-finger protein. The BNC2/Bnc2 gene is abundantly expressed in developing mouse and human periurethral tissues. In all, 6 of 48 unrelated subjects with distal hypospadias had nine novel nonsynonymous substitutions in BNC2, five of which were computationally predicted to be deleterious. In comparison, two of 23 controls with normal penile urethra morphology, each had a novel nonsynonymous substitution in BNC2, one of which was predicted to be deleterious. Bnc2?/? mice of both sexes displayed a high frequency of distal urethral defects; heterozygotes showed similar defects with reduced penetrance. The association of BNC2 disruption with distal urethral defects and the gene's expression pattern indicate that it functions in urethral development.

Bhoj, Elizabeth J; Ramos, Purita; Baker, Linda A; Cost, Nicholas; Nordenskjold, Agneta; Elder, Frederick F; Bleyl, Steven B; Bowles, Neil E; Arrington, Cammon B; Delhomme, Brigitte; Vanhoutteghem, Amandine; Djian, Philippe; Zinn, Andrew R

2011-01-01

156

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

Microsoft Academic Search

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

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

157

Profound obesity associated with a balanced translocation that disrupts the SIM1 gene  

Microsoft Academic Search

Studies of mice and humans have revealed a number of genes that when mutated result in severe obesity. We have studied a unique girl with early-onset obesity and a de novo balanced translocation between chromo- somes 1p22.1 and 6q16.2. Her weight gain is most likely due to excessive food intake, since measured energy expenditure was normal. We cloned and sequenced

J. L. Jr; Nancy F. Butte; Andrew R. Zinn

2000-01-01

158

Structure, evolution and expression of the mitochondrial ADP\\/ATP translocator gene from Chlamydomonas reinhardtii  

Microsoft Academic Search

The first AUG in the Chlamydomonas reinhardtii ADP\\/ATP translocator (CRANT) mRNA initiates an open reading frame (ORF) which is very similar (51–79% amino acid identity) to other ANT proteins. In contrast to higher plants, no evidence for a long amino-terminal extension was obtained. The 5' non-transcribed region of the single-copy CRANT gene contains sequence motifs present in other C. reinhardtii

James A. Sharpe; Anil Day

1993-01-01

159

The pattern and distribution of immunoglobulin VH gene mutations in chronic lymphocytic leukemia B cells are consistent with the canonical somatic hypermutation process  

Microsoft Academic Search

The overexpanded clone in most B-cell- type chronic lymphocytic leukemia (B- CLL) patients expresses an immuno- globulin (Ig) heavy chain variable (VH) region gene with some level of mutation. While it is presumed that these mutations were introduced in the progenitor cell of the leukemic clone by the canonical so- matic hypermutation (SHM) process, di- rect evidence of such is

Bradley T. Messmer; Emilia Albesiano; Davorka Messmer; Nicholas Chiorazzi

2004-01-01

160

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

161

Use of chromosomal translocations with in situ DNA hybridisation to confirm localisation of human 5S ribosomal RNA genes.  

PubMed Central

Two cases of chromosomal translocations involving the long arm of chromosome 1 were investigated for 5S ribosomal gene localisation using in situ hybridisation. In the first family, there was an interstitial translocation of 1q25-32 to chromosome 5; the 5S genes remained on chromosome 1. In the second family, there was a translocation of 1q42-44 to chromosome 21q12; the 5S gene locus in this case was translocated. This shows that the 5S ribosomal genes are at position 1q42-44, confirming a previous assignment based on adenovirus-induced uncoiling and on a partial trisomy (Steffensen et al., 1977). Images

Fennell, S J; Malcolm, S; Williamson, R; Ferguson-Smith, M A

1979-01-01

162

Inheritance and molecular mapping of an alien stripe-rust resistance gene from a wheat- Psathyrostachys huashanica translocation line  

Microsoft Academic Search

The wheat accession H9020-17-15 is a translocation line previously developed from interspecific hybridization between common wheat and Psathyrostachys huashanica Keng. This translocation line showed resistance to all Chinese stripe-rust races. In this study, the gene conferring rust disease resistance in H9020-17-15 was deduced originating from P. huashanica. This resistance gene, temporarily designated as YrHua, was confirmed to be dominant and

Zhangjun Cao; Zhiyong Deng; Meinan Wang; Xianping Wang; Jinxue Jing; Xiangqi Zhang; Hongsheng Shang; Zhenqi Li

2008-01-01

163

Shutoff of BZLF1 gene expression is necessary for immortalization of primary B cells by Epstein-Barr virus.  

PubMed

The BZLF1 gene controls the switch between latent and lytic infection by Epstein-Barr virus (EBV). We previously reported that both the ZV and ZIIR elements within the BZLF1 promoter, Zp, are potent transcription silencers within the context of an intact EBV genome. We report here identification of another sequence element, ZV', which synergized with ZV in repressing Zp via binding ZEB1 or ZEB2. We then determined the phenotype of a variant of EBV strain B95.8 in which the ZV, ZV', and ZIIR elements were concurrently mutated. HEK293 cell lines infected with this triple mutant (tmt) virus spontaneously synthesized 6- to 10-fold more viral BZLF1, BRLF1, BMRF1, and BLLF1 RNAs, 3- to 6-fold more viral Zta, Rta, and EAD proteins, 3- to 5-fold more viral DNA, and 7- to 9-fold more infectious virus than did 293 cell lines latently infected with either the ZV ZV' double mutant (dmt) or ZIIR mutant (mt) virus. While ZV ZV' ZIIR tmt EBV efficiently infected human primary blood B cells in vitro, it was highly defective in immortalizing them. Instead of the nearly complete silencing of BZLF1 gene expression that occurs within 4 days after primary infection with wild-type EBV, the ZV ZV' ZIIR tmt-infected cells continued to synthesize BZLF1 RNA, with 90% of them dying within 9 days postinfection. BL41 cells infected with this "superlytic" virus also exhibited increased synthesis of BZLF1 and BMRF1 RNAs. Thus, we conclude that the ZV, ZV', and ZIIR silencing elements act synergistically to repress transcription from Zp, thereby tightly controlling BZLF1 gene expression, which is crucial for establishing and maintaining EBV latency. PMID:22623769

Yu, Xianming; McCarthy, Patrick J; Wang, Zhenxun; Gorlen, Daniel A; Mertz, Janet E

2012-05-23

164

cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes.  

PubMed Central

We have characterized a 1400-nucleotide cDNA for the human skeletal muscle ADP/ATP translocator. The deduced amino acid sequence is 94% homologous to the beef heart ADP/ATP translocator protein and contains only a single additional amino-terminal methionine. This implies that the human translocator lacks an amino-terminal targeting peptide, a conclusion substantiated by measuring the molecular weight of the protein synthesized in vitro. A 1400-nucleotide transcript encoding the skeletal muscle translocator was detected on blots of total RNA from human heart, kidney, skeletal muscle, and HeLa cells by hybridization with oligonucleotide probes homologous to the coding region and 3' noncoding region of the cDNA. However, the level of this mRNA varied substantially among tissues. Comparison of our skeletal muscle translocator sequence with that of a recently published human fibroblast translocator cognate revealed that the two proteins are 88% identical and diverged about 275 million years ago. Hence, tissues vary both in the level of expression of individual translocator genes and in differential expression of cognate translocator genes. Comparison of the base substitution rates of the ADP/ATP translocator and the oxidative phosphorylation genes encoded by mitochondrial DNA revealed that the mitochondrial DNA genes fix 10 times more synonymous substitutions and 12 times more replacement substitutions; yet, these nuclear and cytoplasmic respiration genes experience comparable evolutionary constraints. This suggests that the mitochondrial DNA genes are highly prone to deleterious mutations. Images

Neckelmann, N; Li, K; Wade, R P; Shuster, R; Wallace, D C

1987-01-01

165

A reappraisal of immunoglobulin variable gene primers and its impact on assessing clonal relationships between PB B cells and BM plasma cells in AL amyloidosis.  

PubMed

Monoclonal tumor plasma cells as well as non-terminally differentiated B cells having a clonal relationship to the tumor cells have been detected in the peripheral blood (PB) of some multiple myeloma (MM) patients but rarely in light chain (primary systemic) amyloidosis (AL) patients. Previously, our group found these peripheral clonotypic B cells in three AL patients. Here, we report detailed analysis of a larger cohort of AL patients to validate the prior findings and to investigate the effect of this cell population on clinical outcome. Fourteen AL patients were selected from a clinical prospective trial, and the relationship between immunoglobulin light chain variable gene (V(L)) representation in PB B cells and the clonal population in the bone marrow (BM) was investigated. A clonal relationship was not detected, and the present study provides important insights into the disparity with the earlier data, including clinical history of the patients and methodological analysis. PMID:21909811

Katoh, Nagaaki; Poshusta, Tanya L; Manske, Michelle K; Dispenzieri, Angela; Gertz, Morie A; Abraham, Roshini S; Ramirez-Alvarado, Marina

2011-09-10

166

Inducible gene deletion reveals different roles for B-Raf and Raf-1 in B-cell antigen receptor signalling  

PubMed Central

Engagement of the B-cell antigen receptor (BCR) leads to activation of the Raf–MEK–ERK pathway and Raf kinases play an important role in the modulation of ERK activity. B lymphocytes express two Raf isoforms, Raf-1 and B-Raf. Using an inducible deletion system in DT40 cells, the contribution of Raf-1 and B-Raf to BCR signalling was dissected. Loss of Raf-1 has no effect on BCR-mediated ERK activation, whereas B-Raf-deficient DT40 cells display a reduced basal ERK activity as well as a shortened BCR-mediated ERK activation. The Raf-1/B-Raf double deficient DT40 cells show an almost complete block both in ERK activation and in the induction of the immediate early gene products c-Fos and Egr-1. In contrast, BCR-mediated activation of nuclear factor of activated T cells (NFAT) relies predominantly on B-Raf. Furthermore, complementation of Raf-1/B-Raf double deficient cells with various Raf mutants demonstrates a requirement for Ras-GTP binding in BCR-mediated activation of both Raf isoforms and also reveals the important role of the S259 residue for the regulation of Raf-1. Our study shows that BCR-mediated ERK activation involves a cooperation of both B-Raf and Raf-1, which are activated specifically in a temporally distinct manner.

Brummer, Tilman; Shaw, Peter E.; Reth, Michael; Misawa, Yukiko

2002-01-01

167

T cell receptor alpha-, beta-, and gamma-genes in T cell and pre-B cell acute lymphoblastic leukemia.  

PubMed Central

We examined alpha-, beta-, and gamma-T cell receptor (TCR) gene activation within acute lymphoblastic leukemias (ALLs) that represent early stages of B and T cell development. We wished to determine if TCR rearrangement and expression was lineage restricted, showed any developmental hierarchy, or could identify new subsets of T cells. Rearrangement of gamma and beta TCR genes occurred early in development but in no set order, and most T-ALLs (22/26) were of sufficient maturity to have rearranged both genes. T-ALLs preferentially rearranged C gamma 2 versus the C gamma 1 complex; no preference within the beta locus was apparent. Once rearranged, the beta TCR continued to be expressed (11/13), whereas the gamma TCR was rarely expressed (3/14). The alpha TCR was expressed only in more mature T-ALLs (8/14) that usually displayed T3. The 3A-1 T cell associated antigen appeared earliest in development followed by T11 and T3. Within pre-B cell ALL a higher incidence of lineage spillover was noted for gamma TCR rearrangements (8/17) than for beta rearrangements (3/17). This also contrasts with the only occasional rearrangement of immunoglobulin (Ig) heavy chains (3/25) in T-ALL. However, in pre-B ALL the pattern of gamma TCR usage was distinct from that of T cells, with the C gamma 1 complex utilized more frequently. Almost all ALLs could be classified as pre-B or T cell in type by combining Ig and TCR genes with monoclonal antibodies recognizing surface antigens, although examples of lineage duality were noted. Unique subpopulations of cells were discovered including two genetically uncommitted ALLs that failed to rearrange either Ig or TCR loci. Moreover, two T lymphoblasts were identified that possessed the T3 molecule but failed to express alpha plus beta TCR genes. These T-ALLs may represent a fortuitous transformation of T cell subsets with alternative T3-Ti complexes. Images

Felix, C A; Wright, J J; Poplack, D G; Reaman, G H; Cole, D; Goldman, P; Korsmeyer, S J

1987-01-01

168

Expression of LAZ3\\/BCL6 in follicular center (FC) B cells of reactive lymph nodes and FC-derived non-Hodgkin lymphomas  

Microsoft Academic Search

Chromosomal translocation resulting in abnormal expression of the LAZ3\\/BCL6 gene in B cells has been implicated in the tumorigenesis of non-Hodgkin lymphoma (NHL). Therefore we studied the expression pattern of LAZ3\\/BCL6 by in situ hybridization with synthetic oligonucleotide probes in frozen tissue sections from five reactive lymph nodes and 38 B cell and non-B NHL. In addition, we investigated the

S Bajalica-Lagercrantz; F Piehl; J Lagercrantz; J Lindahl; G Weber; JP Kerckeart; A Porwit-MacDonald; M Nordenskjöld

1997-01-01

169

A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene  

Microsoft Academic Search

OF the various classes of antibodies that B lymphocytes can produce, class M (IgM) is the first to be expressed on the membrane of the developing cells. Pre-B cells, the precursors of B-lymphocytes, produce the heavy chain of IgM (mu chain), but not light chains1. Recent data suggest that pre-B cells express mu chains on the membrane together with the

Daisuke Kitamura; Jürgen Roes; Ralf Kühn; Klaus Rajewsky

1991-01-01

170

Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization  

Microsoft Academic Search

DNA amplifications are important mechanisms for proto-oncogene activation. Comparative genomic hybridization (CGH) to metaphase chromosome preparations has revealed amplifications in 10–20% of B-cell lymphomas (B-NHL). We analysed a series of 16 aggressive non-Hodgkin lymphomas by the new approach termed Matrix-CGH (M-CGH) using genomic DNA microarrays as hybridization target. For M-CGH, a dedicated B-cell lymphoma chip was constructed containing 496 genomic

Swen Wessendorf; Carsten Schwaenen; Holger Kohlhammer; Dirk Kienle; Gunnar Wrobel; Thomas FE Barth; Michelle Nessling; Peter Möller; Hartmut Döhner; Peter Lichter; Martin Bentz

2003-01-01

171

Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL  

Microsoft Academic Search

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and ‘CLL-like’ MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622

M C Lanasa; S D Allgood; S L Slager; S S Dave; C Love; G E Marti; N E Kay; C A Hanson; K G Rabe; S J Achenbach; L R Goldin; N J Camp; B K Goodman; C M Vachon; L G Spector; L Z Rassenti; J F Leis; J P Gockerman; S S Strom; T G Call; M Glenn; J R Cerhan; M C Levesque; J B Weinberg; N E Caporaso

2011-01-01

172

Dose-dependent repression of T-cell and natural killer cell genes by PU.1 enforces myeloid and B-cell identity.  

PubMed

The Ets transcription factor PU.1, encoded by the gene Sfpi1, functions in a concentration-dependent manner to promote myeloid and B-cell development and has been implicated in myeloid and lymphoid leukemias. To determine the consequences of reducing PU.1 concentration during hematopoiesis, we analyzed mice with two distinct hypomorphic alleles of Sfpi1 that produce PU.1 at approximately 20% (BN) or approximately 2% (Blac) of wild-type levels. Myeloid development was impaired in these mice, but less severely than in Sfpi1 null mice. To identify the downstream target genes that respond to changes in PU.1 concentration, we analyzed ex vivo interleukin-3 dependent myeloid cell lines established from Sfpi1(BN/BN), Sfpi1(Blac/Blac) and Sfpi1(-/-) fetal liver cells. Unexpectedly, many T-cell and natural killer cell genes were expressed in Sfpi1(-/-) cells and repressed in a dose-dependent manner in Sfpi1(Blac/Blac) and Sfpi1(BN/BN) cells. This pattern of dose-dependent T/NK-cell gene repression also occurred in ex vivo interleukin-7 dependent progenitor B cell lines. These results suggest that PU.1 functions in a concentration-dependent manner to repress T-cell and natural killer cell fates while promoting myeloid and B-cell fates. PMID:18354487

Kamath, M B; Houston, I B; Janovski, A J; Zhu, X; Gowrisankar, S; Jegga, A G; DeKoter, R P

2008-03-20

173

Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice.  

PubMed Central

Interferons (IFNs) are well known both as antiviral proteins and as potent regulators of cell growth and differentiation. In fact, IFNs inhibit growth of various normal and transformed cell types. Previously, a nuclear factor, IRF-1 (interferon regulatory factor 1), which binds to type I IFN and some IFN-inducible gene promoters, was identified and cloned. Since the IRF-1 gene is both virus and IFN inducible, an intriguing issue is raised as to whether the IRF-1 gene is functioning in IFN-mediated regulation of cell growth and differentiation. In this study, we generated transgenic mice carrying the human IRF-1 gene linked to the human immunoglobulin heavy-chain enhancer. In the transgenic mice, all the lymphoid tissues examined showed a dramatic reduction in the number of B lymphocytes (B cells). Preparation and analysis of bone marrow cells from the chimeric mice indicated that the bone marrow is the effective site for specific depletion of the B-cell population. In fact, transgenic bone marrow cells cocultured with a bone marrow-derived stromal cell line revealed an altered B-cell maturation pattern. Images

Yamada, G; Ogawa, M; Akagi, K; Miyamoto, H; Nakano, N; Itoh, S; Miyazaki, J; Nishikawa, S; Yamamura, K; Taniguchi, T

1991-01-01

174

Induction of interferon-stimulated genes on the IL-4 response axis by Epstein-Barr virus infected human b cells; relevance to cellular transformation.  

PubMed

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

Smith, Nikki; Tierney, Rosemary; Wei, Wenbin; Vockerodt, Martina; Murray, Paul G; Woodman, Ciaran B; Rowe, Martin

2013-05-27

175

Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation  

PubMed Central

S1P2 sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology and migration in many cell types in vitro. Here we report that S1P2?/? mice develop clonal B cell lymphomas with age, such that approximately half of the animals display this neoplasm by 1.5 to 2 years of age. Histologic, immunophenotypic and molecular analyses revealed a uniform tumor phenotype with features of germinal center (GC) derived diffuse large B cell lymphoma (DLBCL). Tumor formation was preceded by increases in GC B cells and CD69+ T cells, as well as an increased formation of spontaneous GCs, suggesting that S1P2 loss may promote lymphomagenesis in part by disrupting GC B cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P2 gene disruption is remarkably restricted to DLBCL. In humans, 28/106 (26%) DLBCL samples were found to harbor multiple somatic mutations in the 5? sequences of the S1P2 gene. Mutations displayed features resembling those generated by the IgV associated somatic hypermutation mechanism, but were not detected at significant levels in normal GC B cells, indicating a tumor-associated aberrant function. Collectively, our data suggest that S1P2 signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P2?/? mice, its onset at old age, and the relative lack of other neoplasms identify these mice as a novel, and potentially valuable, model for this highly prevalent and aggressive human malignancy.

Cattoretti, Giorgio; Mandelbaum, Jonathan; Lee, Nancy; Chaves, Alicia H.; Mahler, Ashley M.; Chadburn, Amy; Dalla-Favera, Riccardo; Pasqualucci, Laura; MacLennan, A. John

2009-01-01

176

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study.  

PubMed

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count. PMID:19587702

Familiades, J; Bousquet, M; Lafage-Pochitaloff, M; Béné, M-C; Beldjord, K; De Vos, J; Dastugue, N; Coyaud, E; Struski, S; Quelen, C; Prade-Houdellier, N; Dobbelstein, S; Cayuela, J-M; Soulier, J; Grardel, N; Preudhomme, C; Cavé, H; Blanchet, O; Lhéritier, V; Delannoy, A; Chalandon, Y; Ifrah, N; Pigneux, A; Brousset, P; Macintyre, E A; Huguet, F; Dombret, H; Broccardo, C; Delabesse, E

2009-07-09

177

A microarray platform-independent classification tool for cell of origin class allows comparative analysis of gene expression in diffuse large B-cell lymphoma.  

PubMed

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

2013-02-12

178

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.

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

2013-01-01

179

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

Microsoft Academic Search

The transmembrane protein, IgM-[alpha], a product of mb-1 gene, has been shown to be specifically associated with membrane-bound IgM on the plasma membrane of B lymphocytes. Recent studies have suggested that IgM-[alpha] may play a role in transducing signals from the Ag receptors during the activation of B cells. A large amount of information has been obtained in the mouse

Li-Ming Yu; Tse Wen Chang

1992-01-01

180

Dose-dependent repression of T-cell and natural killer cell genes by PU.1 enforces myeloid and B-cell identity  

Microsoft Academic Search

The Ets transcription factor PU.1, encoded by the gene Sfpi1, functions in a concentration-dependent manner to promote myeloid and B-cell development and has been implicated in myeloid and lymphoid leukemias. To determine the consequences of reducing PU.1 concentration during hematopoiesis, we analyzed mice with two distinct hypomorphic alleles of Sfpi1 that produce PU.1 at ?20% (BN) or ?2% (Blac) of

M B Kamath; I B Houston; A J Janovski; X Zhu; S Gowrisankar; A G Jegga; R P DeKoter

2008-01-01

181

Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer  

Microsoft Academic Search

X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mu- tations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of se- rum immunoglobulin, and recurrent bac- terial infections. Using Btk- and Tec- deficient mice (BtkTec\\/) as a model for XLA, we determined if Btk gene therapy could correct this disorder. Bone marrow

Phyllis W. Yu; Ruby S. Tabuchi; Roberta M. Kato; Alexander Astrakhan; Stephanie Humblet-Baron; Kevin Kipp; Keun Chae; Wilfried Ellmeier; Owen N. Witte; David J. Rawlings

2004-01-01

182

64. Rescue of B Cell Development in an Animal Model of X-Linked Agammaglobulinemia (XLA) Via B Lineage-Specific Lentiviral Gene Therapy  

Microsoft Academic Search

X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton's tyrosine kinase (Btk); and characterized by a block in pre B-cell development leading to absence of serum immunoglobulin and recurrent bacterial infections. Using Btk and Tec double deficient (Btk\\/Tec?\\/?) mice as a model for XLA, we previously showed that onco-retroviral-mediated Btk gene transfer into hematopoietic stem cells (HSC)

Wenying Zhang; Stephanie Humblet-Baron; Kevin Kipp; Socheath Khim; Jordan Jarjour; Karen Sommer; Brigid Stirling; Lia Pernell; David J. Rawlings

2006-01-01

183

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

Microsoft Academic Search

Diffuse large B cell lymphoma (DLBCL) is one of the most common non-Hodgkin’s lymphoma types. Methylenetetrahydrofolate reductase\\u000a (MTHFR) balances the pool of folate coenzymes in one carbon metabolism of deoxyribonucleic acid (DNA) synthesis and methylation;\\u000a both are implicated in carcinogenesis of many types of cancer including lymphoma. Two common variants in the MTHFR gene (C677T\\u000a and A1298C) have been associated

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

2007-01-01

184

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

PubMed

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

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

2012-05-21

185

A Large Gene Network in Immature Erythroid Cells Is Controlled by the Myeloid and B Cell Transcriptional Regulator PU.1  

Microsoft Academic Search

PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used

Sandeep N. Wontakal; Xingyi Guo; Britta Will; Minyi Shi; Debasish Raha; Milind C. Mahajan; Sherman Weissman; Michael Snyder; Ulrich Steidl; Deyou Zheng; Arthur I. Skoultchi

2011-01-01

186

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

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; Andrew Norton; T. Andrew Lister; Jill Mesirov; Donna S. Neuberg; Eric S. Lander; Jon C. Aster; Margaret A. Shipp; Todd R. Golub

2002-01-01

187

Renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion: radiological findings mimicking papillary subtype.  

PubMed

The authors describe the computed tomography (CT) and magnetic resonance imaging (MRI) findings of an 18-year-old man with renal cell carcinoma (RCC) associated with the Xp11.2 translocation/transcription factor E3 (TFE3) gene fusion (Xp11 translocation carcinoma). The lesion was hyperdense on unenhanced CT, hypovascular on contrast-enhanced studies, hypointense on T2-weighted MR images, and hemosiderin deposition was suspected on phase-shift gradient-echo MR images. Histopathological specimens revealed pathological findings resembling papillary RCC predominantly and exhibited immunoreactivity for TFE3. Because there is often considerable morphological overlap between this carcinoma and papillary RCC, the imaging findings of Xp11 translocation carcinoma may be similar to those of the papillary subtype. Therefore, Xp11 translocation carcinoma should be considered, particularly in young patients when radiologic images demonstrate a renal tumor mimicking the papillary subtype. PMID:21182142

Kato, Hiroki; Kanematsu, Masayuki; Yokoi, Shigeaki; Miwa, Kousei; Horie, Kengo; Deguchi, Takashi; Hirose, Yoshinobu

2011-01-01

188

Genomic polymorphism in the population of Candida glabrata: gene copy-number variation and chromosomal translocations.  

PubMed

The genomic sequence of the type strain of the opportunist human pathogen Candida glabrata (CBS138, ATCC 2001) is available since 2004. This allows the analysis of genomic structure of other strains by comparative genomic hybridization. We present here the molecular analysis of a collection of 183 C. glabrata strains isolated from patients hospitalized in France and around the world. We show that the mechanisms of microevolution within this asexual species include rare reciprocal chromosomal translocations and recombination within tandem arrays of repeated genes, and that these account for the frequent size heterogeneity between chromosomes across strains. Gene tandems often encode cell wall proteins suggesting a possible role in adaptation to the environment. PMID:19084610

Muller, Héloïse; Thierry, Agnès; Coppée, Jean-Yves; Gouyette, Catherine; Hennequin, Christophe; Sismeiro, Odile; Talla, Emmanuel; Dujon, Bernard; Fairhead, Cécile

2008-12-06

189

B-Cell-Delivered Gene Therapy Induces Functional T Regulatory Cells and Leads to a Loss of Antigen-Specific Effector Cells  

PubMed Central

Previous reports have shown that B-cell-mediated gene therapy can induce tolerance in several animal models for autoimmune diseases and inhibitory antibody formation in hemophilia A mice. We know from our previous work that the induction of tolerance following B-cell therapy is dependent upon CD25+ regulatory T cells (Tregs). To extend these studies and identify the effects of this gene therapy protocol on the target CD4 T cells, we have adapted in vitro suppression assays using Tregs isolated from treated and control mice. Using carboxyfluorescein succinimidyl ester (CFSE) dilution as a measure of T-cell responsiveness to FVIII, we show that CD25+ Tregs from treated mice are more suppressive than those from control animals. To monitor the induction of antigen-specific Tregs, we repeated these studies in ovalbumin (OVA) peptide-specific DO11.10 T-cell receptor (TCR) transgenic mice. Tregs from DO11.10 mice treated with a tolerogenic OVA–Ig construct are better than polyclonal Tregs at suppressing the proliferation of responder cells stimulated with OVA peptide 323–339 (pOVA). Furthermore, we show that following B-cell therapy, there is an increase in antigen-specific FoxP3+ Tregs, and there is also a distinct decrease in antigen-specific CD4+ effector T cells. These changes in the lymphocyte population shift the balance away from effector function toward a tolerogenic phenotype.

Skupsky, Jonathan; Zhang, Ai-Hong; Su, Yan; Scott, David W

2010-01-01

190

DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes  

PubMed Central

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

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

2012-01-01

191

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

2012-02-07

192

Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene.  

PubMed

Primary mediastinal (thymic) B-cell lymphoma is a high-grade non-Hodgkin's lymphoma with unique features. By using comparative genomic hybridization and interphase cytogenetics, 26 tumors were analyzed to identify genomic imbalances. Gains of chromosomal material were much more frequent than losses (110 v 10) and involved chromosomes 9p, 12q, and Xq (31% to 50%). Interestingly, gain of Xq coincided with gain of 9p. Distinct high-level amplifications were found in four subregions. In 2 cases, amplifications of proto-oncogene REL were shown by filter hybridization, indicating a possible pathogenic role of this gene. The characteristic pattern of chromosomal imbalances distinct from other B-cell lymphomas suggests a specific pathway of genetic changes associated with this lymphoma. PMID:8608249

Joos, S; Otaño-Joos, M I; Ziegler, S; Brüderlein, S; du Manoir, S; Bentz, M; Möller, P; Lichter, P

1996-02-15

193

Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(-)/IgM+ B cells.  

PubMed Central

To analyze the immunoglobulin repertoire of human IgM+ B cells and the CD5(+) and CD5(-) subsets, individual CD19(+)/ IgM+/CD5(+) or CD5(-) B cells were sorted and non-productive as well as productive VH gene rearrangements were amplified from genomic DNA and sequenced. In both subsets, the VH3 family was overrepresented largely as a result of preferential usage of a small number of specific individual family members. In the CD5(+) B cell subset, all other VH families were found at a frequency expected from random usage, whereas in the CD5(-) population, VH4 appeared to be overrepresented in the nonproductive repertoire, and also negatively selected since it was found significantly less often in the productive compared to the nonproductive repertoire; the VH1 family was significantly diminished in the productive rearrangements of CD5(-) B cells. 3-23/DP-47 was the most frequently used VH gene segment and was found significantly more often than expected from random usage in productive rearrangements of both CD5(+) and CD5(-) B cells. Evidence for selection based on the D segment and the JH gene usage was noted in CD5(+) B cells. No differences were found between the B cell subsets in CDR3 length, the number of N-nucleotides or evidence of exonuclease activity. Somatically hypermutated VHDJH rearrangements were significantly more frequent and extensive in CD5(-) compared to CD5(+) IgM+ B cells, indicating that IgM+ memory B cells were more frequent in the CD5(-) B cell population. Of note, the frequency of specific VH genes in the mutated population differed from that in the nonmutated population, suggesting that antigen stimulation imposed additional biases on the repertoire of IgM+ B cells. These results indicate that the expressed repertoire of IgM+ B cell subsets is shaped by recombinational bias, as well as selection before and after antigen exposure. Moreover, the influences on the repertoires of CD5(+) and CD5(-) B cells are significantly different, suggesting that human peripheral blood CD5(+) and CD5(-) B cells represent different B cell lineages, with similarities to murine B-1a and B-2 subsets, respectively.

Brezinschek, H P; Foster, S J; Brezinschek, R I; Dorner, T; Domiati-Saad, R; Lipsky, P E

1997-01-01

194

Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation  

SciTech Connect

The complete human BCR gene (152j-141 nt) on chromosome 22 and greater than 80% of the human ABL gene (179-512 nt) on chromosome 9 have been sequenced from mapped cosmid and plasmid clones via a shotgun strategy. Because these two chromosomes are translocated with breakpoints within the BCR and ABL genes in Philadelphia chromosome-positive leukemias, knowledge of these sequences also might provide insight into the validity of various theories of chromosomal rearrangements. Comparison of these genes with their cDNA sequences reveal the positions of 23 BCR exons and putative alternative BCR first and second exons, as well as the common ABL exons 2-11, respectively. Additionally, these regions include the alternative ABL first exons 1b and 1a, a new gene 5` to the first ABL exon, and an open reading frame with homology to an EST within the BCR fourth intron. Further analysis reveals an Alu homology of 38.83 and 39.35% for the BCR and ABL genes, respectively, with other repeat elements present to a lesser extent. Four new Philadelphia chromosome translocation breakpoints from chronic myelogenous leukemia patients also were sequenced, and the positions of these and several other previously sequenced breakpoints now have been mapped precisely, although no consistent breakpoint features immediately were apparent. Comparative analysis of genomic sequences encompassing the murine homologues to the human ABL exons 1b and 1a, as well as regions encompassing the ABL exons 2 and 3, reveals that although there is a high degree of homology in their corresponding exons and promoter regions, these two vertebrate species show a striking lack of homology outside these regions. 122 refs., 5 figs., 4 tabs.

Burian, D.; Clifton, S.W.; Crabtree, J. [ Univ. of Pittsburg, PA (United States)] [and others

1995-05-01

195

Deletions of kappa chain constant region genes in mouse lambda chain-producing B cells involve intrachromosomal DNA recombinations similar to V-J joining.  

PubMed Central

We isolated and characterized the germ-line counterpart of a DNA segment designated RS (for recombining sequence), that is frequently recombined in mouse lambda light chain-producing B lymphocytes. Using Southern blot analyses of myelomas and mouse-Chinese hamster fusion cell lines, we found that RS DNA sequences are located on mouse chromosome 6, evidently more than 15 kilobases downstream of the kappa light-chain locus. We find that a typical recognition site for Ig gene recombination is situated within germ-line RS sequences near the recombination points observed in at least two lambda chain-producing cell lines. This represents a complete and functional Ig recognition site that is not directly associated with Ig genes. We also characterized a recombined RS segment isolated from the cell line BM18-4.13.9. This recombined segment has a variable region kappa light chain gene (V kappa) joined directly to RS sequences. Our results suggest that the deletion of the kappa light chain constant region (C kappa) exon in many lambda chain-producing B cells is the result of RS recombination and that C kappa deletion may be mediated by the same processes as antibody gene V-J joining (J = joining segment gene). We discuss the potential biological significance of RS DNA recombination in B-cell maturation. Images

Moore, M W; Durdik, J; Persiani, D M; Selsing, E

1985-01-01

196

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

PubMed

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

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

2013-09-04

197

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

SciTech Connect

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

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

1992-01-15

198

Molecular cloning and chromosomal mapping of bone marrow stromal cell surface gene, BST2, that may be involved in pre-B-cell growth  

SciTech Connect

Bone marrow stromal cells regulate B-cell growth and development through their surface molecules and cytokines. In this study, we generated a mAb, RS38, that recognized a novel human membrane protein, BST-2, expressed on bone marrow stromal cell lines and synovial cell lines. We cloned a cDNA encoding BST-2 from a rheumatoid arthritis-derived synovial cell line. BST-2 is a 30- to 36-kDa type II transmembrane protein, consisting of 180 amino acids. The BST-2 gene (HGMW-approved symbol BST2) is located on chromosome 19p13.2. BST-2 is expressed not only on certain bone marrow stromal cell lines but also on various normal tissues, although its expression pattern is different from that of another bone marrow stromal cell surface molecule, BST-1. BST-2 surface expression on fibroblast cell lines facilitated the stromal cell-dependent growth of a murine bone marrow-derived pre-B-cell line, DW34. The results suggest that BST-2 may be involved in pre-B-cell growth. 45 refs., 7 figs., 2 tabs.

Ishikawa, Jun; Kaisho, Tsuneyasu; Tomizawa, Hitoshi [Osaka Univ. Medical School, Suita City (Japan)] [and others

1995-04-10

199

Subcongenic analyses reveal complex interactions between distal Chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in NOD mice.1  

PubMed Central

Autoimmune Type 1 Diabetes (T1D) in humans and NOD mice results from interactions between multiple susceptibility genes (termed Idd) located within and outside the MHC. Despite sharing ~88% of their genome with NOD, including the H2g7 MHC haplotype and other important Idd genes, the closely related NOR strain fails to develop T1D due to resistance alleles in residual genomic regions derived from C57BLKS mice mapping to Chromosomes (Chr.) 1, 2 and 4. We previously produced an NOD background strain developing a greatly decreased T1D incidence due to a NOR-derived 44.31 Mb congenic region on distal Chr. 4 containing disease resistance alleles decreasing the pathogenic activity of autoreactive B and CD4 T cells. In this study a series of subcongenic strains for the NOR-derived Chr. 4 region were utilized to significantly refine genetic loci regulating diabetogenic B and CD4 T cell activity. Analyses of these subcongenic strains revealed the presence of at least two NOR origin T1D resistance genes within this region. A 6.22Mb region between rs13477999 and D4Mit32, not previously known to contain a locus affecting T1D susceptibility and now designated Idd25, was found to contain the main NOR gene(s) dampening diabetogenic B cell activity, with Ephb2 and/or Padi2 being strong candidates as the causal variants. Penetrance of this Idd25 effect was influenced by genes in surrounding regions controlling B cell responsiveness and anergy induction. Conversely, the gene(s) controlling pathogenic CD4 T cell activity was mapped to a more proximal 24.26Mb region between the rs3674285 and D4Mit203 markers.

Stolp, Jessica; Chen, Yi-Guang; Cox, Selwyn L.; Henck, Vivien; Zhang, Wenyu; Tsaih, Shirng-Wern; Chapman, Harold; Stearns, Timothy; Serreze, David V.; Silveira, Pablo A.

2012-01-01

200

Disruption of genes in the retinoid cascade may explain the microscopic neuroblastoma in a fetus with de novo unbalanced translocation  

SciTech Connect

The microscopic neuroblastoma in a fetus with de novo unbalanced translocation (3;10)(q21;q26) may be explained as the disruption of genes in the retinoid cascade, rather than simply a two-hit hypothesis for the development of tumor cells. 5 refs.

Goodman, A.B. [Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY (United States)

1995-03-13

201

The phosphoenolpyruvate/phosphate translocator is required for phenolic metabolism, palisade cell development, and plastid-dependent nuclear gene expression.  

PubMed Central

The Arabidopsis chlorophyll a/b binding protein (CAB) gene underexpressed 1 (cue1) mutant underexpresses light-regulated nuclear genes encoding chloroplast-localized proteins. cue1 also exhibits mesophyll-specific chloroplast and cellular defects, resulting in reticulate leaves. Both the gene underexpression and the leaf cell morphology phenotypes are dependent on light intensity. In this study, we determine that CUE1 encodes the plastid inner envelope phosphoenolpyruvate/phosphate translocator (PPT) and define amino acid residues that are critical for translocator function. The biosynthesis of aromatics is compromised in cue1, and the reticulate phenotype can be rescued by feeding aromatic amino acids. Determining that CUE1 encodes PPT indicates the in vivo role of the translocator in metabolic partitioning and reveals a mesophyll cell-specific requirement for the translocator in Arabidopsis leaves. The nuclear gene expression defects in cue1 suggest that a light intensity-dependent interorganellar signal is modulated through metabolites dependent on a plastid supply of phosphoenolpyruvate.

Streatfield, S J; Weber, A; Kinsman, E A; Hausler, R E; Li, J; Post-Beittenmiller, D; Kaiser, W M; Pyke, K A; Flugge, U I; Chory, J

1999-01-01

202

The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL  

PubMed Central

The BCL6 transcriptional repressor is required for development of germinal center (GC) B cells and when expressed constitutively causes diffuse large B-cell lymphomas (DLBCLs). We examined genome-wide BCL6 promoter binding in GC B cells versus DLBCLs to better understand its function in these settings. BCL6 bound to both distinct and common sets of functionally related gene in normal GC cells versus DLBCL cells. Certain BCL6 target genes were preferentially repressed in GC B cells, but not DLBCL cells. Several such genes have prominent oncogenic functions, such as BCL2, MYC, BMI1, EIF4E, JUNB, and CCND1. BCL6 and BCL2 expression was negatively correlated in primary DLBCLs except in the presence of BCL2 translocations. The specific BCL6 inhibitor retro-inverso BCL6 peptidomimetic inhibitor-induced expression of BCL2 and other oncogenes, consistent with direct repression effects by BCL6. These data are consistent with a model whereby BCL6 can directly silence oncogenes in GC B cells and counterbalance its own tumorigenic potential. Finally, a BCL6 consensus sequence and binding sites for other physiologically relevant transcription factors were highly enriched among target genes and distributed in a pathway-dependent manner, suggesting that BCL6 forms specific regulatory circuits with other B-cell transcriptional factors.

Ci, Weimin; Polo, Jose M.; Cerchietti, Leandro; Shaknovich, Rita; Wang, Ling; Yang, Shao Ning; Ye, Kenny; Farinha, Pedro; Horsman, Douglas E.; Gascoyne, Randy D.

2009-01-01

203

Identification of conformation-dependent epitopes and V gene selection in the B cell response to type II collagen in the DA rat.  

PubMed

Collagen-induced arthritis (CIA) is a widely used model for rheumatoid arthritis. Induction of CIA in rats using rat type II collagen (CII) results in a chronic arthritis in which anti-CII antibodies are believed to play a pathogenic role. In this study, we analyzed the epitope selection and V gene usage in the anti-CII response in the DA rat. A panel of CII-reactive B cell hybridomas was established from the draining lymph nodes 11 days after immunization. All of the CII-specific antibodies bound cartilage in vivo, showing that these are true autoantibodies. These antibodies were all IgG and specific for several distinct triple helical epitopes on CII. Interestingly, the major epitope, recognized by four different antibodies, was identical with the major B cell epitope in the mouse CII located at position 359--369 (denoted as C1(III)). The Q52 and PC7183 V(H) gene families encoded 12 out of 14 sequenced heavy chains. There was a relatively more heterogeneous usage of V(L) genes as the antibodies were encoded by four different V(kappa) families (V(kappa)1, V(kappa)2, V(kappa)12/13 and V(kappa)RF). As in the mouse, some of the V genes used showed germline characteristics. We conclude that the immune response in the rat shares epitope specificity and a constrained V gene repertoire with the mouse. However, the V genes used for recognition of the closely related collagen structures differed considerably between mouse and rat, indicating an influence of the species-specific variation in the V gene repertoire. PMID:11431421

Wernhoff, P; Unger, C; Bajtner, E; Burkhardt, H; Holmdahl, R

2001-07-01

204

Increased AICD generation does not result in increased nuclear translocation or activation of target gene transcription  

SciTech Connect

A sequence of amyloid precursor protein (APP) cleavages culminates in the sequential release of the APP intracellular domain (AICD) and the amyloid {beta} peptide (A{beta}) and/or p3 fragment. One of the environmental factors favouring the accumulation of AICD appears to be a rise in intracellular pH. Here we further identified the metabolism and subcellular localization of artificially expressed constructs under such conditions. We also co-examined the mechanistic lead up to the AICD accumulation and explored possible significances for its increased expression. We found that most of the AICD generated under pH neutralized conditions is likely cleaved from C83. While the AICD surplus was unable to further activate transcription of a luciferase reporter via a Gal4-DNA-binding domain, it failed entirely via the endogenous promoter regions of proposed target genes, APP and KAI1. The lack of a specific transactivation potential was also demonstrated by the unchanged levels of target gene mRNA. However, rather than translocating to the nucleus, the AICD surplus remains membrane tethered or free in the cytosol where it interacts with Fe65. Therefore we provide strong evidence that an increase in AICD generation does not directly promote gene activation of previously proposed target 0011gen.

Waldron, Elaine; Isbert, Simone [Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes Gutenberg-University Mainz, 55099 Mainz (Germany); Kern, Andreas [Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University Mainz, 55099 Mainz (Germany); Jaeger, Sebastian; Martin, Anne M. [Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes Gutenberg-University Mainz, 55099 Mainz (Germany); Hebert, Sebastien S. [Department for Molecular and Developmental Genetics, VIB, Leuven (Belgium); Center for Human Genetics, KULeuven, Herestraat 49, Leuven 3000 (Belgium); Behl, Christian [Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University Mainz, 55099 Mainz (Germany); Weggen, Sascha [Institute of Neuropathology, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf (Germany); De Strooper, Bart [Department for Molecular and Developmental Genetics, VIB, Leuven (Belgium); Center for Human Genetics, KULeuven, Herestraat 49, Leuven 3000 (Belgium); Pietrzik, Claus U. [Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes Gutenberg-University Mainz, 55099 Mainz (Germany)], E-mail: pietrzik@uni-mainz.de

2008-08-01

205

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

2013-06-27

206

Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias  

Microsoft Academic Search

Recurring chromosomal translocations involving chromosome 11, band q23, have been observed in acute lymphoid leukemias and especially in acute myeloid leukemias. The authors recently showed that breakpoints in four 11q23 translocations, t(4,11)(q21;q23), t(6;11)(q27;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13.3), were contained within a yeast artificial chromosome clone bearing the CD3D and CD3G gene loci. They have identified within the CD3 yeast artificial chromosome

S. Ziemin-van der Poel; N. R. McCabe; H. J. Gill; R. Espinosa; Y. Patel; A. Harden; P. Rubinelli; S. D. Smith; M. M. LeBeau; J. D. Rowley; M. O. Diaz

1991-01-01

207

Bortezomib induces nuclear translocation of I?B? resulting in gene-specific suppression of NF-?B--dependent transcription and induction of apoptosis in CTCL.  

PubMed

Cutaneous T-cell lymphoma (CTCL) is characterized by constitutive activation of nuclear factor ?B (NF-?B), which plays a crucial role in the survival of CTCL cells and their resistance to apoptosis. NF-?B activity in CTCL is inhibited by the proteasome inhibitor bortezomib; however, the mechanisms remained unknown. In this study, we investigated mechanisms by which bortezomib suppresses NF-?B activity in CTCL Hut-78 cells. We demonstrate that bortezomib and MG132 suppress NF-?B activity in Hut-78 cells by a novel mechanism that consists of inducing nuclear translocation and accumulation of I?B? (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), which then associates with NF-?B p65 and p50 in the nucleus and inhibits NF-?B DNA binding activity. Surprisingly, however, while expression of NF-?B-dependent antiapoptotic genes cIAP1 and cIAP2 is inhibited by bortezomib, expression of Bcl-2 is not suppressed. Chromatin immunoprecipitation indicated that cIAP1 and cIAP2 promoters are occupied by NF-?B p65/50 heterodimers, whereas Bcl-2 promoter is occupied predominantly by p50/50 homodimers. Collectively, our data reveal a novel mechanism of bortezomib function in CTCL and suggest that the inhibition of NF-?B-dependent gene expression by bortezomib is gene specific and depends on the subunit composition of NF-?B dimers recruited to NF-?B-responsive promoters. PMID:21224428

Juvekar, Ashish; Manna, Subrata; Ramaswami, Sitharam; Chang, Tzu-Pei; Vu, Hai-Yen; Ghosh, Chandra C; Celiker, Mahmut Y; Vancurova, Ivana

2011-01-11

208

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

PubMed Central

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

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

2013-01-01

209

Amplified RPS6KB1 and CDC2 genes are potential biomarkers for aggressive HIV+/EBV+ diffuse large B-cell lymphomas  

PubMed Central

RPS6KB1 encodes p70S6K/p85S6K, which plays a role in the PI3K/Akt/mTOR signal transduction pathway. CDC2 gene encodes cdc2, which is critical for G2/M cell cycle progression. We had previously shown that amplified RPS6KB1 and CDC2 are commonly detected in the EBV+ diffuse large B-cell lymphoma (DLBCL) in HIV patients. In current study, we further evaluated the amplified RPS6KB1 and CDC2 genes in 12 HIV-related aggressive B-cell lymphomas and 10 non-HIV-related DLBCL using real time quantitative PCR. The cases were divided into 4 groups: 1) HIV-/EBV-; 2) HIV-/EBV+; 3) HIV+/EBV-; and 4) HIV+/EBV+. Receiver operating characteristic (ROC) curve and the area under the curve (AUC) was used to assess the ability of each gene to distinguish non-HIV+/EBV+ cases from HIV+/EBV+ cases. The AUC was estimated to be 0.76 for RPS6KB1 and 0.74 for CDC2 by using the Mann-Whitney statistic. Amplified RPS6KB1 and CDC2 genes were more frequently detected in common variants of DLBCL associated with HIV infection. Taken together, amplified RPS6KB1 and CDC2 are potential biomarkers for the aggressive DLBCL, particularly in HIV+/EBV+ patients. This study also suggests that the HIV+/EBV+ aggressive DLBCL could be potentially treated by targeting RPS6KB1 and CDC2 genes.

Zhao, Xianfeng F; Zhao, Merry Y; Chai, Ling; Kukuruga, Debra; Tan, Ming; Stass, Sanford A

2013-01-01

210

The proto-oncogene BCL-6 in normal and malignant B cell development.  

PubMed

BCL-6 is an important regulator of the immune system. It is required for GC formation and T cell dependent antibody responses. Mice deficient in BCL-6 fail to form GC and mount reduced levels of T cell-dependent antibody responses. BCL-6 (-/-) mice, in addition, develop a massive inflammatory response in many organs characterized by eosinophilic infiltration and hyper-IgE production, a typical Th2 hyperimmune response. This suggests a negative role of BCL-6 in Th2 pathway. The BCL-6 gene encodes a POZ/zinc finger transcription repressor highly expressed in GC B cells, but not in pre-GC B cells or in more differentiated memory or plasma cells. By functioning as a potent transcriptional repressor of various target genes, BCL-6 modulates IL-4, BCR, and CD40L signals for normal B cell development. In B cell lymphomas, structural alterations of the BCL-6 promoter region, including chromosome translocation and somatic hypermutation, represent the most frequent genetic lesions associated with non-Hodgkin lymphoma, especially of diffuse large cell lymphoma, a malignancy often derived from germinal centre (GC) B cells. This suggests that deregulated expression of BCL-6 may contribute to lymphomagenesis. PMID:12469325

Niu, Huifeng

2002-12-01

211

The transcriptional co-repressor myeloid translocation gene 16 inhibits glycolysis and stimulates mitochondrial respiration.  

PubMed

The myeloid translocation gene 16 product MTG16 is found in multiple transcription factor-containing complexes as a regulator of gene expression implicated in development and tumorigenesis. A stable Tet-On system for doxycycline-dependent expression of MTG16 was established in B-lymphoblastoid Raji cells to unravel its molecular functions in transformed cells. A noticeable finding was that expression of certain genes involved in tumor cell metabolism including 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4 (PFKFB3 and PFKFB4), and pyruvate dehydrogenase kinase isoenzyme 1 (PDK1) was rapidly diminished when MTG16 was expressed. Furthermore, hypoxia-stimulated production of PFKFB3, PFKFB4 and PDK1 was inhibited by MTG16 expression. The genes in question encode key regulators of glycolysis and its coupling to mitochondrial metabolism and are commonly found to be overexpressed in transformed cells. The MTG16 Nervy Homology Region 2 (NHR2) oligomerization domain and the NHR3 protein-protein interaction domain were required intact for inhibition of PFKFB3, PFKFB4 and PDK1 expression to occur. Expression of MTG16 reduced glycolytic metabolism while mitochondrial respiration and formation of reactive oxygen species increased. The metabolic changes were paralleled by increased phosphorylation of mitogen-activated protein kinases, reduced levels of amino acids and inhibition of proliferation with a decreased fraction of cells in S-phase. Overall, our findings show that MTG16 can serve as a brake on glycolysis, a stimulator of mitochondrial respiration and an inhibitor of cell proliferation. Hence, elevation of MTG16 might have anti-tumor effect. PMID:23840896

Kumar, Parveen; Sharoyko, Vladimir V; Spégel, Peter; Gullberg, Urban; Mulder, Hindrik; Olsson, Inge; Ajore, Ram

2013-07-01

212

The SWI/SNF protein ATRX co-regulates pseudoautosomal genes that have translocated to autosomes in the mouse genome  

PubMed Central

Background Pseudoautosomal regions (PAR1 and PAR2) in eutherians retain homologous regions between the X and Y chromosomes that play a critical role in the obligatory X-Y crossover during male meiosis. Genes that reside in the PAR1 are exceptional in that they are rich in repetitive sequences and undergo a very high rate of recombination. Remarkably, murine PAR1 homologs have translocated to various autosomes, reflecting the complex recombination history during the evolution of the mammalian X chromosome. Results We now report that the SNF2-type chromatin remodeling protein ATRX controls the expression of eutherian ancestral PAR1 genes that have translocated to autosomes in the mouse. In addition, we have identified two potentially novel mouse PAR1 orthologs. Conclusion We propose that the ancestral PAR1 genes share a common epigenetic environment that allows ATRX to control their expression.

Levy, Michael A; Fernandes, Andrew D; Tremblay, Deanna C; Seah, Claudia; Berube, Nathalie G

2008-01-01

213

Y-autosome translocation interferes with meiotic sex inactivation and expression of autosomal genes: a case study in the pig.  

PubMed

Y-autosome translocations are rare in humans and pigs. In both species, these rearrangements can be responsible for meiotic arrest and subsequent infertility. Chromosome pairing abnormalities on the SSCX, SSCY and SSC1 chromatin domains were identified by analyzing pachytene spermatocytes from a boar carrying a (Y;1) translocation by immunolocalization of specific meiotic protein combined with FISH. Disturbance of the meiotic sex chromosome inactivation (MSCI) was observed by Cot-RNA-FISH and analysis of ZFY gene expression by sequential RNA- and DNA-FISH on spermatocytes. We hypothesized that the meiotic arrest observed in this boar might be due to the silencing of critical autosomal genes and/or the reactivation of some sex chromosome genes. PMID:21921590

Barasc, H; Mary, N; Letron, R; Calgaro, A; Dudez, A M; Bonnet, N; Lahbib-Mansais, Y; Yerle, M; Ducos, A; Pinton, A

2011-09-13

214

Breakpoint regions of ETO gene involved in (8; 21) leukemic translocations are enriched in acetylated histone H3.  

PubMed

One of the most frequent chromosomal translocation found in patients with acute myeloid leukemia (AML) is the t(8;21). This translocation involves the RUNX1 and ETO genes. The breakpoints regions for t(8;21) are located at intron 5 and intron 1 of the RUNX1 and ETO gene respectively. To date, no homologous sequences have been found in these regions to explain their recombination. The breakpoint regions of RUNX1 gene are characterized by the presence of DNasaI hypersensitive sites and topoisomerase II cleavage sites, but no information exists about complementary regions of ETO gene. Here, we report analysis of chromatin structure of ETO breakpoint regions. Chromatin immunoprecipitation (ChIP) were performed with antibodies specific to acetylated histone H3, H4, and total histone H1. Nucleosomal distribution at the ETO locus was evaluated by determining total levels of histone H3. Our data show that in myeloid cells, the breakpoint regions at the ETO gene are enriched in hyperacetylated histone H3 compared to a control region of similar size where no translocations have been described. Moreover, acetylated H4 associates with both the whole ETO breakpoint regions as well as the control intron. Interestingly, we observed no H1 association either at the breakpoint regions or the control region of the ETO gene. Our data indicate that a common chromatin structure enriched in acetylated histones is present in breakpoint regions involved in formation of (8;21) leukemic translocation. J. Cell. Biochem. 114: 2569-2576, 2013. © 2013 Wiley Periodicals, Inc. PMID:23744730

Stuardo, Marcela; Nicovani, Sandra; Javed, Amjad; Gutierrez, Soraya

2013-11-01

215

The mouse B cell-specific mb - 1 gene encodes an immunoreceptor tyrosine-based activation motif (ITAM) protein that may be evolutionarily conserved in diverse species by purifying selection  

Microsoft Academic Search

The B-lymphocyte accessory molecule Ig-alpha (Ig-?) is encoded by the mouse B cell-specific gene (mb-1), and along with the Ig-beta (Ig-?) molecule and a membrane bound immunoglobulin (mIg) makes up the B-cell receptor (BCR).\\u000a Ig-? and Ig-? form a heterodimer structure that upon antigen binding and receptor clustering primarily initiates and controls\\u000a BCR intracellular signaling via a phosphorylation cascade, ultimately

Richard Sims; Virginia Oberholzer Vandergon; Cindy S. Malone

216

Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression.  

PubMed

Oxidative cellular stress initiates Nrf2 translocation into the nucleus, thus inducing antioxidant response element (ARE)-mediated expression of Phase II enzymes involved in detoxification and antioxidant defence. We investigated whether coffee extracts (CEs) of different proveniences and selected constituents have an impact on the Nrf2/ARE pathway in human colon carcinoma cells (HT29). Assessed as increased nuclear Nrf2 protein, Nrf2 nuclear translocation was modulated by different CEs as observed by Western blot analysis. In addition to the known Nrf2 activator 5-O-caffeoylquinic acid (CGA), pyridinium derivatives like the N-methylpyridinium ion (NMP) were identified as potent activators of Nrf2 nuclear translocation and ARE-dependent gene expression of selected antioxidative Phase II enzymes in HT29. Thereby, the substitution pattern at the pyridinium core structure determined the impact on Nrf2-signalling. In contrast, trigonelline was found to interfere with Nrf2 activation, effectively suppressing the NMP-mediated induction of Nrf2/ARE-dependent gene expression. In conclusion, several coffee constituents, partly already present in the raw material as well as those generated during the roasting process, contribute to the Nrf2-translocating properties of consumer-relevant coffee. A fine tuning in the degradation/formation of activating and deactivating constituents of the Nrf2/ARE pathway during the roasting process appears to be critical for the chemopreventive properties of the final coffee product. PMID:20655719

Boettler, Ute; Sommerfeld, Katharina; Volz, Nadine; Pahlke, Gudrun; Teller, Nicole; Somoza, Veronika; Lang, Roman; Hofmann, Thomas; Marko, Doris

2010-07-23

217

Induced rearrangement of kappa genes in the BLIN-1 human pre-B cell line correlates with germline J-C kappa and V kappa transcription  

PubMed Central

The human pre-B acute lymphoblastic leukemia cell line, BLIN-1, has been previously shown to undergo kappa light chain rearrangement in vitro, making it a valuable resource for analyzing pre-B to B cell differentiation. We have examined the recombination potential of BLIN-1 by characterizing several independently derived kappa-expressing subclones for DNA rearrangement and V kappa gene usage. Analysis of five kappa-expressing subclones (all having the same heavy chain rearrangement) demonstrated independent kappa light chain rearrangement events by DNA hybridization analysis. Northern blot analysis using probes recognizing the four different V kappa families revealed that two subclones used the most proximal V kappa (V kappa IV), one subclone used a V kappa I, and one subclone used a V kappa II. By polymerase chain reaction analyses, we detected transcripts from rearranged V-J-C kappa genes as well as transcripts from germline J-C kappa and V kappa in BLIN-1 cells induced to rearrange the kappa locus. kappa germline transcripts were also detected in normal developing B cell populations in fetal liver and bone marrow. Our collective results indicate that: (a) BLIN-1 can be induced to rearrange the kappa locus, and this correlates with the expression of germline kappa locus transcripts that may play a role in activating or targeting gene rearrangement; and (b) active rearrangement and usage of V genes representing different kappa families suggest that, like in the mouse, repertoire diversification in humans occurs in the presence of a fixed heavy chain rearrangement.

1991-01-01

218

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

Microsoft Academic Search

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

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

1982-01-01

219

Prevalence and polymorphism of genes encoding translocated effector proteins among clinical isolates of Salmonella enterica  

Microsoft Academic Search

Pathogenic Salmonella enterica strains are capable of causing local and\\/or systemic infections. They employ two type III secretion systems to translocate an array of virulence-associated proteins (effector proteins) directly into the cytosol of target cells of the host. Earlier data had shown that changes in the repertoire of translocated effector proteins may contribute to the adaptation of Salmonella strains to

Rita Prager; Susanne Mirold; Erhard Tietze; Ute Strutz; Barbara Knüppel; Wolfgang Rabsch; Wolf-Dieter Hardt; Helmut Tschäpe

2000-01-01

220

Clinicopathological study of gene rearrangement and microRNA expression of primary central nervous system diffuse large B-cell lymphomas  

PubMed Central

We studied the clinicopathological and imaging characteristics of primary central nervous system diffuse large B-cell lymphomas (PCNS-DLBCL). Imaging, pathologic histology, and immunohistochemical staining characteristics were analyzed, and the immunoglobulin heavy and light chain gene rearrangement of 25 PCNS-DLBCL cases was examined. MicroRNA was extracted from 10 cases each of PCNS-DLBCL, extracerebral germinal center DLBCL (GC-DLBCL), and extracerebral non-GC-DLBCL (NGC-DLBCL); we conducted chip hybridization and comparatively analyzed the difference among the three. PCNS-DLBCLs typically involved no less than two cerebral lobes (10/25); the frontal lobe was affected most often (6/25). Target-shaped structures were observed in all PCNS-DLBCLs due to the proliferation of centroblast-like large lymphocytes surrounding the vessels. There was strong and diffuse immunostaining for CD20 and CD79a, and negative immunostaining for CD3, CD5, CD23, and cyclin D1 for all PCNS-DLBCLs. The percentage of cells with nuclear positivity for anti-Ki67 antibody ranged 50-90% (mean, 80%). Three, 19, and 22 PCNS-DLBCLs were CD10-, Bcl-6-, and melanoma ubiquitous mutated 1-positive, respectively. Twenty-four PCNS-DLBCLs were B-cell monoclonal. MicroRNA hybridization showed that 788 PCNS-DLBCL microRNAs/segments increased to at least twice that of NGC-DLBCLs, and 401 PCNS-DLBCL microRNAs/segments declined to less than half of that of NGC-DLBCLs. Six hundred and eleven PCNS-DLBCL microRNAs/segments increased to at least twice that of GC-DLBCLs, and 229 PCNS-DLBCL microRNAs/segments declined to less than half of that in GC-DLBCLs. PCNS-DLBCL typically affected multiple sites, tended to occur in older men, arose from activated B cells, had high B-cell monoclonality; its microRNA expression differed from that of NGC-DLBCL and GC-DLBCL.

Zheng, Jinfeng; Xu, Jiagang; Ma, Shufang; Sun, Xiyan; Geng, Ming; Wang, Lin

2013-01-01

221

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

PubMed Central

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

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

2013-01-01

222

Influence of genes encoding proton-translocating enzymes on suppression of Salmonella typhimurium growth and colonization.  

PubMed Central

Twenty-four-hour-old, aerobically grown, Luria-Bertani broth cultures of Salmonella typhimurium F98 suppressed the growth of a spectinomycin-resistant (Spcr) derivative of the same strain inoculated at 10(3) CFU ml(-1). This growth suppression is genus specific and RpoS independent, and it is not solely a result of nutrient depletion (P. A. Barrow, M. A. Lovell, and L. Zhang-Barber, J. Bacteriol. 178:3072-3076, 1996). Mutations in three genes are shown here to significantly reduce growth suppression under these conditions. The mutations were located in the nuo, cyd, and unc operons, which code for the NADH dehydrogenase I, cytochrome d oxidase, and F0F1 proton-translocating ATPase complexes, respectively. When cultures were grown under strictly anaerobic conditions, only the unc mutant did not suppress growth. Prior colonization of the alimentary tract of newly hatched chickens with the S. typhimurium F98 wild type or nuo or cyd mutants suppressed colonization by an S. typhimurium F98 Spcr derivative inoculated 24 h later. In contrast, the S. typhimurium unc mutant did not suppress colonization. The nuo and unc mutants showed poorer growth on certain carbon sources. The data support the hypothesis that growth suppression operates because of the absence of a utilizable carbon source or electron acceptor.

Zhang-Barber, L; Turner, A K; Martin, G; Frankel, G; Dougan, G; Barrow, P A

1997-01-01

223

Influence of genes encoding proton-translocating enzymes on suppression of Salmonella typhimurium growth and colonization.  

PubMed

Twenty-four-hour-old, aerobically grown, Luria-Bertani broth cultures of Salmonella typhimurium F98 suppressed the growth of a spectinomycin-resistant (Spcr) derivative of the same strain inoculated at 10(3) CFU ml(-1). This growth suppression is genus specific and RpoS independent, and it is not solely a result of nutrient depletion (P. A. Barrow, M. A. Lovell, and L. Zhang-Barber, J. Bacteriol. 178:3072-3076, 1996). Mutations in three genes are shown here to significantly reduce growth suppression under these conditions. The mutations were located in the nuo, cyd, and unc operons, which code for the NADH dehydrogenase I, cytochrome d oxidase, and F0F1 proton-translocating ATPase complexes, respectively. When cultures were grown under strictly anaerobic conditions, only the unc mutant did not suppress growth. Prior colonization of the alimentary tract of newly hatched chickens with the S. typhimurium F98 wild type or nuo or cyd mutants suppressed colonization by an S. typhimurium F98 Spcr derivative inoculated 24 h later. In contrast, the S. typhimurium unc mutant did not suppress colonization. The nuo and unc mutants showed poorer growth on certain carbon sources. The data support the hypothesis that growth suppression operates because of the absence of a utilizable carbon source or electron acceptor. PMID:9371470

Zhang-Barber, L; Turner, A K; Martin, G; Frankel, G; Dougan, G; Barrow, P A

1997-11-01

224

High MET gene copy number predicted poor prognosis in primary intestinal diffuse large B-cell lymphoma  

PubMed Central

Background MET is a proto-oncogene with its copy number (CN) alterations been reported in some cancers, but not in primary intestinal diffuse large B-cell lymphoma (PI-DLBL) yet. Methods In this retrospective study, we performed histology and chart reviews, immunohistochemistry and quantitative polymerase chain reaction for MET CN alterations on 28 surgically resected PI-DLBLs. Results There were 12 men and 16 women with a median age of 70 and a mean follow-up of 32 months. The median MET CN was 2.20 (range, 1.04 to 3.35). CN gain was observed in 11 cases, including 5 with CN greater than 3. Nine patients (32%) had diploid CN and eight (29%) with CN loss. Patients with gain or diploid CN showed significantly worse prognosis (P = 0.046) than those with CN loss. Furthermore, MET CN greater than 3 was associated with an adverse outcome (P = 0.003). Intestinal perforation at presentation was the sole clinicopathological factor associated with a poor prognosis (P = 0.004) and perforation was correlated with CN greater than 3 (P = 0.002). Conclusions Our finding of MET CN gain as a poor prognostic factor in PI-DLBL patients might serve as the rationale for targeting MET signaling pathway in the treatment of these patients.

2013-01-01

225

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

SciTech Connect

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

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

1994-02-01

226

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

PubMed

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 nonbiased 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, non-CA tandem repeats, and SINEs. PMID:21255732

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

2011-01-21

227

Seven Novel and Stable Translocations Associated with Oncogenic Gene Expression in Malignant Melanoma1  

PubMed Central

Abstract 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.

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

2005-01-01

228

B-cell Lymphoma  

Cancer.gov

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

229

Rituximab regulates signaling pathways and alters gene expression associated with cell death and survival in diffuse large B-cell lymphoma.  

PubMed

Rituximab, a CD20-specific antibody, is used with chemotherapy as a treatment for diffuse large B cell lymphoma (DLBCL). Although many patients benefit from the addition of rituximab to chemotherapy, a favourable response is not achieved in approximately 30% of cases. This sets a prerequisite to better understand the response and resistance mechanisms of rituximab. To do so, we analyzed the gene expression profiles of one rituximab unresponsive and two responsive DLBCL cell lines. In the responsive cells, rituximab affected the expression of genes related to apoptosis, lymphocyte signaling and cytokine response. Our data show rituximab-response to be associated with gene expression in classical signaling cascades involved in cell growth and differentiation, such as previously identified MAPK and completely novel Wnt and TGF-? pathways. Furthermore, our findings support earlier observations that rituximab can induce direct apoptosis and suggest the cell of origin to be associated with the cellular outcome. After validation of cellular results, we used a cohort of 233 R-CHOP treated DLBCL patients and found several of the most differentiating genes to have impact on survival. Together, the results provide an advanced picture of the CD20 mediated signaling of DLBCL cells and may provide new targets in future treatment protocols. PMID:21318224

Koivula, Satu; Valo, Erkka; Raunio, Anna; Hautaniemi, Sampsa; Leppä, Sirpa

2011-02-10

230

The human PD1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors  

Microsoft Academic Search

We report the complete cDNA sequence and the genomic structure of the human PD-1 homologue. An analysis of the expression pattern of the human PD-1 gene (hPD-1) and the murine PD-1 gene (mPD-1) in developing bone marrow B-lineage cells was also undertaken. The full length hPD-1 cDNA is 2106 nucleotides long and encodes a predicted protein of 288 amino acid

Lawrence R Finger; Jaiyu Pu; Robert Wasserman; Rajeev Vibhakar; Elaine Louie; Richard R Hardy; Peter D Burrows; Linda G Billips

1997-01-01

231

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development  

Microsoft Academic Search

We studied a man with distal hypospadias, partial anomalous pulmonary venous return, mild limb-length inequality and a balanced translocation involving chromosomes 9 and 13. To gain insight into the etiology of his birth defects, we mapped the translocation breakpoints by high-resolution comparative genomic hybridization (CGH), using chromosome 9- and 13-specific tiling arrays to analyze genetic material from a spontaneously aborted

Elizabeth J Bhoj; Purita Ramos; Linda A Baker; Agneta Nordenskjöld; Frederick F Elder; Steven B Bleyl; Neil E Bowles; Cammon B Arrington; Brigitte Delhomme; Amandine Vanhoutteghem; Philippe Djian; Andrew R Zinn

2011-01-01

232

Brachytelephalangic dwarfism due to the loss of ARSE and SHOX genes resulting from an X;Y translocation.  

PubMed

Here we report an 8-year-old male patient who had mesomelic shortening of forearms and legs, brachytelephalangia and ichthyotic skin lesions. Chromosomal analysis showed an X;Y translocation involving the short arm of the X chromosome (Xp). Fluorescence in situ hybridization (FISH) and molecular studies localized the breakpoints on Xp22.3 in the immediate vicinity of the KAL gene demonstrating deletions of steroid sulfatase (STS), arylsulfatase E (ARSE), and short stature homeo box (SHOX) genes. It was suspected that the patient was suffering from chondrodysplasia punctata because of a loss of the arylsulfatase E (ARSE) gene. However, no stippled epiphyses were to be seen in the neonatal radiograph. Interestingly, this patient is the first case with a proven loss of the ARSE gene without chondrodysplasia punctata, assuming that chondrodysplasia punctata is not an obligatory sign of ARSE gene loss. Brachytelephalangia was the only result of ARSE gene deletion in this case. The patient's mother also had dwarfism and showed Madelung deformity of the forearms. She was detected as a carrier of the same aberrant X chromosome. The male patient did not show Madelung deformity, demonstrating that Lerri-Weill syndrome phenotype may be still incomplete in children with SHOX gene deletion. The wide clinical spectrum in the male and the Leri-Weill phenotype in his mother are the results of both a deletion involving several sulfatase genes in Xp22.3 and the SHOX gene located in the pseudoautosomal region. Nevertheless, there is no explanation for the absence of chondrodysplasia punctata despite the total loss of the ARSE gene. Further studies are necessary to investigate genotype/phenotype correlation in cases with translocations or microdeletions on Xp22.3, including the ARSE and the SHOX gene loci. PMID:11260213

Seidel, J; Schiller, S; Kelbova, C; Beensen, V; Orth, U; Vogt, S; Claussen, U; Zintl, F; Rappold, G A

2001-02-01

233

Genetic variation in chromosomal translocation breakpoint and immune function genes and risk of non-Hodgkin lymphoma  

Microsoft Academic Search

Background  Tumor necrosis factor (TNF) and interleukin 10 (IL10) are promising candidate susceptibility genes for non-Hodgkin lymphoma (NHL). Chromosomal translocation breakpoint genes\\u000a are of interest, given their documented involvement in lymphoma progression.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We analyzed 11 polymorphisms in BCL2, CCND1, MYC, TNF, and IL10 in a large, population-based, Danish-Swedish case–control study including 2,449 NHL cases and 1,980 controls. Relative risk\\u000a of NHL

Pia Fernberg; Ellen T. Chang; Kristina Duvefelt; Henrik Hjalgrim; Sandra Eloranta; Karina Meden Sørensen; Anna Porwit; Keith Humphreys; Mads Melbye; Karin Ekström Smedby

2010-01-01

234

Induction of Early B Cell Factor (EBF) and Multiple B Lineage Genes by the Basic Helix-Loop-Helix Transcription Factor E12  

PubMed Central

The transcription factors encoded by the E2A and early B cell factor (EBF) genes are required for the proper development of B lymphocytes. However, the absence of B lineage cells in E2A- and EBF-deficient mice has made it difficult to determine the function or relationship between these proteins. We report the identification of a novel model system in which the role of E2A and EBF in the regulation of multiple B lineage traits can be studied. We found that the conversion of 70Z/3 pre-B lymphocytes to cells with a macrophage-like phenotype is associated with the loss of E2A and EBF. Moreover, we show that ectopic expression of the E2A protein E12 in this macrophage line results in the induction of many B lineage genes, including EBF, IL7R?, ?5, and Rag-1, and the ability to induce ? light chain in response to mitogen. Activation of EBF may be one of the critical functions of E12 in regulating the B lineage phenotype since expression of EBF alone leads to the activation of a subset of E12-inducible traits. Our data demonstrate that, in the context of this macrophage line, E12 induces expression of EBF and together these transcription factors coordinately regulate numerous B lineage–associated genes.

Kee, Barbara L.; Murre, Cornelis

1998-01-01

235

Pediatric renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions and clinicopathologic associations.  

PubMed

Renal cell carcinomas (RCCs) are rare in children and studies of their subtypes and clinicopathologic associations are limited to small series. We identified 8 patients with RCC treated at our institution between 1981 and 2003, reviewed their clinicopathologic features, cytogenetics findings, and evaluated the status of TFE3 expression by immunohistochemistry and numerical chromosomal alterations by interphase fluorescent in situ hybridization on paraffin-embedded tissue. These 8 patients (5 female and 3 male) had diploidy, and 5 had morphologic features compatible with the recently described RCC associated with Xp11.2 translocations/TFE3 gene fusions and demonstrated nuclear labeling for TFE3 protein by immunohistochemistry. The translocation was confirmed in 2 of these 5 patients by conventional cytogenetics. One case was a high-grade nonpapillary RCC and the other was compatible with type 2 papillary RCC. Four patients showed at least 1 chromosomal gain including trisomy 7 and/or trisomy 17. None of the tumors from male patients showed evidence of loss of the Y chromosome, but 2 patients showed numerical abnormalities of X chromosome +add(X). Two patients had sickle cell disease, and 1 of these also had stage IV-S neuroblastoma. This study suggests that many cases of RCC in children reported under the terms "papillary" and "clear cell" likely represent Xp11.2 translocation/TFE3 gene fusion-associated RCC. It also emphasizes the unusual associations of RCC with neuroblastoma and sickle cell hemoglobinopathy, which need further study. PMID:15747097

Altinok, G; Kattar, M M; Mohamed, A; Poulik, J; Grignon, D; Rabah, R

2005-03-08

236

Phenobarbital-Responsive Nuclear Translocation of the Receptor CAR in Induction of the CYP2B Gene  

PubMed Central

The constitutively active receptor (CAR) transactivates a distal enhancer called the phenobarbital (PB)-responsive enhancer module (PBREM) found in PB-inducible CYP2B genes. CAR dramatically increases its binding to PBREM in livers of PB-treated mice. We have investigated the cellular mechanism of PB-induced increase of CAR binding. Western blot analyses of mouse livers revealed an extensive nuclear accumulation of CAR following PB treatment. Nuclear contents of CAR perfectly correlate with an increase of CAR binding to PBREM. PB-elicited nuclear accumulation of CAR appears to be a general step regulating the induction of CYP2B genes, since treatments with other PB-type inducers result in the same nuclear accumulation of CAR. Both immunoprecipitation and immunohistochemistry studies show cytoplasmic localization of CAR in the livers of nontreated mice, indicating that CAR translocates into nuclei following PB treatment. Nuclear translocation of CAR also occurs in mouse primary hepatocytes but not in hepatocytes treated with the protein phosphatase inhibitor okadaic acid. Thus, the CAR-mediated transactivation of PBREM in vivo becomes PB responsive through an okadaic acid-sensitive nuclear translocation process.

Kawamoto, Takeshi; Sueyoshi, Tatsuya; Zelko, Igor; Moore, Rick; Washburn, Kimberly; Negishi, Masahiko

1999-01-01

237

A role for AID in chromosome translocations between c-myc and the IgH variable region  

PubMed Central

Chromosome translocations between oncogenes and the region spanning the immunoglobulin (Ig) heavy chain (IgH) variable (V), diversity (D), and joining (J) gene segments (Ig V-JH region) are found in several mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences targeted by recombination activating genes 1 and 2 during antigen receptor assembly in pre–B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-JH region–associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-JH translocations, we searched for such events in both interleukin (IL) 6 transgenic (IL-6 tg) and AID?/? IL-6 tg mice. Here, we report that AID is required for c-myc to Ig V-JH translocations induced by IL-6.

Dorsett, Yair; Robbiani, Davide F.; Jankovic, Mila; Reina-San-Martin, Bernardo; Eisenreich, Thomas R.; Nussenzweig, Michel C.

2007-01-01

238

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

PubMed Central

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

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

2012-01-01

239

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

2007-08-22

240

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

PubMed

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

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

2013-02-28

241

B cell targeted therapies  

PubMed Central

Although the precise pathogenesis of rheumatoid arthritis (RA) remains unclear, many cell populations, including monocytes, macrophages, endothelial cells, fibroblasts and B cells, participate in the inflammatory process. Ongoing research continues to evaluate the critical roles played by B cells in sustaining the chronic inflammatory process of RA. These findings have contributed to the development of targeted therapies that deplete B cells, such as rituximab, as well as inhibitors of B lymphocyte stimulation, such as belimumab. In a phase I trial, belimumab treatment significantly reduced CD20+ levels in patients with systemic lupus erythematosus. Phase I and phase II trials of rituximab found that rituximab plus methotrexate achieved significantly better American College of Rheumatology 50% responses for patients with RA than those patients receiving monotherapy with methotrexate. These clinical trial data present promising evidence for B cell targeted therapies as future therapeutic options for RA.

2005-01-01

242

Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature.  

PubMed

We report clinicopathologic features of a large series of renal translocation carcinomas from a multicentric study. Diagnosis was performed by cytogenetic examination of fresh material and/or by immunochemistry with antibodies directed against the C-terminal part of transcription factor E3 (TFE3) and native transcription factor EB (TFEB) proteins. Clinical data, follow-up, and histologic features were assessed. Antibodies against CK7, CD10, vimentin, epithelial membrane antigen, AE1-AE3, E-cadherin, alpha-methylacyl-coenzyme A racemase, melan A, and HMB45 were tested on tissue microarrays. Whole-genome microarray expression profiling was performed on 4 tumors. Twenty-nine cases were diagnosed as TFE3 and 2 as TFEB renal translocation carcinomas, including 13 males and 18 females, mean age 24.6 years. Two patients had a previous history of chemotherapy and 1 had a history of renal failure. Mean size of the tumor was 6.9 cm. Thirteen cases were > or = pT3 stage. Twelve cases were N+ or M+. Mean follow-up was 29.5 months. Three patients presented metastases and 5 have died. Mixed papillary and nested patterns with clear and/or eosinophilic cells represented the most consistent histologic appearance, with common foci of calcifications regardless of the type of translocation. Using a 30 mn incubation at room temperature, TFE3 immunostainings were positive in only 82% of our TFE3 translocation carcinomas. Both TFE3 and TFEB renal translocation carcinomas expressed CD10 and alpha-methylacyl-coenzyme A racemase in all cases. An expression of E-cadherin was observed in two-third of cases. Cytokeratins were expressed in less than one-third of cases. Melanocytic markers were expressed at least weakly in all cases except two. Unsupervised clustering on the basis of the gene expression profiling indicated a distinct subgroup of tumors. TRIM 63 glutathione S-transferase A1 and alanyl aminopeptidase are the main differentially expressed genes for this group of tumors. Our results suggest that these differentially expressed genes may serve as novel diagnostic or prognostic markers. PMID:18344867

Camparo, Philippe; Vasiliu, Viorel; Molinie, Vincent; Couturier, Jerome; Dykema, Karl J; Petillo, David; Furge, Kyle A; Comperat, Eva M; Lae, Marick; Bouvier, Raymonde; Boccon-Gibod, Liliane; Denoux, Yves; Ferlicot, Sophie; Forest, Eric; Fromont, Gaelle; Hintzy, Marie C; Laghouati, Myriam; Sibony, Mathilde; Tucker, Marie L; Weber, Nina; Teh, Bin T; Vieillefond, Annick

2008-05-01

243

CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study.  

PubMed

CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ?14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+), 79% vs CD30(-), 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor ?B activation and lymphocyte survival, and downregulation of genes encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL. PMID:23343832

Hu, Shimin; Xu-Monette, Zijun Y; Balasubramanyam, Aarthi; Manyam, Ganiraju C; Visco, Carlo; Tzankov, Alexander; Liu, Wei-min; Miranda, Roberto N; Zhang, Li; Montes-Moreno, Santiago; Dybkær, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L; Hsi, Eric D; Choi, William W L; Han van Krieken, J; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J M; Zhao, Xiaoying; Winter, Jane N; Zhang, Mingzhi; Li, Ling; Møller, Michael B; Piris, Miguel A; Li, Yong; Go, Ronald S; Wu, Lin; Medeiros, L Jeffrey; Young, Ken H

2013-01-23

244

Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma.  

PubMed

The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL. In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly. In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues. In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel "proto-oncogenes" involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcgammaRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described. PMID:11701542

Macintyre, Elizabeth; Willerford, Dennis; Morris, Stephan W.

2000-01-01

245

Monitoring of adult B-cell lineage acute lymphoblastic leukemia: validation of a simple method for detecting immunoglobulin heavy chain gene clonality.  

PubMed

Most approaches to demonstrating immunoglobulin heavy chain gene rearrangements are relatively laborious for routine follow-up of acute lymphoblastic leukemia (ALL). Here the use of a simple polymerase chain reaction (PCR) approach to monitor ALL disease activity has been validated. In the dilution experiments the method revealed a detection sensitivity 0.5% clonal cells in a background of 99.5% normal cells. To validate the immunoglobulin heavy chain gene PCH (IgH-PCR) in practice, we monitored the disease activity of 26 adult ALL patients showing a B-cell lineage component in immunophenotyping at the diagnosis of the disease. In 18 of those 26 patients, an IgH-PCR product could be demonstrated in the samples taken either at diagnosis or in relapse. These 18 patients were followed with a total of 158 consecutive samples by IgH-PCR. The mean follow-up time for the IgH-PCR-positive patients was 13.6 months (range 4 to 26 months). Eleven of these patients underwent altogether 18 relapses. In nine patients (81.8%), ten relapses (55.6%) could be predicted using the IgH-PCR approach. The mean time of IgH-PCR clonality detection, preceding a cytologic relapse, was 9.1 weeks (range 1.0 to 30.7 weeks). It seems that in three patients the predictive value of the IgH-PCR was remarkable, showing a repetitive positivity in spite of a cytologic remission, even one year prior to the relapse. We find that IgH-PCR provides a straightforward additional tool for monitoring B-cell lineage ALL. Due to the straightforward technical performance the method has low running costs and it is thus suitable for a routine service laboratory. Even if a negative finding in IgH-PCR does not rule out a forthcoming relapse in the patient, a positive finding is a definitive warning signal. All of the patients that showed an IgH-PCR clonality in the follow-up samples relapsed sooner or later. PMID:8371595

Salo, A; Pakkala, S; Jansson, S E; Helminen, P; Palotie, A

1993-09-01

246

Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas.  

PubMed

Most lipomas are characterized by translocations involving the HMGA2 gene in 12q14.3. These rearrangements lead to the fusion of HMGA2 with an ectopic sequence from the translocation chromosome partner. Only five fusion partners of HMGA2 have been identified in lipomas so far. The identification of novel fusion partners of HMGA2 is important not only for diagnosis in soft tissue tumors but also because these genes might have an oncogenic role in other tumors. We observed that t(1;12)(p32;q14) was the second most frequent translocation in our series of lipomas after t(3;12)(q28;q14.3). We detected overexpression of HMGA2 mRNA and protein in all t(1;12)(p32;q14) lipomas. We used a fluorescence in situ hybridization-based positional cloning strategy to characterize the 1p32 breakpoint. In 11 cases, we identified PPAP2B, a member of the lipid phosphate phosphatases family as the 1p32 target gene. Reverse transcription-polymerase chain reaction analysis followed by nucleotide sequencing of the fusion transcript indicated that HMGA2 3' untranslated region (3'UTR) fused with exon 6 of PPAP2B in one case. In other t(1;12) cases, the breakpoint was extragenic, located in the 3'region flanking PPAP2B 3'UTR. Moreover, in one case showing a t(1;6)(p32;p21) we observed a rearrangement of PPAP2B and HMGA1, which suggests that HMGA1 might also be a fusion partner for PPAP2B. Our results also revealed that adipocytic differentiation of human mesenchymal stem cells derived from adipose tissue was associated with a significant decrease in PPAP2B mRNA expression suggesting that PPAP2B might play a role in adipogenesis. PMID:23508853

Bianchini, Laurence; Birtwisle, Loïc; Saâda, Esma; Bazin, Audrey; Long, Elodie; Roussel, Jean-François; Michiels, Jean-François; Forest, Fabien; Dani, Christian; Myklebost, Ola; Birtwisle-Peyrottes, Isabelle; Pedeutour, Florence

2013-03-18

247

BCL6 promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells.  

PubMed

BCL6 encodes a transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis. Although its promoter has been well studied, little is known concerning its possible regulation by more distal elements. To gain such information, we mapped critical histone modifications associated with active transcription within BCL6 as well as far upstream sequences at nucleosomal resolution in B-cell lines and in normal naive and GC B cells. Promoter-associated and intronic CpG islands (CGIs) in BCL6 showed a reciprocal pattern of histone modifications. Gene expression correlated with a paradoxical loss from the intronic CGI of histone H3 lysine-4 trimethylation, normally associated with transcription, suggesting that the intronic CGI may interfere with transcription. In an approximately 110-kb region extending 150-260 kb upstream of BCL6, highly active histone modifications were present only in normal GC B cells and a GC B-cell line; this region overlaps with an alternative breakpoint region for chromosomal translocations and contains a GC-specific noncoding RNA gene. By chromosome conformation capture, we determined that the BCL6 promoter interacts with this distant upstream region. It is likely that transcriptional enhancers in this region activate BCL6 and overcome strong autorepression in GC B cells. PMID:20547840

Ramachandrareddy, Himabindu; Bouska, Alyssa; Shen, Yulei; Ji, Ming; Rizzino, Angie; Chan, Wing C; McKeithan, Timothy W

2010-06-14

248

BCL6 promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells  

PubMed Central

BCL6 encodes a transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis. Although its promoter has been well studied, little is known concerning its possible regulation by more distal elements. To gain such information, we mapped critical histone modifications associated with active transcription within BCL6 as well as far upstream sequences at nucleosomal resolution in B-cell lines and in normal naive and GC B cells. Promoter-associated and intronic CpG islands (CGIs) in BCL6 showed a reciprocal pattern of histone modifications. Gene expression correlated with a paradoxical loss from the intronic CGI of histone H3 lysine-4 trimethylation, normally associated with transcription, suggesting that the intronic CGI may interfere with transcription. In an ?110-kb region extending 150–260 kb upstream of BCL6, highly active histone modifications were present only in normal GC B cells and a GC B-cell line; this region overlaps with an alternative breakpoint region for chromosomal translocations and contains a GC-specific noncoding RNA gene. By chromosome conformation capture, we determined that the BCL6 promoter interacts with this distant upstream region. It is likely that transcriptional enhancers in this region activate BCL6 and overcome strong autorepression in GC B cells.

Ramachandrareddy, Himabindu; Bouska, Alyssa; Shen, Yulei; Ji, Ming; Rizzino, Angie; Chan, Wing C.; McKeithan, Timothy W.

2010-01-01

249

Double isotype production by a neoplastic B cell line. II. Allelically excluded production of mu and gamma 1 heavy chains without CH gene rearrangement  

PubMed Central

In our accompanying paper, we described a switch variant (BCL1.2.58) that expresses membrane and secreted forms of IgM and IgG1. Both IgM and IgG1 share the same idiotype and use the same VDJ rearrangement. Here, a detailed Southern blot analysis of the entire constant region of the Ig heavy chain (Ig CH) locus of parental (BCL1.B1) and variants (BCL1.B2) DNA showed no detectable rearrangement. Similar analysis of the JH-C mu region led to the conclusion that two heavy chain alleles present in the IgM/IgG1-producing variants carried the same VDJ rearrangement but differed in their 3' flanking regions. One chromosome 12 did not carry any Ig CH genes, whereas, the other chromosome 12 carried one copy of CH genes. In BCL1.B1, however, each of the chromosome 12 alleles carried a full copy of CH genes. Karyotypic analysis confirmed the presence of two translocated t(12;16) chromosomes in both BCL1.2.58 and BCL1.B1 cells, with a break 5' to the VH locus at the distal region (12F2) of chromosome 12, and at the proximal region below the centromere (16B3) of chromosome 16. We conclude that double production of IgM and IgG1 in BCL1.B2 is accomplished by transcription of the corresponding CH genes in germline configuration using a single VDJ on the same chromosome 12.

1986-01-01

250

Transcription of the Epstein-Barr virus nuclear antigen 1 (EBNA1) gene occurs before induction of the BCR2 (Cp) EBNA gene promoter during the initial stages of infection in B cells.  

PubMed

The purpose of this study was to gain insights into the regulation of Epstein-Barr virus (EBV) gene transcription during the establishment of viral latency in B cells. During the early stages of EBV infection in B lymphocytes, transcription of six viral nuclear antigens (EBNAs) is initiated from an early promoter (Wp). This is followed by a switch of promoter usage to an upstream promoter, Cp, whose activity is autoregulated by both EBNA1 and EBNA2. Previously it was demonstrated that infection of primary B cells with EBNA2-negative (EBNA2-) EBNA4-mutant (EBNA4mut) virus resulted only in the expression of mutant EBNA4 protein and failure to express the other EBNA gene products (C. Rooney H. G. Howe, S. H. Speck, and G. Miller, J. Virol. 63:1531-1539, 1989). We extended this research to demonstrate that Wp-to-Cp switching did not occur upon infection of primary B cells with an EBNA2- EBNA4mut virus (M. Woisetschlaeger, X. W. Jin, C. N. Yandara, L. A. Furmanski, J. L. Strominger, and S. H. Speck, Proc. Natl. Acad. Sci. USA 88:3942-3946, 1991). Further characterization of this phenomenon led to the identification of an EBNA2-dependent enhancer upstream of Cp. On the basis of these data, a model was proposed in which initial transcription from Wp gives rise to the expression of EBNA2 and EBNA4, and then transcription is upregulated from Cp via the EBNA2- dependent enhancer (Woisetschlaeger et al., as noted above). Implicit in this model is that transcription of the EBNA1 and EBNA3a to -3c genes is dependent on the switch from Wp to Cp, since primary cells infected with EBNA2- EBNA4mut virus fail to switch and also fail to express these viral antigens. Here we critically evaluate this model and demonstrate, in contrast to the predictions of the model, that transcription of both the EBNA1 and EBNA2 genes precedes activation of Cp. Furthermore, the level of EBNA1 gene transcription was strongly reduced in primary B cells infected with EBNA2- EBNA4mut virus compared with that of cells infected with wild-type virus. Switching to Cp, as well as EBNA1 gene transcription, was observed upon infection of EBV-negative Burkitt's lymphoma (BL) cell lines with EBNA2- EBNA4mut virus, thus establishing a correlation between early EBNA1 gene transcription and upregulation of transcription initiation from Cp. However, in EBV-negative BL cell lines infected with EBNA2- EBNA4mut virus, transcription of the EBNA1 gene at early time points postinfection initiated from Qp, the EBNA1 gene promoter active in group I BL cells (B. C. Schaefer, J. L. Strominger, and S. H. Speck, Proc. Natl. Acad. Sci. USA 92:10565-10569, 1995), rather than from Wp. The data support a model in which EBNA1 plays an important role in the cascade of events leading to successful switching from Wp to Cp and subsequent immortalization of the infected B cell. PMID:8648690

Schlager, S; Speck, S H; Woisetschläger, M

1996-06-01

251

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

PubMed Central

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

2011-01-01

252

Balanced translocation in a patient with craniosynostosis disrupts the SOX6 gene and an evolutionarily conserved non-transcribed region.  

PubMed

Craniosynostosis is a congenital developmental disorder involving premature fusion of cranial sutures, which results in an abnormal shape of the skull. Significant progress in understanding the molecular basis of this phenotype has been made for a small number of syndromic craniosynostosis forms. Nevertheless, in the majority of the approximately 100 craniosynostosis syndromes and in non-syndromic craniosynostosis the underlying gene defects and pathomechanisms are unknown. Here we report on a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. Three dimensional cranial computer tomography showed fusion of the lambdoid sutures and distal part of the sagittal suture with a gaping anterior fontanelle. Mutations in the genes for FGFR2 and FGFR3 were excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes. SOX6 mutation screening of another 104 craniosynostosis patients revealed one missense mutation leading to the exchange of a highly conserved amino acid (p.D68N) in a single patient and his reportedly healthy mother. The breakpoint on chromosome 9 is located in a region without any known or predicted genes but, interestingly, disrupts patches of evolutionarily highly conserved non-genic sequences and may thus led to dysregulation of flanking genes on chromosome 9 or 11 involved in skull vault development. The present case is one of the very rare reports of an apparently balanced translocation in a patient with syndromic craniosynostosis, and reveals novel candidate genes for craniosynostoses and cranial suture formation. PMID:16258006

Tagariello, A; Heller, R; Greven, A; Kalscheuer, V M; Molter, T; Rauch, A; Kress, W; Winterpacht, A

2005-10-28

253

Bruton's Tyrosine Kinase Links the B Cell Receptor to Nuclear Factor ?b Activation  

PubMed Central

The recognition of antigen by membrane immunoglobulin M (mIgM) results in a complex series of signaling events in the cytoplasm leading to gene activation. Bruton's tyrosine kinase (BTK), a member of the Tec family of tyrosine kinases, is essential for the full repertoire of IgM signals to be transduced. We examined the ability of BTK to regulate the nuclear factor (NF)-?B/Rel family of transcription factors, as the activation of these factors is required for a B cell response to mIgM. We found greatly diminished IgM- but not CD40-mediated NF-?B/Rel nuclear translocation and DNA binding in B cells from X-linked immunodeficient (xid) mice that harbor an R28C mutation in btk, a mutation that produces a functionally inactive kinase. The defect was due, in part, to a failure to fully degrade the inhibitory protein of NF-?B, I?B?. Using a BTK-deficient variant of DT40 chicken B cells, we found that expression of wild-type or gain-of-function mutant BTK, but not the R28C mutant, reconstituted NF-?B activity. Thus, BTK is essential for activation of NF-?B via the B cell receptor.

Bajpai, Urmila D.; Zhang, Keming; Teutsch, Mark; Sen, Ranjan; Wortis, Henry H.

2000-01-01

254

Activation-induced Cytidine Deaminase in B Cell Immunity and Cancers.  

PubMed

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

Park, Seok-Rae

2012-12-31

255

Monocytoid B cell lymphoma.  

PubMed Central

The clinical, light microscopic, ultrastructural, immunocytochemical and cytogenetic features of a case of monocytoid B cell lymphoma were investigated. The tumour initially affected the cervical and supraclavicular nodes, but 33 months later affected the left parotid salivary gland. The patient had subclinical Sjögren's syndrome. The neoplastic cells showed characteristic morphological features and had peri- and interfollicular distribution in the node. Immunocytochemically the tumour cells were L26, 4KB5, MB2, CD19, CD20, CD22 and IgM/kappa positive. Prominent plasmablastic plasmacytoid differentiation was present in the recurrent tumour, suggesting an origin from post-follicular B cells. The lymphoma cells showed unusual cytogenetic abnormalities. Images

Banerjee, S S; Harris, M; Eyden, B P; Radford, J A; Harrison, C J; Mainwaring, A R

1991-01-01

256

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

257

Expression pattern of a nuclear encoded mitochondrial arginine-ornithine translocator gene from Arabidopsis  

Microsoft Academic Search

BACKGROUND: Arginine and citrulline serve as nitrogen storage forms, but are also involved in biosynthetic and catabolic pathways. Metabolism of arginine, citrulline and ornithine is distributed between mitochondria and cytosol. For the shuttle of intermediates between cytosol and mitochondria transporters present on the inner mitochondrial membrane are required. Yeast contains a mitochondrial translocator for ornithine and arginine, Ort1p\\/Arg11p. Ort1p\\/Arg11p is

Elisabetta Catoni; Marcelo Desimone; Melanie Hilpert; Daniel Wipf; Reinhard Kunze; Anja Schneider; U. I. Flugge; Karin Schumacher; Wolf B Frommer

2003-01-01

258

Characterization of an echinocandin B-producing strain blocked for sterigmatocystin biosynthesis reveals a translocation in the stcW gene of the aflatoxin biosynthetic pathway.  

PubMed

Echinocandin B (ECB), a lipopolypeptide used as a starting material for chemical manufacture of the anti-Candida agent LY303366, is produced by fermentation using a strain of Aspergillus nidulans. In addition to ECB, the wild-type strain also produces a significant level of sterigmatocystin (ST), a potent carcinogen structurally related to the aflatoxins. Characterization of a mutant designated A42355-OC-1 (OC-1), which is blocked in ST biosynthesis, was the result of a chromosomal translocation. The chromosomal regions containing the breakpoints of the translocation were isolated and DNA sequencing and PCR analysis of the chromosomal breakpoints demonstrated the translocation occurred within the stcW gene of the ST biosynthetic pathway, resulting in disruption of the open reading frame for this gene. Biochemical feeding studies indicate the involvement of this gene product in the conversion of averufin to 1-hydroxy versicolorone. This work demonstrates an effective synergy between classical strain improvement methods and molecular genetics. PMID:11320421

Hodges, R L; Kelkar, H S; Xuei, X; Skatrud, P L; Keller, N P; Adams, T H; Kaiser, R E; Vinci, V A; McGilvray, D

2000-12-01

259

Interleukin21 regulates expression of the immediate-early lytic cycle genes and proteins in Epstein-Barr Virus infected B cells  

Microsoft Academic Search

The switch between the latent and the lytic cycle of Epstein-Barr Virus (EBV) infection is characterized by the induction of viral transcriptional activators Zta and Rta. CD4+ T cell-derived cytokines are likely to regulate expression of these proteins in EBV-infected B cells. Here we show that interleukin-21 decreases constitutive expression of Rta and its target EA-D in EBV-infected B cell

Danijela Konforte; Christopher J. Paige

2009-01-01

260

Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation  

Microsoft Academic Search

Plasma cells (PCs), the end point of B-cell differentiation, are a heterogeneous cell compartment comprising several cell sub- sets from short-lived highly proliferative plasmablasts to long-lived nondividing fully mature PCs. Whereas the major tran- scription factors driving the differentia- tion of B cells to PCs were recently identi- fied, the subtle genetic changes that underlie the transition from plasmablasts to

Karin Tarte; Fenghuang Zhan; John De Vos; Bernard Klein; John Shaughnessy Jr

2003-01-01

261

Islands of non-essential genes, including a DNA translocation operon, in the genome of bacteriophage 0305?8-36.  

PubMed

We investigate genes of lytic, Bacillus thuringiensis bacteriophage 0305?8-36 that are non-essential for laboratory propagation, but might have a function in the wild. We isolate deletion mutants to identify these genes. The non-permutation of the genome (218.948 Kb, with a 6.479 Kb terminal repeat and 247 identified orfs) simplifies isolation of deletion mutants. We find two islands of non-essential genes. The first island (3.01% of the genomic DNA) has an informatically identified DNA translocation operon. Deletion causes no detectable growth defect during propagation in a dilute agarose overlay. Identification of the DNA translocation operon begins with a DNA relaxase and continues with a translocase and membrane-binding anchor proteins. The relaxase is in a family, first identified here, with homologs in other bacteriophages. The second deleted island (3.71% of the genome) has genes for two metallo-protein chaperonins and two tRNAs. Deletion causes a significant growth defect. In addition, (1) we find by "in situ" (in-plaque) single-particle fluorescence microscopy that adsorption to the host occurs at the tip of the 486 nm long tail, (2) we develop a procedure of 0305?8-36 purification that does not cause tail contraction, and (3) we then find by electron microscopy that 0305?8-36 undergoes tail tip-tail tip dimerization that potentially blocks adsorption to host cells, presumably with effectiveness that increases as the bacteriophage particle concentration increases. These observations provide an explanation of the previous observation that 0305?8-36 does not lyse liquid cultures, even though 0305?8-36 is genomically lytic. PMID:22666654

Pathria, Saurav; Rolando, Mandy; Lieman, Karen; Hayes, Shirley; Hardies, Stephen; Serwer, Philip

2012-01-01

262

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

PubMed Central

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

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

2011-01-01

263

Integrative Gene Expression Profiling Reveals G6PD-Mediated Resistance to RNA-Directed Nucleoside Analogues in B-Cell Neoplasms  

PubMed Central

The nucleoside analogues 8-amino-adenosine and 8-chloro-adenosine have been investigated in the context of B-lineage lymphoid malignancies by our laboratories due to the selective cytotoxicity they exhibit toward multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL) cell lines and primary cells. Encouraging pharmacokinetic and pharmacodynamic properties of 8-chloro-adenosine being documented in an ongoing Phase I trial in CLL provide additional impetus for the study of these promising drugs. In order to foster a deeper understanding of the commonalities between their mechanisms of action and gain insight into specific patient cohorts positioned to achieve maximal benefit from treatment, we devised a novel two-tiered chemoinformatic screen to identify molecular determinants of responsiveness to these compounds. This screen entailed: 1) the elucidation of gene expression patterns highly associated with the anti-tumor activity of 8-chloro-adenosine in the NCI-60 cell line panel, 2) characterization of altered transcript abundances between paired MM and MCL cell lines exhibiting differential susceptibility to 8-amino-adenosine, and 3) integration of the resulting datasets. This approach generated a signature of seven unique genes including G6PD which encodes the rate-determining enzyme of the pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase. Bioinformatic analysis of primary cell gene expression data demonstrated that G6PD is frequently overexpressed in MM and CLL, highlighting the potential clinical implications of this finding. Utilizing the paired sensitive and resistant MM and MCL cell lines as a model system, we go on to demonstrate through loss-of-function and gain-of-function studies that elevated G6PD expression is necessary to maintain resistance to 8-amino- and 8-chloro-adenosine but insufficient to induce de novo resistance in sensitive cells. Taken together, these results indicate that G6PD activity antagonizes the cytotoxicity of 8-substituted adenosine analogues and suggests that administration of these agents to patients with B-cell malignancies exhibiting normal levels of G6PD expression may be particularly efficacious.

McBrayer, Samuel K.; Yarrington, Michael; Qian, Jun; Feng, Gang; Shanmugam, Mala; Gandhi, Varsha; Krett, Nancy L.; Rosen, Steven T.

2012-01-01

264

The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression under control of the LIFR promoter  

Microsoft Academic Search

We have previously shown that the PLAG1 gene on chromosome 8q12 is consistently rearranged in pleomorphic adenomas of the salivary glands with t(3;8)(p21;q12) translocations. The t(3;8) results in promoter swapping between the PLAG1 gene, which encodes a novel zinc finger protein, and the constitutively expressed gene for ?-catenin (CTNNB1), a protein with roles in cell-cell adhesion and the WG\\/WNT signalling

Marianne L Voz; Anna-Karin Åström; Koen Kas; Joachim Mark; Göran Stenman; Wim JM Van de Ven; WJM Van de Ven

1998-01-01

265

Interleukin-6 is responsible for aberrant B-cell receptor-mediated regulation of RAG expression in systemic lupus erythematosus  

PubMed Central

Defective regulation of secondary immunoglobulin V(D)J gene rearrangement promotes the production of autoantibodies in systemic lupus erythematosus (SLE). It remains unclear, however, whether the regulation of the recombination-activating genes RAG1 and RAG2 is effective in SLE. RAG1 and RAG2 messenger RNA expression was analysed before and after in vitro activation of sorted CD19+ CD5– B cells with anti-immunoglobulin M antibodies, in 20 SLE patients and 17 healthy controls. The expression of CDK2 and p27Kip1 regulators of the RAG2 protein, were examined. The levels of interleukin-6 (IL-6) and its influence on RAG regulation were also evaluated in vitro. SLE patients had increased frequency of RAG-positive B cells. B-cell receptor (BCR) engagement induced a shift in the frequency of ?- and ?-positive cells, associated with a persistence of RAG messenger RNA and the maintenance of RAG2 protein within the nucleus. While expression of the RAG2-negative regulator CDK2 was normal, the positive regulator p27Kip1 was up-regulated and enhanced by BCR engagement. This effect was the result of the aberrant production of IL-6 by SLE B cells. Furthermore, IL-6 receptor blockade led to a reduction in p27Kip1 expression, and allowed the translocation of RAG2 from the nucleus to the cytoplasm. Our study indicates that aberrant production of IL-6 contributes to the inability of SLE B cells to terminate RAG protein production. Therefore, we hypothesize that because of constitutive IL-6 signalling in association with BCR engagement, SLE B cells would become prone to secondary immunoglobulin gene rearrangements and autoantibody production.

Hillion, Sophie; Garaud, Soizic; Devauchelle, Valerie; Bordron, Anne; Berthou, Christian; Youinou, Pierre; Jamin, Christophe

2007-01-01

266

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

267

Deletion of the factor IX gene as a result of translocation t(X;1) in a girl affected by haemophilia B.  

PubMed

A balanced de novo translocation t(X;1) is described in a girl with severe haemophilia B. The translocated X was shown cytologically to be preferentially active, and methylation analysis of the DXS255 locus confirmed the skewed X-inactivation with the paternal allele being the active one. Cytogenetic and molecular analysis showed that this chromosomal rearrangement led to the deletion of at least part of the factor IX gene. Therefore, the girl was heterozygous for factor IX deficiency and expression of her clinical phenotype was the result of the inactivation of the normal maternal X chromosome. The localization of one of the X chromosome translocation breakpoints in YAC clone 957F9, that was demonstrated to map distally to the factor IX gene, revealed the complexity of this chromosomal rearrangement. PMID:11380446

Krepischi-Santos, A C; Carneiro, J D; Svartman, M; Bendit, I; Odone-Filho, V; Vianna-Morgante, A M

2001-06-01

268

Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED2 Concerted Action BHM4CT98-3936  

Microsoft Academic Search

Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig\\/TCR rearrangement

P A S Evans; Ch Pott; P. J. T. A. Groenen; G. Salles; F. Davi; F. Berger; J. F. Garcia; S. Pals; Ph Kluin; E. Schuuring; M. Spaargaren; E. Boone; D. Gonzalez; B. Martinez; R. Villuendas; P. Gameiro; T. C. Diss; K. Mills; G. J. Morgan; G. I. Carter; B. J. Milner; D. Pearson; M. Hummel; W. Jung; M. Ott; D. Canioni; K. Beldjord; C. Bastard; M. H. Delfau-Larue; J. J. M. van Dongen; T. J. Molina; J. Cabecadas

2007-01-01

269

Short consensus probes with 3?-minor groove binder of the immunoglobulin heavy-chain gene for real-time quantitative PCR in B-cell non-Hodgkin lymphomas  

Microsoft Academic Search

We used 3?-minor groove binder (MGB) technology to develop consensus fluorogenically labeled probes of the immunoglobulin heavy-chain (IgH) gene for detecting minimal residual disease (MRD) in B-cell non-Hodgkin lymphoma (B-NHL). Sequence data from 59 patients with B-NHLs revealed a narrow consensus region as a result of somatic hypermutations and variable VH usage, indicating that it would be difficult to design

Michihiro Uchiyama; Chihaya Maesawa; Akiko Yashima-Abo; Mitsu Tarusawa; Mamoru Satoh; Takashi Satoh; Yoji Ishida; Shigeki Ito; Kazunori Murai; Sanae Enomoto; Taiju Utsugisawa; Tomoyuki Masuda

2004-01-01

270

Over-expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B-cell lymphoma.  

PubMed

The basic region-leucine zipper (bZip) factor BTB, CNC homology 2 (BACH2) is known to have important roles in class switch recombination and somatic hypermutation (SHM) of the immunoglobulin (Ig) gene. In this study, we investigated the relationship between the expression of BACH2 and the status of SHM of the Ig heavy chain gene variable region (IgHV) for SHM in diffuse large B-cell lymphoma (DLBCL). We examined 20 cases of DLBCL, 13 of which were germinal center B-cell (GCB) DLBCL and 7 were non-GCB DLBCL. Seven cases were negative, 6 were positive (cytoplasmic expression) and 7 were strongly positive (both nuclear and cytoplasmic expression) for BACH2. Confirmed mutation (CM) was identified in 8 cases and the CM index (number of confirmed mutations per 10 subclones) was distributed from 0 to 5. A CM index of 7 strongly positive (over-expression) cases with BACH2 were distributed from 0 to 5, and that of 7 negative and 6 positive cases were distributed from 0 to 1. Over-expression of BACH2 was statistically related to CM index (P = 0.008). In conclusion, over-expression of BACH2 is critical for ongoing SHM of IgHV in DLBCL, and our data suggest that BACH2 may play an essential role for SHM of the Ig gene in B-cell lymphoma. PMID:23865571

Kikuchi, Tomoki; Tokunaka, Mami; Kikuti, Yara Yukie; Carreras, Joaquim; Ogura, Go; Takekoshi, Susumu; Kojima, Minoru; Ando, Kiyoshi; Hashimoto, Yuko; Abe, Masafumi; Takata, Katsuyoshi; Yoshino, Tadashi; Muto, Akihiko; Igarashi, Kazuhiko; Nakamura, Naoya

2013-07-01

271

Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma  

Microsoft Academic Search

A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of `chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of

R. Eric Davis; Vu N. Ngo; Georg Lenz; Pavel Tolar; Ryan M. Young; Paul B. Romesser; Holger Kohlhammer; Laurence Lamy; Hong Zhao; Yandan Yang; Weihong Xu; Arthur L. Shaffer; George Wright; Wenming Xiao; John Powell; Jian-Kang Jiang; Craig J. Thomas; Andreas Rosenwald; German Ott; Hans Konrad Muller-Hermelink; Randy D. Gascoyne; Joseph M. Connors; Nathalie A. Johnson; Lisa M. Rimsza; Elias Campo; Elaine S. Jaffe; Wyndham H. Wilson; Jan Delabie; Erlend B. Smeland; Richard I. Fisher; Rita M. Braziel; Raymond R. Tubbs; J. R. Cook; Dennis D. Weisenburger; Wing C. Chan; Susan K. Pierce; Louis M. Staudt

2010-01-01

272

Comparison of constitutive and inducible transcriptional enhancement mediated by kappa B-related sequences: modulation of activity in B cells by human T-cell leukemia virus type I tax gene.  

PubMed Central

The kappa B sequence (GGGACTTTCC) binds a factor, NF-kappa B, that is constitutively found in its functional, DNA binding form only in B lymphocytes. A factor with apparently indistinguishable sequence specificity can be induced in many other cell types, where it is used to regulate inducible gene expression. For example, kappa B-related sequences have been shown to be important for the transcription of a few inducible genes, such as the interleukin 2 receptor alpha-chain gene and the beta-interferon gene. However, these genes are not constitutively active in B lymphocytes, suggesting that other regulatory mechanisms must play a role in determining the patterns of expression. We have investigated the constitutive and inducible transcriptional activity mediated by five kappa B-related sequence elements in two different cell types. We show that in S194 plasma cells the activity of each element correlates well with the relative affinity of B-cell-derived NF-kappa B for that element. This leads to significantly lower transcription enhancement by sites derived from the interleukin 2 receptor or T-cell receptor genes in S194 cells. However, in either EL-4 (T) cells or S194 cells, both lower-affinity sites can be significantly induced by the tax gene product of human T-cell leukemia virus type I, showing that NF-kappa B activity can be modulated even in a B-cell line that constitutively expresses this factor.

Mauxion, F; Jamieson, C; Yoshida, M; Arai, K; Sen, R

1991-01-01

273

Bruton's tyrosine kinase regulates the activation of gene rearrangements at the lambda light chain locus in precursor B cells in the mouse  

Microsoft Academic Search

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase involved\\u000a in precursor B (pre-B) cell receptor signaling. Here we demonstrate that\\u000a Btk-deficient mice have an approximately 50% reduction in the frequency of\\u000a immunoglobulin (Ig) lambda light chain expression, already at the immature\\u000a B cell stage in the bone marrow. Conversely, transgenic mice expressing\\u000a the activated mutant Btk(E41K) showed increased lambda

G. M. Dingjan; S. Middendorp; K. Dahlenborg; A. Maas; R. W. Hendriks; F. G. Grosveld

2001-01-01

274

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

PubMed

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

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

2013-04-19

275

Restoring balance to B cells in ADA deficiency.  

PubMed

It is paradoxical that immunodeficiency disorders are associated with autoimmunity. Adenosine deaminase (ADA) deficiency, a cause of X-linked severe combined immunodeficiency (SCID), is a case in point. In this issue of the JCI, Sauer and colleagues investigate the B cell defects in ADA-deficient patients. They demonstrate that ADA patients receiving enzyme replacement therapy had B cell tolerance checkpoint defects. Remarkably, gene therapy with a retrovirus that expresses ADA resulted in the apparent correction of these defects, with normalization of peripheral B cell autoantibody frequencies. In vitro, agents that either block ADA or overexpress adenosine resulted in altered B cell receptor and TLR signaling. Collectively, these data implicate a B cell-intrinsic mechanism for alterations in B cell tolerance in the setting of partial ADA deficiency that is corrected by gene therapy. PMID:22622034

Luning Prak, Eline T

2012-05-24

276

DISSECTING TELEOST B CELL DIFFERENTIATION USING TRANSCRIPTION FACTORS  

PubMed Central

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

Zwollo, Patty

2011-01-01

277

Identification of novel Runx1 (AML1) translocation partner genes SH3D19, YTHDf2, and ZNF687 in acute myeloid leukemia.  

PubMed

Three patients diagnosed with acute myeloid leukemia (AML) with reciprocal 21q22/RUNX1(AML1) translocations involving chromosomes 1 and 4 were studied. Three novel RUNX1 translocation partner genes on 1q21.2 (ZNF687), 1p35 (YTHDF2), and 4q31.3 (SH3D19) were identified using a panhandle polymerase chain reaction and the 3' rapid amplification of cDNA ends method. The translocation events occurred between exons 3 and 7 of the RUNX1 gene. The partner gene breakpoints localized to the region in the partner gene with the highest Alu density, suggesting that Alus may contribute to the recombination events. Two out of three of the cases retained RUNX1's entire RUNT domain in the translocation, and RUNX1 mutations were absent in the fusion transcripts, confirmed by reverse transcription-polymerase chain reaction and sequencing analysis. SH3D19 encodes a cytoplasmic protein EBP known to suppress RAS-induced cellular transformation, which can be inhibited by nuclear recruitment. The t(4;21) created a hybrid RUNX1-EBP protein retaining RUNX1's DNA binding domain, which may result in nuclear localization of the chimeric protein and inhibition of EBP's RAS-suppressive functions. Future studies would be useful to further characterize these novel fusion protein products. PMID:16858696

Nguyen, TuDung T; Ma, Lisa N; Slovak, Marilyn L; Bangs, Charles D; Cherry, Athena M; Arber, Daniel A

2006-10-01

278

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

Microsoft Academic Search

BACKGROUND: 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 in various chromosome abnormalities found in cancer. However, there has been no comprehensive and quantitative examination of the location of fragile sites in relation to all chromosomal aberrations.

Allison A Burrow; Laura E Williams; Yuh-Hwa Wang

2009-01-01

279

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...

280

Pediatric renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion.  

PubMed

Renal cell carcinoma (RCC) in children and young adults is rare and pathologically problematic. RCC can be either hereditary or sporadic and has a guarded prognosis because appropriate management has not been established. A case of RCC in an 11-year-old is reported. The clinical presentation was a right abdominal mass, hematuria, urinary tract infection, and wasting. Radio-logically, the mass was found within the right kidney with calcification and paraaortic lymphadenopathy. The postsurgical diagnosis was Wilms' tumor stage T4N2M0. On gross inspection, the tumor was ill defined, extending across Gerota's fascia and into the ureter lumina. Microscopically, the tumor consisted of malignant epithelial cells with clear and eosinophilic cytoplasm in nested, papillary, and alveolar configuration. Hyaline nodules, psammoma bodies, vascular invasion, capsular invasion, and extension into the ureter were also found. Immunohistochemically, the cells showed strong nuclear immunoreactivity for TFE3. We concluded that this case was an RCC associated with Xp11.2 translocation/TFE3 fusion, Fuhrman grade 3, stage IV. PMID:18203790

Winarti, Ni Wayan; Argani, Pedram; De Marzo, Angelo M; Hicks, Jessica; Mulyadi, Ketut

2008-01-01

281

Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain.  

PubMed

In the brain, the expression of 5-lipoxygenase (5-LO), the enzyme responsible for the synthesis of inflammatory leukotrienes, increases during aging. Antiinflammatory drugs are currently being evaluated for the treatment of aging-associated neurodegenerative diseases such as Alzheimer's disease. Although generally considered antiinflammatory, glucocorticoids, whose production also increases during aging, are not particularly effective in this disease. In human monocytes, 5-LO mRNA content increases on exposure to the synthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids might increase 5-LO expression in the brain as well. We treated rats for 10 days either with corticosterone (implanted subcutaneously) or with dexamethasone (injected daily); they were killed on day 10 after pellet implantation or 24 h after the 10th dexamethasone injection. We found increased levels of 5-LO mRNA and protein in hippocampus and cerebellum of glucocorticoid-treated rats; 5-LO-activating protein (FLAP) mRNA content was not affected. Using western immunobloting, we also observed the concurrent translocation of 5-LO protein from cytosol to membrane, an indication of its activation. Thus, glucocorticoid-mediated up-regulation of the neuronal 5-LO pathway may contribute to rendering an aging brain vulnerable to degeneration. PMID:10428066

Uz, T; Dwivedi, Y; Savani, P D; Impagnatiello, F; Pandey, G; Manev, H

1999-08-01

282

Disruption of the SCL gene by a t(1;3) translocation in a patient with T cell acute lymphoblastic leukemia  

PubMed Central

SCL gene disruptions are the most common chromosomal abnormality associated with the development of T cell acute lymphoblastic leukemia (ALL). Such disruptions can be the result of t(1;14) and t(1;7) translocations, as well as a cytogenetically undetectable interstitial deletion of chromosome 1. We present here a case of T cell ALL with a t(1;3)(p34;p21) translocation that also disrupts the SCL locus and leads to dysregulated SCL gene expression. This translocation, similar to previously reported SCL gene disruptions, appears to have been mediated, at least in part, by the V(D)J recombinase complex, since cryptic heptamer recognition sequences, as well as nontemplated N region nucleotide addition, are present at the breakpoints. The t(1;3) also disrupts a region on chromosome 3 characterized by alternating purine and pyrimidine residues, which can form a Z-DNA structure, reported to be prone to recombination events. A previously undescribed, evolutionarily conserved transcript unit is detected within 8 kb of the breakpoint on chromosome 3. This report extends the spectrum of recognized SCL translocations associated with T cell ALL, and underscores the contention that dysregulated SCL expression may be a causal event in T cell ALL.

1992-01-01

283

Germinal center B-cells.  

PubMed

Within the B-cell follicle of secondary lymphoid organs, germinal center (GC) reactions produce high affinity antibody-secreting plasma cells (PCs) and memory B-cells necessary for the host's defense against invading pathogens. This process of GC formation is reliant on the activation of antigen-specific B-cells by T-cells capable of recognizing epitopes of the same antigenic complex. The unique architecture of secondary lymphoid organs facilitates these initial GC events through the placement of large clonally-diverse B-cell follicles near equally diverse T-cell zones. Antigen-activated B-cells that receive proper differentiation signals at the T-cell border of the B-cell follicle initiate an early GC B-cell transcriptional profile and migrate to follicular dendritic cell (FDC) networks within the B-cell follicle to seed the GC reaction. Peripheral to FDCs, GC B-cells rapidly divide in dark zones of the GC, and undergo somatic hypermutation of their immunoglobulin (Ig) variable domain. Newly formed GC B-cell clones then migrate into the GC light zone where they compete for antigen and secondary signals presented by FDCs and a specialized subset of CD4(+) T-cells known as T-follicular helper (T(FH)) cells. Survival, proliferative and differentiation signals delivered by mature FDCs and T(FH) cells initiate transcriptional programs that determine if GC B-cells become memory B-cells or terminally differentiated PCs. To prevent oncogenic transformation and/or the escape of autoreactive clones, there are several regulatory mechanisms that restrict GC B-cell proliferation and survival. Here we will detail the recent advances in GC B-cell biology that relate to their generation and fate-determination as well as their pathogenic potential. PMID:22390182

Hamel, Keith M; Liarski, Vladimir M; Clark, Marcus R

2012-04-02

284

B Cell Tolerance—How to Make It and How to Break It  

Microsoft Academic Search

A series of checkpoints for antigen receptor fitness and specificity during B cell development ensures the elimination or\\u000a anergy of primary, high-avidity — autoantigen-reactive B cells. Defects in genes encoding molecules with which this purging\\u000a of the original B cell repertoires is achieved may break this B cell tolerance, allowing the development of B cell- and autoantibody-mediated\\u000a immune diseases. Furthermore,

F. Melchers; A. R. Rolink

285

A Case of Anaplastic Lymphoma Kinase-Positive Large B-Cell Lymphoma: Aspiration Cytology Findings.  

PubMed

Anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma (LBCL) is a rare subtype of non-Hodgkin B-cell lymphoma that exhibits a more aggressive clinical course and poorer prognosis than the typical diffuse large B-cell lymphoma. In this study, we report the case of a 67-year-old man with left cervical lymph node swelling. Aspiration cytology revealed many clusters of cohesive, large, and solitary cells. The tumor cells had abundant cytoplasm and large round-to-oval nuclei with prominent nucleoli. The Giemsa staining specimens exhibited amorphous global bodies adjacent to some clusters. Histologically, large tumor cells occupied the lymph nodes in a sinusoidal pattern, and immunohistochemically, these cells were cytokeratin-, CD19(-) , CD20(-) , CD79a(-) , CD3(-) , CD30(-) , CD138(+) , IgG(-) , IgA(+) , and ALK(+) . Chromogenic in situ hybridization revealed restricted immunoglobulin light-chain expression. Fluorescent in situ hybridization demonstrated translocation of the ALK gene. The tumor cells were negative for Epstein-Barr virus and human herpesvirus 8. It is important to differentiate ALK+LBCL from metastatic carcinoma and other lymphoma subtypes with similar histological features to ensure a proper treatment strategy and prediction of prognosis. Diagn. Cytopathol. 2013;. © 2013 Wiley Periodicals, Inc. PMID:23457005

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

2013-03-01

286

Heterozygous Submicroscopic Inversions Involving Olfactory Receptor-Gene Clusters Mediate the Recurrent t(4;8)(p16;p23) Translocation  

PubMed Central

The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)–gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.

Giglio, Sabrina; Calvari, Vladimiro; Gregato, Giuliana; Gimelli, Giorgio; Camanini, Silvia; Giorda, Roberto; Ragusa, Angela; Guerneri, Silvana; Selicorni, Angelo; Stumm, Marcus; Tonnies, Holger; Ventura, Mario; Zollino, Marcella; Neri, Giovanni; Barber, John; Wieczorek, Dagmar; Rocchi, Mariano; Zuffardi, Orsetta

2002-01-01

287

MLL Translocations Specify a Distinct Gene Expression Profile, Distinguishing a Unique Leukemia.  

National Technical Information Service (NTIS)

The present invention relates to the diagnosis of mixed lineage leukemia (MLL), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML) according to the gene expression profile of a sample from an individual, as well as to methods of ther...

S. A. Armstrong S. J. Korsmeyer T. R. Golub

2005-01-01

288

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.

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

2013-01-01

289

Expression pattern of a nuclear encoded mitochondrial arginine-ornithine translocator gene from Arabidopsis  

PubMed Central

Background Arginine and citrulline serve as nitrogen storage forms, but are also involved in biosynthetic and catabolic pathways. Metabolism of arginine, citrulline and ornithine is distributed between mitochondria and cytosol. For the shuttle of intermediates between cytosol and mitochondria transporters present on the inner mitochondrial membrane are required. Yeast contains a mitochondrial translocator for ornithine and arginine, Ort1p/Arg11p. Ort1p/Arg11p is a member of the mitochondrial carrier family (MCF) essential for ornithine export from mitochondria. The yeast arg11 mutant, which is deficient in Ort1p/Arg11p grows poorly on media lacking arginine. Results High-level expression of a nuclear encoded Arabidopsis thaliana homolog (AtmBAC2) of Ort1p/Arg11p was able to suppress the growth deficiency of arg11. RT-PCR analysis demonstrated expression of AtmBAC2 in all tissues with highest levels in flowers. Promoter-GUS fusions showed preferential expression in flowers, i.e. pollen, in the vasculature of siliques and in aborted seeds. Variable expression was observed in leaf vasculature. Induction of the promoter was not observed during the first two weeks in seedlings grown on media containing NH4NO3, arginine or ornithine as sole nitrogen sources. Conclusion AtmBAC2 was isolated as a mitochondrial transporter for arginine in Arabidopsis. The absence of expression in developing seeds and in cotyledons of seedlings indicates that other transporters are responsible for storage and mobilization of arginine in seeds.

Catoni, Elisabetta; Desimone, Marcelo; Hilpert, Melanie; Wipf, Daniel; Kunze, Reinhard; Schneider, Anja; Flugge, Ulf-Ingo; Schumacher, Karin; Frommer, Wolf B

2003-01-01

290

From Gene Amplification to V(D)J Recombination and Back: a Personal Account of My Early Years in B Cell Biology  

PubMed Central

Summary I have been invited to write a short historical review in the context of being a co-recipient with Klaus Rajewsky and Fritz Melchers of the 2007 Novartis Prize in Basic Immunology that was given in the general area of the molecular biology of B cells. In this review, I cover the main points of the short talk that I presented at the Award Ceremony at the International Immunology Congress in Rio de Janeiro, Brazil. This talk focused primarily on the work and people involved early on in generating the models and ideas that have formed the basis for my ongoing efforts in the areas of V(D)J recombination and B cell Development.

Alt, Frederick W.

2008-01-01

291

Interleukin-21 regulates expression of the immediate-early lytic cycle genes and proteins in Epstein-Barr Virus infected B cells.  

PubMed

The switch between the latent and the lytic cycle of Epstein-Barr Virus (EBV) infection is characterized by the induction of viral transcriptional activators Zta and Rta. CD4(+) T cell-derived cytokines are likely to regulate expression of these proteins in EBV-infected B cells. Here we show that interleukin-21 decreases constitutive expression of Rta and its target EA-D in EBV-infected B cell lines during the first 3 days of culture. In some cell lines this is followed by a strong increase in the expression of Zta, Rta, and EA-D during prolonged culture. Additionally, we provide evidence that IL-21-mediated JAK/STAT signals regulate increase in the Zta expression. PMID:19447148

Konforte, Danijela; Paige, Christopher J

2009-05-15

292

From gene amplification to V(D)J recombination and back: a personal account of my early years in B cell biology.  

PubMed

I have been invited to write a short historical feature in the context of being a co-recipient with Klaus Rajewsky and Fritz Melchers of the 2007 Novartis Prize in Basic Immunology that was given in the general area of the molecular biology of B cells. In this feature, I cover the main points of the short talk that I presented at the Award Ceremony at the International Immunology Congress in Rio de Janeiro, Brazil. This talk focused primarily on the work and people involved early on in generating the models and ideas that have formed the basis for my ongoing efforts in the areas of V(D)J recombination and B cell development. PMID:17972338

Alt, Frederick W

2007-11-01

293

The molecular biology of diffuse large B-cell lymphoma  

PubMed Central

Diffuse large B-cell lymphoma (DLBCL) represents the most common type of malignant lymphoma. In the last few years, significant progress has been achieved in the understanding of the molecular pathogenesis of this entity. Gene expression profiling has identified three molecular DLBCL subtypes, termed germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). In this review, we summarize our current understanding of the biology of these DLBCL subtypes with a special emphasis on novel diagnostic and therapeutic approaches.

Frick, Mareike; Dorken, Bernd

2011-01-01

294

FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma  

Microsoft Academic Search

The precise mechanism of rituximab plus cyclophosphamide\\/doxorubicin\\/vincris- tine\\/prednisone (R-CHOP) therapy in dif- fuse large B-cell lymphoma (DLBCL) is not fully elucidated. Besides overcoming bcl-2-mediated chemoresistance, anti- body-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) frag- ment C receptors (FcRs), was also pro- posed as a mechanism of rituximab. The current study evaluated the impact

Dong Hwan Kim; Hee Du Jung; Jong Gwang Kim; Je-Jung Lee; Deok-Hwan Yang; Yeon Hee Park; Ho Jin Shin; Min Kyoung Kim; Myung Soo Hyun; Sang Kyun Sohn

295

Molecular cloning, genomic organization and expression analysis of the gene encoding bovine ( Bos taurus) B-cell activating factor belonging to the TNF family (BAFF)  

Microsoft Academic Search

A novel bovine cDNA has been isolated by EST assembly and subsequently confirmed by using RT-PCR and designated bovine B-cell activating factor belonging to TNF family (bBAFF). The open reading frame (ORF) of this cDNA covers 843 bp, encoding 280 amino acids. The functional soluble part of bBAFF (bsBAFF) shows 96% and 91% identity with its pig and human counterparts, respectively,

Zheng-Bing Guan; Yan Shui; Jia-Xin Zhang; Shuang-Quan Zhang

2008-01-01

296

Differential programming of B cells in AID deficient mice.  

PubMed

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

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

2013-07-29

297

Burkitt lymphoma cell line carrying a variant translocation creates new DNA at the breakpoint and violates the hierarchy of immunoglobulin gene rearrangement.  

PubMed Central

The Burkitt lymphoma cell line KK124, which contains a reciprocal t(8;22) translocation, was shown to have rearranged in a region 3' to the c-myc proto-oncogene on chromosome 8 and 5' to the lambda constant region on chromosome 22. The breakpoint was cloned and sequenced, revealing that c-myc and a portion of its 3' region abutted a complete lambda variable gene that had undergone V-J recombination. Since this cell line expresses kappa light chain, this lambda rearrangement violates the previously proposed hierarchy of immunoglobulin gene rearrangement. A novel duplication of normal chromosome 8 sequences was also found at the breakpoint. The first exon of c-myc and its flanking sequence from the translocated allele was sequenced and compared with a normal counterpart. Extensive mutation was found within the first exon in contrast to its 3' and 5' flanking regions. S1 nuclease analysis revealed that it was the translocated c-myc being expressed and that there was a promoter shift from P2 to P1. The detailed structural analysis of this cell line provides clues concerning mechanisms of chromosomal translocation and c-myc deregulation in Burkitt lymphomas. Images

Denny, C T; Hollis, G F; Magrath, I T; Kirsch, I R

1985-01-01

298

Translocal spatiality  

Microsoft Academic Search

•Instead of exploring the global\\/local logic of glocalization, this case study specifically concentrates on a form of local-to-local spatial dynamics. The spatial history of Hong Kong underground bandrooms is exploited to illustrate the translocal reproduction of spatiality. While the construction of this space was translocally inspired by music subculture from abroad, local spatiality absorbs transborder subcultural energies and re-channels them

Eric Kit-wai Ma

2002-01-01

299

Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells.  

PubMed

Mixed Lineage Leukemia (MLL1) translocations encode fusion proteins retaining the N terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis and thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs); therefore, disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B cells, menin- or MLL1-regulated genes can be classified into 3 categories: (1) a relatively small group of coregulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of (2) exclusively menin-regulated and (3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these 2 proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1-disrupting drugs as safe and selective leukemia targeting agents. PMID:23908472

Li, Bin E; Gan, Tao; Meyerson, Matthew; Rabbitts, Terence H; Ernst, Patricia

2013-08-01

300

B-cell selection and the development of autoantibodies  

PubMed Central

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

2012-01-01

301

In Vivo Rescue of a Silent tax-Deficient Bovine Leukemia Virus from a Tumor-Derived Ovine B-Cell Line by Recombination with a Retrovirally Transduced Wild-Type tax Gene  

PubMed Central

The lack of bovine leukemia virus (BLV) expression is a consistent finding in freshly isolated ovine tumor cells and in the B-cell lines derived from these tumors. In order to gain further insight into the mechanisms of BLV silencing in these tumors, we have used the YR2 B-cell line, which was derived from the leukemic cells of a BLV-infected sheep. This cell line contains a single, monoclonally integrated, silent provirus, which cannot be reactivated either by stimulation in vitro or by in vivo injection of the tumor cells or cloned proviral DNA in sheep. Sequence analysis of the tax gene from the YR2 cell line identified two G-to-A transitions (G7924 to A7924 and G8149 to A8149) that result in E-to-K amino acid changes at positions 228 and 303 in the Tax protein. Following retroviral vector-mediated transfer of a wild-type tax gene into YR2 cells, we showed that BLV mRNA, viral proteins, and virions were produced, demonstrating that the cellular factors required for virus expression were present in the original YR2 cell line. Injection of this transduced YR2 cell line in sheep led to the rescue of replication-competent BLV proviruses. The integrated competent proviruses exhibited unique chimeric tax genes, which arose from homologous recombination between the transduced wild-type tax and the YR2-derived tax sequences. Furthermore, in one of these functional recombinant proviruses, only the A8149-to-G8149 reversion was present, providing clear evidence that the defect underlying the silent phenotype in YR2 cells results from a single C-terminal E303-to-K303 amino acid substitution in the BLV Tax protein. Our observations suggest that a single strategically located mutation in tax provides a mechanism for BLV inactivation in B-cell tumors.

Van Den Broeke, Anne; Bagnis, Claude; Ciesiolka, Malgorzata; Cleuter, Yvette; Gelderblom, Hans; Kerkhofs, Pierre; Griebel, Philip; Mannoni, Patrice; Burny, Arsene

1999-01-01

302

Yeast genome analysis identifies chromosomal translocation, gene conversion events and several sites of Ty element insertion  

PubMed Central

Paired end mapping of chromosomal fragments has been used in human cells to identify numerous structural variations in chromosomes of individuals and of cancer cell lines; however, the molecular, biological and bioinformatics methods for this technology are still in development. Here, we present a parallel bioinformatics approach to analyze chromosomal paired-end tag (ChromPET) sequence data and demonstrate its application in identifying gene rearrangements in the model organism Saccharomyces cerevisiae. We detected several expected events, including a chromosomal rearrangement of the nonessential arm of chromosome V induced by selective pressure, rearrangements introduced during strain construction and gene conversion at the MAT locus. In addition, we discovered several unannotated Ty element insertions that are present in the reference yeast strain, but not in the reference genome sequence, suggesting a few revisions are necessary in the latter. These data demonstrate that application of the chromPET technique to a genetically tractable organism like yeast provides an easy screen for studying the mechanisms of chromosomal rearrangements during the propagation of a species.

Shibata, Yoshiyuki; Malhotra, Ankit; Bekiranov, Stefan; Dutta, Anindya

2009-01-01

303

A translocation associated, loss-of-function mutation in the nitrogen metabolite repression regulatory gene of Aspergillus nidulans can revert intracistronically  

Microsoft Academic Search

The areAr-18 mutation is a loss-of-function mutation in areA, the positive acting regulatory gene mediating nitrogen metabolite repression in Aspergillus nidulans. It results from a reciprocal translocation which splits the coding region into 5' and 3' moieties. Surprisingly, we have selected rare intracistronic revertants of areAr-18. From crosses heterozygous for areAr-18 revertant alleles, duplication-deficiency progeny containing two copies of a

Herbert N. Arst; David Tollervey; Mark X. Caddick

1989-01-01

304

Diagnostic pitfall on the histological spectrum of adult-onset renal carcinoma associated with Xp11.2 translocations\\/ TFE3 gene fusions  

Microsoft Academic Search

Renal cell carcinoma (RCC) associated with Xp11.2 translocation\\/TFE3 gene fusion recently has been found. In this article, we demonstrate an unusual features of such a case. A 73-year-old Japanese\\u000a woman presented with macroscopic hematuria. The imaging examinations disclosed the renal tumor. Histological examination showed\\u000a the finding of ASPL-TFE3 RCC, which was characterized by papillary, alveolar, or solid growth of voluminous

Naoto Kuroda; Kazunobu Katto; Yukichi Tanaka; Tadanori Yamaguchi; Kaori Inoue; Masahiko Ohara; Keiko Mizuno; Ondrej Hes; Michal Michal; Gang-Hong Lee

2010-01-01

305

Cloning of a new familial t(3;8) translocation associated with conventional renal cell carcinoma reveals a 5 kb microdeletion and no gene involved in the rearrangement  

Microsoft Academic Search

This study describes the molecular cloning of a familial translocation, t(3;8)(p14.2;q24.2), that segregates with the conventional renal cell carcinoma (conventional RCC). We had previously reported the family history and, through loss of heterozigosity and comparative genomic hybridization, detected the loss of the 3p chromosome arm and somatic mutation in the retained von Hippel-Lindau gene in some members of the family.

Sandra Rodriguez-Perales; Susan M. Gribble; Laura Valle; Nigel P. Carter; Lucia Conde; Miguel Urioste; Javier Benitez; Juan C. Cigudosa

2004-01-01

306

Adult-onset renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusion with smooth muscle stroma and abnormal vessels.  

PubMed

Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion has been recently identified. Herein is presented a case of RCC with Xp11.2 translocations/TFE3 gene fusions with unusual histological findings. A 68-year-old Japanese woman was incidentally found to have a renal mass on CT. Histological examination showed clear cell neoplasm with alveolar and papillary growth patterns. The nuclear atypia corresponded to Fuhrman grade 3. Additionally, smooth muscle stroma was observed and abnormal vessels showing a heterogeniety in thickness were also identified. On immunohistochemistry, neoplastic cells were diffusely positive for transcription factor E3 (TFE3) and Melan A, and focally positive for CD10 and RCC marker. The smooth muscle stroma was positive for alpha-smooth muscle actin and h-caldesmon, but reverse transcription-polymerase chain reaction of the tumor using frozen material could not detect any previously reported chimeric transcripts including ASPL-TFE3, PRCC-TFE3, CLTC-TFE3, PSF-TFE3 or NoNo-TFE3. G-band karyotype was unsuccessful. Pathologists should pay attention to the afore-described unusual stromal reaction of adult-onset RCC associated with Xp11.2 translocations/TFE3 gene fusions. PMID:19563413

Kuroda, Naoto; Tamura, Masato; Tanaka, Yukichi; Hes, Ondrej; Michal, Michal; Inoue, Kaori; Ohara, Masahiko; Mizuno, Keiko; Lee, Gang-Hong

2009-07-01

307

Diagnostic pitfall on the histological spectrum of adult-onset renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.  

PubMed

Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion recently has been found. In this article, we demonstrate an unusual features of such a case. A 73-year-old Japanese woman presented with macroscopic hematuria. The imaging examinations disclosed the renal tumor. Histological examination showed the finding of ASPL-TFE3 RCC, which was characterized by papillary, alveolar, or solid growth of voluminous cell with clear and eosinophilic cells, and stromal psammoma body and hyaline nodules. Additionally, shrunken nuclei, thick cell border, and perinuclear clearing characteristic of chromophobe renal cell carcinoma were observed in the alveolar growth area and the transitional zone between stromal hyalinization, and osseous metaplasia was identified. Immunohistochemically, nuclei of tumorous cell were diffusely positive for TFE3. A RT-PCR study revealed the ASPL-TFE3 chimeric transcript. Finally, pathologists should recognize that the histology of RCC associated with Xp11.2 translocation/TFE3 gene fusion may focally resemble that of chromophobe RCC, but TFE3 immunohistochemistry and molecular genetic study may be helpful in the differential diagnosis. Moreover, osseous metaplasia as well as psammoma bodies should be added to the histological spectrum of the stromal change in RCC associated with Xp11.2 translocations/TFE3 gene fusions. PMID:20683695

Kuroda, Naoto; Katto, Kazunobu; Tanaka, Yukichi; Yamaguchi, Tadanori; Inoue, Kaori; Ohara, Masahiko; Mizuno, Keiko; Hes, Ondrej; Michal, Michal; Lee, Gang-Hong

2010-08-04

308

Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice.  

PubMed

On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-?B activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK. PMID:22383797

Kil, Laurens P; de Bruijn, Marjolein J W; van Nimwegen, Menno; Corneth, Odilia B J; van Hamburg, Jan Piet; Dingjan, Gemma M; Thaiss, Friedrich; Rimmelzwaan, Guus F; Elewaut, Dirk; Delsing, Dianne; van Loo, Pieter Fokko; Hendriks, Rudi W

2012-03-01

309

Anaplastic Lymphoma Kinase-Positive Large B-Cell Lymphoma: An Underrecognized Aggressive Lymphoma  

PubMed Central

Anaplastic lymphoma kinase-(ALK-) positive large B-cell lymphoma (ALK+ LBCL) is a rare, aggressive tumor characterized by an immunoblastic or plasmablastic morphologic appearance, expression of ALK, CD138, CD45, EMA, and often IgA by immunohistochemistry, and characteristic chromosomal translocations or rearrangements involving the ALK locus. The morphologic and immunophenotypic overlap of this tumor with other hematologic and nonhematologic malignancies may result in misdiagnosis. The tumor has been identified in both pediatric and adult populations and demonstrates a male predominance. Presentation is most often nodal, particularly cervical. No association with immunocompromise or geographic location has been recognized. The most common gene rearrangement is between clathrin and ALK (t(2;17)(p23;q23)), resulting in the CLTC-ALK chimeric protein, although other fusions have been described. Response to conventional chemotherapy is poor. The recent introduction of the small molecule ALK inhibitor, crizotinib, may provide a potential new therapeutic option for patients with this disease.

Morgan, Elizabeth A.; Nascimento, Alessandra F.

2012-01-01

310

Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression  

Microsoft Academic Search

Oxidative cellular stress initiates Nrf2 translocation into the nucleus, thus inducing antioxidant response element (ARE)-mediated expression of Phase II enzymes involved in detoxification and antioxidant defence. We investigated whether coffee extracts (CEs) of different proveniences and selected constituents have an impact on the Nrf2\\/ARE pathway in human colon carcinoma cells (HT29). Assessed as increased nuclear Nrf2 protein, Nrf2 nuclear translocation

Ute Boettler; Katharina Sommerfeld; Nadine Volz; Gudrun Pahlke; Nicole Teller; Veronika Somoza; Roman Lang; Thomas Hofmann; Doris Marko

2011-01-01

311

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

SciTech Connect

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

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

1993-08-15

312

B Cell Subsets in Atherosclerosis  

PubMed Central

Atherosclerosis, the underlying cause of heart attacks and strokes, is a chronic inflammatory disease of the artery wall. Immune cells, including lymphocytes modulate atherosclerotic lesion development through interconnected mechanisms. Elegant studies over the past decades have begun to unravel a role for B cells in atherosclerosis. Recent findings provide evidence that B cell effects on atherosclerosis may be subset-dependent. B-1a B cells have been reported to protect from atherosclerosis by secretion of natural IgM antibodies. Conventional B-2 B cells can promote atherosclerosis through less clearly defined mechanism that may involve CD4 T cells. Yet, there may be other populations of B cells within these subsets with different phenotypes altering their impact on atherosclerosis. Additionally, the role of B cell subsets in atherosclerosis may depend on their environmental niche and/or the stage of atherogenesis. This review will highlight key findings in the evolving field of B cells and atherosclerosis and touch on the potential and importance of translating these findings to human disease.

Perry, Heather M.; Bender, Timothy P.; McNamara, Coleen A.

2012-01-01

313

Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry.  

PubMed Central

Mitogen-activated protein kinase (MAPK) modules, composed of three protein kinases activated by successive phosphorylation, are involved in the signal transduction of a wide range of extracellular agents. In mammalian cells, mitogenic stimulation triggers the translocation of p42/p44MAPK from the cytoplasm to the nucleus, whereas the other protein kinases of the module remain cytosolic. Since MAPK has been shown to phosphorylate and activate nuclear targets, such as the transcription factor Elk1, it has been proposed, but not yet demonstrated, that MAPK nuclear translocation could represent a critical step in signal transduction. In this study, we sequestered p42/p44MAPK in the cytoplasm by the expression of a catalytically inactive form of cytoplasmic MAP kinase phosphatase (MKP-3/Pyst-1). Sequestering MAPK in the cytoplasm did not alter its activation or its ability to phosphorylate cytoplasmic substrates of MAPK (p90RSK1 or an engineered cytoplasmic form of Elk1). In contrast, prevention of MAPK nuclear translocation strongly inhibited Elk1-dependent gene transcription and the ability of cells to reinitiate DNA replication in response to growth factors. Thus the relocalization of MAPK to the nucleus appears to be an important regulatory step for mitogen-induced gene expression and cell cycle re-entry.

Brunet, A; Roux, D; Lenormand, P; Dowd, S; Keyse, S; Pouyssegur, J

1999-01-01

314

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

315

Smith-Lemli-Opitz syndrome in a female with a de novo, balanced translocation involving 7q32: Probable disruption of an SLOS gene  

SciTech Connect

A 3-month-old infant girl had manifestations of the Smith-Lemli-Opitz syndrome (SLOS) including typical positional anomalies of the limbs, apparent Hirschsprung disease, cataracts, ptosis, anteverted nares, cleft of the posterior palate, small tongue, broad maxillary alveolar ridges, and abnormally low serum cholesterol levels. Chromosomal analysis showed a de novo balanced translocation interpreted as 46,XX,t(7;20)(q32.1;q13.2). We hypothesize that the translocation breakpoint in this case interrupts one SLOS allele and that the other allele at the same locus has a more subtle mutation that was inherited from the other parent. This case, as well as cytogenetic observations in other SLOS cases, suggests that SLOS could be due to autosomal recessive mutation at a gene in 7q32. 33 refs., 3 figs., 1 tab.

Wallace, M.; Zori, R.T.; Alley, T.; Whidden, E.; Gray, B.A.; Williams, C.A. [Univ. of Florida College of Medicine, Gainesville, FL (United States)

1994-05-01

316

[B-cell neoplasms with plasmacellular and plasmablastic differentiation].  

PubMed

Plasma cell malignancies are tumors of terminally differentiated B-cells in which the neoplastic plasma cells are the dominant and proliferating tumor cell component. Plasma cell myeloma (PCM) is one of the most common hematological neoplasms and typically does not cause diagnostic problems. A morphologically and immunophenotypically detectable plasmacellular orplasmablastic differentiation is, however, commonly observed in a wide range of mature B-cell lymphomas. A confident separation of the distinct entities requires the integration of clinical and morphological findings as well as an adequate phenotyping of both the plasma cell and the B-cell component if present. Detection of lymphotropic viruses, specific translocations and novel molecular markers, such as the MYD88 L265P mutation occurring in the vast majority of lymphoplasmacytic lymphomas complement our diagnostic repertoire. In this review we describe the most commonly observed diagnostic problems in separating small B-cell lymphomas from PCM and high-grade B-cell non-Hodgkin lymphoma (B-NHL) with plasmablastic differentiation from extramedullary spread of aggressive PCM and provide helpful criteria for routine diagnostics. PMID:23462793

Fend, F; Quintanilla-Martínez, L

2013-05-01

317

A Unique Case of Renal Carcinoma with Xp11.2 Translocations\\/ TFE3 Gene Fusions in a 3Yearold Child, with Coexistent von Hippel-Lindau Gene Mutation  

Microsoft Academic Search

Renal cell carcinomas (RCCs) are rare in the pediatric population; when they occur, a significant percentage are associated with specific cytogenetic abnormalities and germline mutations. These include mutations in the von Hippel-Lindau ( VHL) gene and translocations involving the TFE3 transcription factor gene on Xp11.2. Here we report a case of a 3-year-old child with a large renal mass. Histologic

Mana M. Parast; Grant Eudy; Kenneth W. Gow; Mahul Amin; Bahig Shehata

2004-01-01

318

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.

2012-01-01

319

Cellular Immediate-Early Gene Expression Occurs Kinetically Upstream of Epstein-Barr Virus bzlf1 and brlf1 following Cross-Linking of the B Cell Antigen Receptor in the Akata Burkitt Lymphoma Cell Line ?  

PubMed Central

The Epstein-Barr virus (EBV) lytic activator genes bzlf1 and brlf1 are conventionally referred to as immediate-early (IE) genes. However, previous studies showed that the earliest expression of these genes was blocked by cycloheximide when the EBV lytic cycle was induced by histone deacetylase (HDAC) inhibitors and protein kinase C agonists. Anti-IgG activates a complex signal transduction pathway that leads to EBV lytic activation in the Akata cell line. Here we demonstrate that in Akata cells, where lytic cycle activation occurs very rapidly after anti-IgG treatment, de novo protein synthesis is also required for induction of bzlf1 and brlf1 expression. New protein synthesis is required up to 1.25 h after application of anti-IgG; bzlf1 and brlf1 mRNAs can be detected 1.5 h after anti-IgG. Five cellular IE genes were shown to be expressed by 1 h after addition of anti-IgG, and their expression preceded that of bzlf1 and brlf1. These include early growth response genes (egr1, egr2, and egr3) and nuclear orphan receptors (nr4a1 and nr4a3). These genes were activated by anti-IgG treatment of Akata cells with and without the EBV genome; therefore, their expression was not dependent on expression of any EBV gene product. EGR1, EGR2, and EGR3 proteins were kinetically upstream of ZEBRA and Rta proteins. Expression of EGR1, ZEBRA, and Rta proteins were inhibited by bisindolylmaleimide X, a selective inhibitor of PKC. The findings suggest a revised model in which the signal transduction cascade activated by cross-linking of the B cell receptor induces expression of cellular IE genes, such as early growth response and nuclear orphan receptor genes, whose products, in turn, regulate bzlf1 and brlf1 expression.

Ye, Jianjiang; Gradoville, Lyndle; Miller, George

2010-01-01

320

In vitro Induction of Myeloid Leukemia-Specific CD4 and CD8 T Cells by CD40 Ligand-Activated B Cells Gene Modified to Express Primary Granule Proteins  

PubMed Central

The primary granule proteins (PGP) of myeloid cells are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. Therefore, we developed a method to induce T-cell responses to PGP protein sequences. We found that gene-transfected antigen-presenting cells efficiently expand functionally competent PGP-specific CD4 and CD8 T cells. The system was optimized using T-cell responses to autologous CD40-activated B cells (CD40-B) transfected with a cytomegalovirus pp65-encoding expression vector. To generate leukemia-specific T cells, expression vectors encoding the PGP proteinase 3 (PR3) human neutrophil elastase, and cathepsin-G were transfected into CD40-B cells to stimulate postallogeneic stem cell transplantation T cells from five patients with myeloid and three with lymphoid leukemias. T-cell responses to PGP proteinase 3 and human neutrophil elastase were observed in CD8+ and CD4+ T cells only in patients with myeloid leukemias. T-cell responses against cathepsin-G occurred in both myeloid and lymphoblastic leukemias. T cells from a patient with chronic myelogenous leukemia (CML) and from a posttransplant CML patient, expanded against PGP, produced IFN-? or were cytotoxic to the patient's CML cells, demonstrating specific antileukemic efficacy. This study emphasizes the clinical potential of PGP for expansion and adoptive transfer of polyclonal leukemia antigen-specific T cells to treat leukemia.

Fujiwara, Hiroshi; Melenhorst, J. Joseph; El Ouriaghli, Frank; Kajigaya, Sachiko; Grube, Matthias; Sconocchia, Giuseppe; Rezvani, Katayoun; Price, David A.; Hensel, Nancy F.; Douek, Daniel C.; Barrett, A. John

2008-01-01

321

The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity  

Microsoft Academic Search

The chemokine receptor CXCR4 is expressed in B cells at multiple stages of their development. CXCR4 function in humoral immunity has not been fully investigated. We have generated gene-targeted mice in which CXCR4 can be selectively inactivated in B cells and have shown that it is required for retention of B cell precursors in the bone marrow. CXCR4-deficient B cell

Yuchun Nie; Janelle Waite; Faraha Brewer; Mary-Jean Sunshine; Dan R. Littman; Yong-Rui Zou

322

Essential role of EBF1 in the generation and function of distinct mature B cell types  

PubMed Central

The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro–B cell development, and subsequent transition to the pre–B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity.

Vilagos, Bojan; Hoffmann, Mareike; Souabni, Abdallah; Sun, Qiong; Werner, Barbara; Medvedovic, Jasna; Bilic, Ivan; Minnich, Martina; Axelsson, Elin; Jaritz, Markus

2012-01-01

323

Cytoplasmic H2O2 prevents translocation of NPR1 to the nucleus and inhibits the induction of PR genes in Arabidopsis  

PubMed Central

Plants activate a number of defense reactions in response to pathogen attack. One of the major pathways involves biosynthesis of Salicylic acid (SA), which acts as a signaling molecule that regulates local defense reaction at the infection site and in induction of systemic acquired resistance (SAR). SA is sensed and transduced by NPR1 protein, which is a redox sensitive protein that acts as a central transcription activator of many pathogenesis related and defense related genes. In its uninduced state NPR1 exists as an oligomer in the cytoplasm. Following pathogen attack and SAR induction, cells undergo a biphasic change in cellular redox, resulting in reduction of NPR1 to a monomeric form, which moves to the nucleus. Recently, it was shown that pathogen attack or SA treatment cause S-nitrosylation of NPR1, promoting NPR1 oligomerization and restricting it in the cytoplasm. We used A. thaliana mutants in cytosolic ASCORBATE PEROXIDASE, apx1 and plants expressing antisense CATALASE gene, as well as the CATALASE inhibitor 3-amino-1,2,4-triazole, to examine the effect of H2O2 on the pathogen-triggered translocation of the NPR1 to the nucleus. Our results show that the pathogen-triggered or SA-induced nuclear translocation is prevented by accumulation of H2O2 in the cytosol. Moreover, we show that increased accumulation of cytoplasmic ROS in apx1 mutants reduced the NPR1-dependent gene expression. We suggest that H2O2 has a signaling role in pathogenesis, acting as a negative regulator of NPR1 translocation to the nucleus, limiting the NPR1-dependent gene expression.

Peleg-Grossman, Smadar; Melamed-Book, Naomi; Cohen, Gil

2010-01-01

324

Generation of immunoglobulin light chain gene diversity in Raja erinacea is not associated with somatic rearrangement, an exception to a central paradigm of B cell immunity  

PubMed Central

In all vertebrate species examined to date, rearrangement and somatic modification of gene segmental elements that encode portions of the antigen-combining sites of immunoglobulins are integral components of the generation of antibody diversity. In the phylogenetically primitive cartilaginous fishes, gene segments encoding immunoglobulin heavy and light chain loci are arranged in multiple clusters, in which segmental elements are separated by only 300-400 bp. In some cases, segmental elements are joined in the germline of nonlymphoid cells (joined genes). Both genomic library screening and direct amplification of genomic DNA have been used to characterize at least 89 different type I light chain gene clusters in the skate, Raja. Analyses of predicted nucleotide sequences and predicted peptide structures are consistent with the distribution of genes into different sequence groups. Predicted amino acid sequence differences are preferentially distributed in complementarity-determining versus framework regions, and replacement-type substitutions exceed neutral substitutions. When specific germline sequences are related to the sequences of individual cDNAs, it is apparent that the joined genes are expressed and are potentially somatically mutated. No evidence was found for the presence of any type I light chain gene in Raja that is not germline joined. The type I light chain gene clusters in Raja appear to represent a novel gene system in which combinatorial and junctional diversity are absent.

1995-01-01

325

The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.  

PubMed

Retinoic acid is a vitamin A derivative with striking effects on development and cell differentiation. Several nuclear retinoic acid receptors (RARs), acting as ligand-inducible transcription factors, have been characterized and indirect evidence suggests that they have distinct roles. One of the most intriguing properties of retinoic acid is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. Because the RAR alpha gene maps to chromosome 17q21 (ref. 14), close to the t(15;17) (q21-q11-22) translocation specifically associated with APL, we analysed RAR alpha gene structure and expression in APL cells. We report here that, in one APL-derived cell line, the RAR alpha gene has been translocated to a locus, myl, on chromosome 15, resulting in the synthesis of a myl/RAR alpha fusion messenger RNA. Using two probes located on either side of the cloned breakpoint, we have found genomic rearrangements of one or other locus in six patients out of eight, demonstrating that the RAR alpha and/or myl genes are frequently rearranged in APL and the breakpoints are clustered. These findings strongly implicate retinoic acid receptor alpha in leukaemogenesis. PMID:2170850

de Thé, H; Chomienne, C; Lanotte, M; Degos, L; Dejean, A

1990-10-11

326

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

PubMed

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 apparently simple 1q41;3q27.1 translocation was actually combined with a 4-Mb inversion, also de novo, of material within 1q41. We therefore localized all four breakpoints and found that no known transcription units were disrupted. However we present a case, based on functional considerations, synteny and position of highly conserved non-coding sequence elements, and the heterozygous Prox1(+/-) mouse phenotype (ventricular hypoplasia), for the involvement of dysregulation of the PROX1 gene in the aetiology of HLH in this case. Accordingly, we show that the spatial expression pattern of PROX1 in the developing human heart is consistent with a role in cardiac development. We suggest that dysregulation of PROX1 gene expression due to separation from its conserved upstream elements is likely to have caused the heart defects observed in this patient, and that PROX1 should be considered as a potential candidate gene for other cases of HLH. The relevance of another breakpoint separating the cardiac gene ESRRG from a conserved downstream element is also discussed. PMID:19471316

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

2009-05-27

327

B-cell memory and the persistence of antibody responses.  

PubMed Central

Antigens such as viral envelope proteins and bacterial exotoxins induce responses which result in the production of neutralizing antibody. These responses persist for years and provide highly efficient defence against reinfection. During these antibody responses a proportion of participating B cells mutate the genes that encode their immunoglobulin variable regions. This can increase the affinity of the antibody, but can also induce autoreactive B cells. Selection mechanisms operate which allow the cells with high affinity for the provoking antigen to persist, while other B cells recruited into the response die.

MacLennan, I C; Garcia de Vinuesa, C; Casamayor-Palleja, M

2000-01-01

328

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

PubMed Central

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

2012-01-01

329

Ewing sarcoma arising after treatment of diffuse large B-cell lymphoma.  

PubMed

We report the case of a patient in whom the diagnosis of Ewing sarcoma arising from a soft tissue was made after successful treatment of diffuse large B-cell lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left scapular region 8 years after successful chemotherapy with the cyclophosphamide, hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse large B-cell lymphoma. Computed tomographic examination and magnetic resonance imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size in the left scapular region. Histopathological examination of an open biopsy specimen revealed a small round cell tumour that showed positive staining for CD99. Fluorescence in situ hybridization showed a split signal by a break-apart probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on these findings, the patient was diagnosed as having secondary Ewing sarcoma. Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years after the diagnosis of Ewing sarcoma. Therapy-related haematological malignancies with balanced translocations have been reported previously. A mechanism similar to that underlying the development of secondary malignancy might explain the occurrence of this solid cancer. PMID:23475435

Hiramoto, Nobuhiro; Kobayashi, Yukio; Nomoto, Junko; Maruyama, Dai; Watanabe, Takashi; Tochigi, Naobumi; Furuta, Koh; Takeda, Ken; Chuman, Hirokazu; Yagyu, Shigeki; Hosoi, Hajime; Tobinai, Kensei

2013-03-08

330

Structure of the human receptor tyrosine phosphatase gamma gene (PTPRG) and relation to the familial RCC t(3;8) chromosome translocation  

SciTech Connect

The receptor protein tyrosine phosphatase {gamma} gene, PTP{gamma} (locus name PTPRG), was previously mapped to chromosome region 3p14.2, within a 2- to 4-Mb region centromeric to the 3p14.2 breakpoint of the t(3;8) familial renal cell carcinoma (RCC)-associated constitutional chromosome translocation. Because of its chromosomal position, its enzymatic properties as a receptor phosphatase, which might oppose a growth activating kinase activity, its homozygous deletion in murine L cells, and its transcriptional activity in numerous normal tissues, including kidney, the PTP{gamma} gene was an attractive tumor suppressor gene candidate for renal cell carcinoma. To determine whether the PTP{gamma} gene was a target of loss of heterozygosity or mutation in RCCs and to determine its map position relative to the t(3;8) break at 3p14.2, we have isolated YAC and {lambda} genomic clones for the PTP{gamma} gene and other 3p14.2 markers and determined the relative positions of the t(3;8) break, a 3p14.2 de novo break possibly in a fragile site, and the 5{prime} end of the PTP{gamma} gene. Additionally, the genomic structure, position of the proximal promotor, and intron-exon border sequences of the 30-exon {approximately} 780-kb PTP{gamma} gene have been determined, which will facilitate analysis of the PTP{gamma} gene in tumors. 49 refs., 3 figs., 3 tabs.

Kastury, K.; Ohta, M.; Druck, T.; Huebner, K. [Jefferson Medical College, Philadelphia, PA (United States)] [and others

1996-03-01

331

Dysfunctional B-cell activation in cirrhosis due to hepatitis C infection associated with disappearance of CD27+ B-cell population  

PubMed Central

Background Chronic hepatitis C virus infection is a leading cause of cirrhosis and hepatocellular carcinoma. Both advanced solid tumors and hepatitis C have previously been associated with memory B-cell dysfunction. In this study we sought to dissect the impact of viral infection, cirrhosis and liver cancer on memory B-cell frequency and function in the spectrum of HCV disease. Methods Peripheral blood from healthy donors, HCV-infected patients with F1–F2 liver fibrosis, HCV-infected patients with cirrhosis, patients with HCV-related hepatocellular carcinoma and non-HCV-infected cirrhotics were assessed for B-cell phenotype by flow cytometry. Isolated B-cells were stimulated with anti-CD40 antibodies and TLR9 agonist for assessment of costimulation marker expression, cytokine production, immunoglobulin production and CD4+ T-cell allostimulatory capacity. Results CD27+ memory B-cells, and more specifically CD27+IgM+ B-cells, were markedly less frequent in cirrhotic patients independent of HCV infection. Circulating B-cells in cirrhotics were hyporesponsive to CD40/TLR9 activation as characterized by CD70 upregulation, TNF? secretion, IgG production and T-cell allostimulation. Lastly, blockade of TLR4 and TLR9 signaling abrogated the activation of normal donor B-cells by cirrhotic plasma suggesting a role for bacterial translocation in driving B-cell changes in cirrhosis. Conclusion Profound abnormalities in B-cell phenotype and function occur in cirrhosis independent of hepatitis C viral infection. These B-cell defects may explain in part the vaccine hyporesponsiveness and susceptibility to bacterial infection in this population.

Doi, Hiroyoshi; Iyer, Tara K.; Carpenter, Erica; Li, Hong; Chang, Kyong-Mi; Vonderheide, Robert H.; Kaplan, David E.

2011-01-01

332

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

PubMed Central

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

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

1994-01-01

333

CHROMOSOMAL LOCATION OF TWO MITOCHONDRIAL MALATE DEHYDROGENASE STRUCTURAL GENES IN ZEA MAYS USING TRISOlLIICS AND BA TRANSLOCATIONS1  

Microsoft Academic Search

Maize mitochondrial malate dehydrogenase is coded by four genetic loci, Mdhl, Mdh.2, Mdh3 and Mdh4. Two of the four loci have been located on the long arm of chromosome 6, using trisomic analysis and B-A translocations. MULTIPLE forms of mitochondrial malate dehydrogenase (m-MDH) and soluble malate dehydrogenase (s-MDH) are found in maize (YANG and SCANDALIOS 1974, 1975). Each of the

D. G. ROUPAKIAS; JOHN G. SCANDALIOS

334

B cell targets in rheumatoid arthritis  

Microsoft Academic Search

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

Edward M. Vital; Shouvik Dass; Paul Emery

335

Nuclear translocation and carboxyl-terminal domain phosphorylation of RNA polymerase II delineate the two phases of zygotic gene activation in mammalian embryos.  

PubMed Central

In mammalian embryos, zygotic gene transcription initiates after a limited number of cell divisions through a two-step process termed the zygotic gene activation (ZGA). Here we report that RNA polymerase II undergoes major changes in mouse and rabbit preimplantation embryos during the ZGA. In transcriptionally inactive unfertilized oocytes, the RNA polymerase II largest subunit is predominantly hyperphosphorylated on its carboxy-terminal domain (CTD). The CTD is markedly dephosphorylated several hours after fertilization, before the onset of a period characterized by a weak transcriptional activity. The largest subunit of RNA polymerase II then lacks immunological and drug-sensitivity characteristics related to its phosphorylation by the TFIIH-associated kinase and gradually translocates into the nuclei independently of DNA replication and mitosis. A phosphorylation pattern of the largest subunit, close to that observed in somatic cells, is established in both mouse and rabbit embryos at the stage when transcription becomes a requirement for further development (respectively at the 2- and 8/16-cell stage). As these events occurred in the presence of actinomycin D, the nuclear translocation of RNA polymerase II and the phosphorylation of the CTD might be major determinants of ZGA.

Bellier, S; Chastant, S; Adenot, P; Vincent, M; Renard, J P; Bensaude, O

1997-01-01

336

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

Microsoft Academic Search

A poly(A)-trap gene targeting strategy was used to disrupt the single functional heavy chain (HC) joining region (JH) of swine in primary fibroblasts. Genetically modified piglets were then generated via somatic cell nuclear transfer (SCNT)\\u000a and bred to yield litters comprising JH wild-type littermate (+\\/+), JH heterozygous knockout (±) and JH homozygous knockout (?\\/?) piglets in the expected Mendelian ratio

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

2011-01-01

337

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.

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

2013-01-01

338

Modeling the evolution of ETV6-RUNX1-induced B-cell precursor acute lymphoblastic leukemia in mice  

PubMed Central

The t(12;21) translocation which generates the ETV6-RUNX1 (TEL-AML1) fusion gene, is the most common chromosomal rearrangement in childhood cancer and is exclusively associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The translocation arises in utero and is necessary but insufficient for the development of leukemia. SNP array analysis of ETV6-RUNX1 patient samples have identified multiple additional genetic alterations, however the role of these lesions in leukemogenesis remains undetermined. Moreover, murine models of ETV6-RUNX1 ALL that faithfully recapitulate the human disease are lacking. To identify novel genes that co-operate with ETV6-RUNX1 in leukemogenesis, we generated a mouse model that uses the endogenous Etv6 locus to co-express the ETV6-RUNX1 fusion and Sleeping Beauty (SB) transposase. An insertional mutagenesis screen was performed by intercrossing these mice with those carrying a SB transposon array. In contrast to previous models, a substantial proportion (20%) of the offspring developed BCP-ALL. Isolation of the transposon insertion sites identified genes known to be associated with BCP-ALL, including Ebf1 and Epor, in addition to other novel candidates. This is the first mouse model of ETV6-RUNX1 to develop BCP-ALL and provides important insights into the cooperating genetic alterations in ETV6-RUNX1 leukemia.

van der Weyden, Louise; Giotopoulos, George; Rust, Alistair G.; Matheson, Louise S.; van Delft, Frederik W.; Kong, Jun; Corcoran, Anne E.; Greaves, Mel F.; Mullighan, Charles G.; Huntly, Brian J.; Adams, David J.

2013-01-01

339

Translocation breakpoint at 7q31 associated with tics: further evidence for IMMP2L as a candidate gene for Tourette syndrome.  

PubMed

Gilles de la Tourette syndrome is a complex neuropsychiatric disorder with a strong genetic basis. We identified a male patient with Tourette syndrome-like tics and an apparently balanced de novo translocation [46,XY,t(2;7)(p24.2;q31)]. Further analysis using array comparative genomic hybridisation (CGH) revealed a cryptic deletion at 7q31.1-7q31.2. Breakpoints disrupting this region have been reported in one isolated and one familial case of Tourette syndrome. In our case, IMMP2L, a gene coding for a human homologue of the yeast inner mitochondrial membrane peptidase subunit 2, was disrupted by the breakpoint on 7q31.1, with deletion of exons 1-3 of the gene. The IMMP2L gene has previously been proposed as a candidate gene for Tourette syndrome, and our case provides further evidence of its possible role in the pathogenesis. The deleted region (7q31.1-7q31.2) of 7.2 Mb of genomic DNA also encompasses numerous genes, including FOXP2, associated with verbal dyspraxia, and the CFTR gene. PMID:21386874

Patel, Chirag; Cooper-Charles, Lisa; McMullan, Dominic J; Walker, Judith M; Davison, Val; Morton, Jenny

2011-03-09

340

B Cell Receptor-Mediated Sustained c-Rel Activation Facilitates Late Transitional B Cell Survival through Control of B Cell Activating Factor Receptor and NF-?B21  

PubMed Central

Signaling from the BCR and B cell activating factor receptor (BAFF-R or BR3) differentially regulates apoptosis within early transitional (T1) and late transitional (T2; CD21int-T2) B cells during selection processes to generate mature B lymphocytes. However, molecular mechanisms underlying the differential sensitivity of transitional B cells to apoptosis remain unclear. In this study, we demonstrate that BCR signaling induced more long-term c-Rel activation in T2 and mature than in T1 B cells leading to increased expression of anti-apoptotic genes as well as prosurvival BAFF-R and its downstream substrate p100 (NF-?B2). Sustained c-Rel activation required de novo c-Rel gene transcription and translation via Btk-dependent mechanisms. Like T1 cells, mature B cells from Btk- and c-Rel-deficient mice also failed to activate these genes. These findings suggest that the gain of survival potential within transitional B cells is dependent on the ability to produce a long-term c-Rel response, which plays a critical role in T2 B cell survival and differentiation in vivo by inducing anti-apoptotic genes, BAFF-R and NF-?B2, an essential component for BAFF-R survival signaling. Thus, acquisition of resistance to apoptosis during transitional B cell maturation is achieved by integration of BCR and BAFF-R signals.

Castro, Iris; Wright, Jacqueline A.; Damdinsuren, Bazarragchaa; Hoek, Kristen L.; Carlesso, Gianluca; Shinners, Nicholas P.; Gerstein, Rachel M.; Woodland, Robert T.; Sen, Ranjan; Khan, Wasif N.

2009-01-01

341

Ig Allotypic Inclusion Does Not Prevent B Cell Development or Response1  

Microsoft Academic Search

B cells expressing two different Ig L chains (allotype included) have been occasionally observed. To determine frequency and function of these cells, we have analyzed gene-targeted mice that carry a human and a mouse Igk C region genes. Using different methodologies, we found that cells expressing two distinct -chains were 1.4 -3% of all B cells and that they were

Maria-Gabriela Velez; Melissa Kane; Sucai Liu; Stephen B. Gauld; John C. Cambier; Raul M. Torres; Roberta Pelanda

342

BCL2 Translocation Frequency Rises with Age in Humans  

Microsoft Academic Search

The background frequency of t(14;18) (q32;q21) chromosomal translocations at the locus associated with B-cell leukemia\\/lymphoma-2 (BCL2) was determined from a survey of the peripheral blood lymphocytes (PBLs) of 53 living individuals and from tissues of 31 autopsies by using a nested PCR assay. The translocation was detected in 55% of PBLs and 35% of autopsied spleens with a frequency of

Yafei Liu; Antonio M. Hernandez; Darryl Shibata; Gino A. Cortopassi

1994-01-01

343

TAL2, a helix-loop-helix gene activated by the (7; 9)(q34; q32) translocation in human T-cell leukemia  

SciTech Connect

Tumor-specific alteration of the TAL1 gene occurs in almost 25% of patients with T-cell acute lymphoblastic leukemia (T-ALL). The authors now report the identification of TAL2, a distinct gene that was isolated on the basis of its sequence homology with TAL1. The TAL2 gene is located 33 kilobase pairs from the chromosome 9 breakpoint of t(7;9)(q34;q32), a recurring translocation specifically associated with T-ALL. As a consequence of t(7;9)(q34;q32), TAL2 is juxtaposed with sequences from the T-cell receptor {beta}-chain gene on chromosome 7. TAL2 sequences are actively transcribed in SUP-T3, a T-ALL cell line that harbors the t(7;9)(q34;q32). The TAL2 gene product includes a helix-loop-helix protein dimerization and DNA binding domain that is especially homologous to those encoded by the TAL1 and LYL1 protooncogenes. Hence, TAL2, TAL1, and LYL1 constitute a discrete subgroup of helix-loop-helix proteins, each of which can potentially contribute to the development of T-ALL.

Ying Xia; Brown, L.; Yang, C.Y.; Tsan, J.T.; Baer, R.J. (Univ. of Texas, Dallas (United States)); Siciliano, M.J. (Univ. of Texas, Houston (United States)); Espinosa, R. III; Le Beau, M.M. (Univ. of Chicago, IL (United States))

1991-12-15

344

B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK.  

PubMed

B and T lymphocyte attenuator (BTLA) functions as a negative regulator of T cell activation and proliferation. Although the role of BTLA in regulating T cell responses has been characterized, a thorough investigation into the precise molecular mechanisms involved in BTLA-mediated lymphocyte attenuation and, more specifically, its role in regulating B cell activation has not been presented. In this study, we have begun to elucidate the biochemical mechanisms by which BTLA functions to inhibit B cell activation. We describe the cell surface expression of BTLA on various human B cell subsets and confirm its ability to attenuate B cell proliferation upon associating with its known ligand, herpesvirus entry mediator (HVEM). BTLA associates with the BCR and, upon binding to HVEM, recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 and reduces activation of signaling molecules downstream of the BCR. This is exemplified by a quantifiable decrease in tyrosine phosphorylation of the protein tyrosine kinase Syk, as measured by absolute quantification mass spectrometry. Furthermore, effector molecules downstream of BCR signaling, including the B cell linker protein, phospholipase Cgamma2, and NF-kappaB, display decreased activation and nuclear translocation, respectively, after BTLA activation by HVEM. These results begin to provide insight into the mechanism by which BTLA negatively regulates B cell activation and indicates that BTLA is an inhibitory coreceptor of the BCR signaling pathway and attenuates B cell activation by targeting the downstream signaling molecules Syk and B cell linker protein. PMID:19155498

Vendel, Andrew C; Calemine-Fenaux, Jill; Izrael-Tomasevic, Anita; Chauhan, Vandana; Arnott, David; Eaton, Dan L

2009-02-01

345

Immune response gene control of determinant selection. I. Intramolecular mapping of the immunogenic sites on insulin recognized by guinea pig T and B cells  

PubMed Central

T-cell DNA synthesis and T-helper cell function in response to isolated insulin chains and naturally occurring insulin variants was assessed in insulin immune guinea pigs. Two distinct antigenic determinants, recognized by T cells, were defined. One localized in the B chain and the other one constituted by amino acids A8, A9, and A10 of the insulin A-chain loop. Recognition of the B-chain determinant is under the control of Ir genes linked to the strain 13 major histocompatibility complex. This was shown by studying the response to isolated insulin B chain in F1(2 x 13) guinea pigs, as well as serologically defined backcrosses and outbred animals. Insulin recognition through the A- chain loop determinant is specific for strain 2 guinea pigs. These animals recognize this region of the molecule even when displaying different amino acid sequences. The strain differences observed in those antigenic sites eliciting T-cell recognition was not found at an antibody level. No differences could be detected in the ability of the different insulin variants to inhibit the binding of 125I-labeled pork insulin to strain 2 guinea pig anti-pork insulin or to strain 13 guinea pig anti-pork insulin.

1977-01-01

346

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

Microsoft Academic Search

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

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

347

The Protein Product of the ccb! Protooncogene Is Phosphorylated after B Cell Receptor Stimulation and Binds the SH3 Domain of Bruton's Tyrosine Kinase  

Microsoft Academic Search

Summary X-linked agammaglobulinemia, a B cell immunodeficiency, is caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The absence of a functional Btk protein leads to a failure of B cell differentiation and antibody production. B cell receptor stimulation leads to the phosphorylation of the Btk protein and it is, therefore, likely that Btk is involved in B cell

Giles O. C. Cory; Ruth C. Lovering; Steve Hinshelwood; Roland J. Levinsky; Christine Kinnon

1995-01-01

348

Ten-eleven translocation 1 (Tet1) is regulated by O-linked N-acetylglucosamine transferase (Ogt) for target gene repression in mouse embryonic stem cells.  

PubMed

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

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

2013-05-31

349

MsmR, a specific positive regulator of the Streptococcus pyogenes FCT pathogenicity region and cytolysin-mediated translocation system genes.  

PubMed

As a prerequisite for colonization or causing local infections, Streptococcus pyogenes (group A streptococci, GAS) need to specifically adhere to eukaryotic cell surfaces. Predominantly responsible adhesin genes are contained in a genotype-specific pattern within the FCT region of the GAS genome. In this study, MsmR, belonging to AraC/XylS type transcriptional regulators, was identified in the FCT region as a positive regulator of the major fibronectin-binding adhesin protein F2 in a serotype M49 strain. Compared with the wild-type strain, the msmR mutant showed reduced binding to immobilized fibronectin and decreased adherence to and internalization into human pharyngeal epithelial cells. These results suggested that altered levels of fibronectin-binding proteins in the mutant affect eukaryotic cell attachment and internalization. Complete transcriptome and reporter fusion assay data revealed that MsmR positively regulates FCT region genes including Nra and cytolysin-mediated translocation system genes. Consistent with the genetic data, the mutant showed attenuated streptolysin O activity and eukaryotic cell cytotoxity. Direct binding of recombinant MsmR to nga, nra/cpa and prtF2 promoter regions was confirmed by EMSA assays. As prior analysis demonstrated the Nra regulator negatively affects gene expression from the FCT region, MsmR and Nra appear to adversely control crucial virulence factor expression in GAS and thus contribute to a fine-tuned balance between local destructive process and metastatic spreading of the bacteria. PMID:16045622

Nakata, Masanobu; Podbielski, Andreas; Kreikemeyer, Bernd

2005-08-01

350

A unique case of renal carcinoma with Xp11.2 translocations/ TFE3 gene fusions in a 3-year-old child, with coexistent von Hippel-Lindau gene mutation.  

PubMed

Renal cell carcinomas (RCCs) are rare in the pediatric population; when they occur, a significant percentage are associated with specific cytogenetic abnormalities and germline mutations. These include mutations in the von Hippel-Lindau ( VHL) gene and translocations involving the TFE3 transcription factor gene on Xp11.2. Here we report a case of a 3-year-old child with a large renal mass. Histologic examination of the tumor showed a predominantly nested growth pattern with some papillary foci. Cytogenetic analysis revealed a karyotype of t(X;1)(p11.2; p34.3), consistent with a TFE3-associated RCC. Interestingly, sequencing of the patient's VHL gene revealed a single point mutation, previously seen in a subgroup of patients with von Hippel-Lindau disease. This is the first reported case, to our knowledge, of t(X;1)-associated RCC in a patient with concurrent VHL gene mutation. PMID:15383938

Parast, Mana M; Eudy, Grant; Gow, Kenneth W; Amin, Mahul; Shehata, Bahig

2004-07-15

351

The Phosphoenolpyruvate\\/Phosphate Translocator Is Required for Phenolic Metabolism, Palisade Cell Development, and Plastid-Dependent Nuclear Gene Expression  

Microsoft Academic Search

The Arabidopsis chlorophyll a \\/ b binding protein ( CAB ) gene underexpressed 1 ( cue1 ) mutant underexpresses light-reg- ulated nuclear genes encoding chloroplast-localized proteins. cue1 also exhibits mesophyll-specific chloroplast and cellular defects, resulting in reticulate leaves. Both the gene underexpression and the leaf cell morphology phenotypes are dependent on light intensity. In this study, we determine that CUE1

Stephen J. Streatfield; Andreas Weber; Elizabeth A. Kinsman; Rainer E. Häusler; Jianming Li; Dusty Post-Beittenmiller; Werner M. Kaiser; Kevin A. Pyke; Ulf-Ingo Flügge; Joanne Chory

1999-01-01

352

Curcumin diminishes the impacts of hyperglycemia on the activation of hepatic stellate cells by suppressing membrane translocation and gene expression of glucose transporter-2  

PubMed Central

Diabetes is featured by elevated levels of blood glucose, i.e. hyperglycemia, which might be a risk factor for hepatic fibrogenesis in patients with non-alcoholic steatohepatitis. Hepatic stellate cells (HSCs) are the major effectors during hepatic fibrogenesis. This study was designed to evaluate impacts of high levels of glucose on HSC activation, assess roles of the phytochemical curcumin in attenuating the glucose impacts, and elucidate underlying mechanisms. In this report, levels of intracellular glucose were measured. Contents and gene expression of glucose transporter-2 (GLUT2) in cell fractions were examined. Levels of cellular glutathione and oxidative stress were analyzed. We observed that high levels of glucose induced cell proliferation, type I collagen production and expression of genes relevant to HSC activation, and elevated intracellular glucose levels in cultured HSCs. Curcumin eliminated the stimulatory impacts. Curcumin abrogated the membrane translocation of GLUT2 by interrupting the p38 MAPK signaling pathway. In addition, curcumin suppressed glut2 expression by stimulating the activity of peroxisome proliferator-activated receptor-gamma (PPAR?) and de novo synthesis of glutathione. In conclusion, hyperglycemia stimulated HSC activation in vitro by increasing intracellular glucose, which was eliminated by curcumin by blocking the membrane translocation of GLUT2 and suppressing glut2 expression. The latter was mediated by activating PPAR? and attenuating oxidative stress. Our results presented evidence to impacts of hyperglycemia on stimulating HSC activation and hepatic fibrogenesis, and provided novel insights into the mechanisms by which curcumin eliminated the hyperglycemia-caused HSC activation and potential therapeutic strategies for treatment of diabetes-associated hepatic fibrogenesis.

Lin, Jianguo; Chen, Anping

2011-01-01

353

RNA-sequence analysis of human B-cells  

PubMed Central

RNA-sequencing (RNA-seq) allows quantitative measurement of expression levels of genes and their transcripts. In this study, we sequenced complementary DNA fragments of cultured human B-cells and obtained 879 million 50-bp reads comprising 44 Gb of sequence. The results allowed us to study the gene expression profile of B-cells and to determine experimental parameters for sequencing-based expression studies. We identified 20,766 genes and 67,453 of their alternatively spliced transcripts. More than 90% of the genes with multiple exons are alternatively spliced; for most genes, one isoform is predominantly expressed. We found that while chromosomes differ in gene density, the percentage of transcribed genes in each chromosome is less variable. In addition, genes involved in related biological processes are expressed at more similar levels than genes with different functions. Besides characterizing gene expression, we also used the data to investigate the effect of sequencing depth on gene expression measurements. While 100 million reads are sufficient to detect most expressed genes and transcripts, about 500 million reads are needed to measure accurately their expression levels. We provide examples in which deep sequencing is needed to determine the relative abundance of genes and their isoforms. With data from 20 individuals and about 40 million sequence reads per sample, we uncovered only 21 alternatively spliced, multi-exon genes that are not in databases; this result suggests that at this sequence coverage, we can detect most of the known genes. Results from this project are available on the UCSC Genome Browser to allow readers to study the expression and structure of genes in human B-cells.

Toung, Jonathan M.; Morley, Michael; Li, Mingyao; Cheung, Vivian G.

2011-01-01

354

IFN Regulatory Factor 8 Restricts the Size of the Marginal Zone and Follicular B Cell Pools  

PubMed Central

Transcriptional control of marginal zone (MZ) and follicular (FO) B cell development remains incompletely understood. The transcription factor, IFN regulatory factor (IRF)8, is known to play important roles in the differentiation of early B cells. In this article, we demonstrate that IRF8 is also required for normal development of MZ and FO B cells. Mice with a conventional knockout of Irf8 (IRF8–/–) or a point mutation in the IRF association domain of IRF8 had increased numbers of MZ B cells. To determine the B cell-intrinsic effects of IRF8 deficiency, we generated mice with a conditional allele of Irf8 crossed with CD19-Cre mice (designated IRF8-conditional knockout [CKO]). These mice had enlarged MZ and increased numbers of MZ and FO B cells compared with controls. The FO B cells of CKO mice exhibited reduced expression of CD23 and moderately increased expression of CD21. Gene-expression profiling showed that increased B cell production in IRF8-CKO mice was associated with changes in expression of genes involved in regulation of transcription, signaling, and inflammation. Functional studies showed that IRF8-CKO mice generated normal Ab responses to T-independent and T-dependent Ags. Thus, IRF8 controls the expansion and maturation of MZ and FO B cells but has little effect on B cell function.

Feng, Jianxun; Wang, Hongsheng; Shin, Dong-Mi; Masiuk, Marek; Qi, Chen-Feng; Morse, Herbert C.

2012-01-01

355

[Historical development and current concepts on B-cell lymphomas of the marginal extraganglionar site of lymphoid tissue associated with MALT lymphoma. A tribute to Dennis H Wright and Peter G Isaacson].  

PubMed

Significant advances in the understanding of marginal zone lymphoma since the first description in 1983 by Peter Isaacson and Dennis Wright have been noted. MALT lymphomas are a subgroup of low-grade B-cell lymphomas that arise from extranodal sites, comprising 7-8% of all B-cell lymphomas and displaying distinct clinicopathological characteristics. MALT lymphomas remain localized in the primary site for long periods of time and seldom disseminate unto other organs. These type of lymphomas infrequently arise in native MALT, but instead arise in MALT acquired in the course of chronic inflammatory disorders, such as Sjögren's syndrome and Helicobacter pylori infection. Eradication of H. pylori produces a clinical regression of the lymphoma in about 75% of cases. The histological hallmarks of MALT lymphoma include neoplastic centrocyte-like B cells, cells resembling monocytoid cells and the presence of lymphoepithelial lesions. The gastrointestinal tract, particularly the stomach, include two-thirds of cases; however MALT lymphomas also occur in other organs such as salivary glands, lung, thyroid, ocular adnexa, breast and skin. Genetic studies have identified three chromosomal translocations specifically associated with MALT lymphomas that include: t(1l:18)(q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21). Although these translocations involve different genes, they appear to share a common oncogenic pathway involving NFkappaB. PMID:17722452

Piña-Oviedo, Sergio; Ortiz-Hidalgo, Carlos

356

Impaired expansion of mouse B cell progenitors lacking Btk  

Microsoft Academic Search

Mutations in the gene encoding the protein tyrosine kinase Btk are associated with the human B cell immunodeficiency X-linked agammaglobulinemia (XLA). In the mouse, a point mutation in the Btk pleckstrin homology domain segregates with a milder X-linked immunodeficiency (xid). To assessthe importance of Btk function in murine lymphopoiesis, we generated multiple embryonic stem cell clones bearing a targeted disruption

James D. Kerner; Mark W. Appleby; Randolph N. Mohr; Sylvia Chien; David J. Rawlings; Charles R. Maliszewski; Owen N. Witte; Roger M. Perlmutte

1995-01-01

357

Predominant Autoantibody Production by Early Human B Cell Precursors  

Microsoft Academic Search

During B lymphocyte development, antibodies are assembled by random gene segment reassortment to produce a vast number of specificities. A potential disadvantage of this process is that some of the antibodies produced are self-reactive. We determined the prevalence of self-reactive antibody formation and its regulation in human B cells. A majority (55 to 75%) of all antibodies expressed by early

Hedda Wardemann; Sergey Yurasov; Anne Schaefer; James W. Young; Eric Meffre; Michel C. Nussenzweig

2003-01-01

358

Impaired B cell maturation in mice lacking Bruton's tyrosine kinase (Btk) and CD40  

Microsoft Academic Search

Mutations in Bruton's tyrosine kinase (Btk) gene, in mice, result in reduced numbers and responses of peripheral B cells. Surface Ig-mediated signaling is defective in Btk mutant B cells as they do not proliferate upon sIg cross-linking and lack thymus-independent (TI) type II responses. Signals through sIg and CD40 play a critical role in B cell maturation. To investigate the

Wasif N. Khan; Anna Nilsson; Emiko Mizoguchi; Emanuella Castigli; Johan Forsell; Atul K. Bhan; Raif Geha; Paschalis Sideras; Frederick W. Alt

1997-01-01

359

The dynamics of the B follicle: understanding the normal counterpart of B-cell-derived malignancies  

Microsoft Academic Search

The repertoire of B cells secreting antibodies with unique antigen-binding specificities is produced at two stages: a primary B-cell repertoire is formed in the bone marrow through immunoglobulin gene rearrangements, whereas a secondary B-cell repertoire is generated in the peripheral lymphoid organs (spleen, lymph nodes and mucosa-associated lymphoid tissue) through somatic hypermutation and class-switch recombination upon antigen encounter. The latter

X Sagaert; B Sprangers; C De Wolf-Peeters

2007-01-01

360

An Integrated Genomic Analysis of Aryl Hydrocarbon Receptor-Mediated Inhibition of B-Cell Differentiation  

PubMed Central

The aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters differentiation of B cells and suppresses antibody production. A combination of whole-genome, microarray-based chromatin immunoprecipitation (ChIP-on-chip), and time course gene expression microarray analysis was performed on the mouse B-cell line CH12.LX following exposure to lipopolysaccharide (LPS) or LPS and TCDD to identify the primary and downstream transcriptional elements of B-cell differentiation that are altered by the AHR. ChIP-on-chip analysis identified 1893 regions with a significant increase in AHR binding with TCDD treatment. Transcription factor binding site analysis on the ChIP-on-chip data showed enrichment in AHR response elements. Other transcription factors showed significant coenrichment with AHR response elements. When ChIP-on-chip regions were compared with gene expression changes at the early time points, 78 genes were identified as potential direct targets of the AHR. AHR binding and expression changes were confirmed for a subset of genes in primary mouse B cells. Network analysis examining connections between the 78 potential AHR target genes and three transcription factors known to regulate B-cell differentiation indicated multiple paths for potential regulation by the AHR. Enrichment analysis on the differentially expressed genes at each time point evaluated the downstream impact of AHR-regulated gene expression changes on B-cell–related processes. AHR-mediated impairment of B-cell differentiation occurred at multiple nodes of the B-cell differentiation network and potentially through multiple mechanisms including direct cis-acting effects on key regulators of B-cell differentiation, indirect regulation of B-cell differentiation–related pathways, and transcriptional coregulation of target genes by AHR and other transcription factors.

De Abrew, K. Nadira; Kaminski, Norbert E.; Thomas, Russell S.

2010-01-01

361

Phagocytic B cells in a reptile.  

PubMed

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

2009-10-21

362

B cell-derived cytokines in disease.  

PubMed

B cells regulate immune responses during infectious, inflammatory and autoimmune diseases. Beside their unique and characteristic antibody production, B lymphocytes can modulate physiological and pathological processes by presenting antigens or synthesizing signaling molecules. In human and mouse diseases, immuno-intervention, targeting B cells, has revealed and highlighted their antibody-independent regulatory contribution. In this review, we focus on B cell-cytokine production, which is commonly disturbed in inflammatory disorders, and describe the B cell cytokine profile in different diseases. Finally, we discuss some key issues for future B cell-targeted therapies. PMID:23614878

Hamze, Moustafa; Desmetz, Caroline; Guglielmi, Paul

2013-03-01

363

Temsirolimus in the treatment of renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion proteins: a case report and review of literature.  

PubMed

Xp11.2 translocation renal cell carcinomas (TRCCs) are a rare family of tumors newly recognized by the World Health Organization (WHO) in 2004. These tumors result in the fusion of partner genes to the TFE3 gene located on Xp11.2. They are most common in the pediatric population, but have been recently implicated in adult renal cell carcinoma (RCC) presenting at an early age. TFE3-mediated direct transcriptional upregulation of the Met tyrosine kinase receptor triggers dramatic activation of downstream signaling pathways including the protein kinase B (Akt)/phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of malignant cells. Here we present a case of a 22-year old female who has been treated with temsirolimus for her Xp11.2/TFE3 gene fusion RCC. PMID:21139932

Parikh, Jigarkumar; Coleman, Teresa; Messias, Nidia; Brown, James

2009-12-28

364

Temsirolimus in the treatment of renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion proteins: a case report and review of literature  

PubMed Central

Xp11.2 translocation renal cell carcinomas (TRCCs) are a rare family of tumors newly recognized by the World Health Organization (WHO) in 2004. These tumors result in the fusion of partner genes to the TFE3 gene located on Xp11.2. They are most common in the pediatric population, but have been recently implicated in adult renal cell carcinoma (RCC) presenting at an early age. TFE3-mediated direct transcriptional upregulation of the Met tyrosine kinase receptor triggers dramatic activation of downstream signaling pathways including the protein kinase B (Akt)/phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of malignant cells. Here we present a case of a 22-year old female who has been treated with temsirolimus for her Xp11.2/TFE3 gene fusion RCC.

Parikh, Jigarkumar; Coleman, Teresa; Messias, Nidia; Brown, James

2009-01-01

365

Treatment of Diffuse Large B Cell Lymphoma  

PubMed Central

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

2012-01-01

366

DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation  

PubMed Central

The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair.

Shaknovich, Rita; Cerchietti, Leandro; Tsikitas, Lucas; Kormaksson, Matthias; De, Subhajyoti; Figueroa, Maria E.; Ballon, Gianna; Yang, Shao Ning; Weinhold, Nils; Reimers, Mark; Clozel, Thomas; Luttrop, Karin; Ekstrom, Tomas J.; Frank, Jared; Vasanthakumar, Aparna; Godley, Lucy A.; Michor, Franziska; Elemento, Olivier

2011-01-01

367

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.

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

2012-01-01

368

HCV Infection and B-Cell Lymphomagenesis  

PubMed Central

Hepatitis C virus (HCV) has been recognized as a major cause of chronic liver diseases worldwide. It has been suggested that HCV infects not only hepatocytes but also mononuclear lymphocytes including B cells that express the CD81 molecule, a putative HCV receptor. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma (NHL). Epidemiological data indicate an association between HCV chronic infection and the occurrence of B-cell NHL, suggesting that chronic HCV infection is associated at least in part with B-cell lymphomagenesis. In this paper, we aim to provide an overview of recent literature, including our own, to elucidate a possible role of HCV chronic infection in B-cell lymphomagenesis.

Ito, Masahiko; Kusunoki, Hideki; Mochida, Keiko; Yamaguchi, Kazunari; Mizuochi, Toshiaki

2011-01-01

369

Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival  

PubMed Central

Many cells latently infected with Epstein-Barr virus (EBV), including certain virus-associated tumors, express latent membrane protein 2A (LMP2A), suggesting an important role for this protein in viral latency and oncogenesis. LMP2A mimics B-cell receptor signaling but can also act as a decoy receptor blocking B-cell receptor (BCR) activation. Studies of peripheral B cells have not resolved this apparent contradiction because LMP2A seems to be dispensable for EBV-induced transformation of these B cells in vitro. We show here that LMP2A is essential for growth transformation of germinal center B cells, which do not express the genuine BCR because of deleterious somatic hypermutations in their immunoglobulin genes. BCR-positive (BCR+) and BCR-negative (BCR?) B cells are readily transformed with a recombinant EBV enc