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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although primary mediastinal (thymic) large B-cell lymphoma has been primarily studied, its precise phenotype, molecular characteristics, and histogenesis are still a matter of debate. The International Extranodal Lymphoma Study Group collected 137 such cases for extensive pathological review. Histologically, the lymphomatous growth was predominantly diffuse with fibrosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. On immunohistochemistry, the following phenotype was observed: CD45(+), CD20(+), CD79a(+), PAX5/BSAP(+), BOB.1(+), Oct-2(+), PU.1(+), Bcl-2(+), CD30(+), HLA-DR(+), MAL protein(+/-), Bcl-6(+/-), MUM1/IRF4(+/-), CD10(-/+), CD21(-), CD15(-), CD138(-), CD68(-), and CD3(-). Immunoglobulins were negative both at immunohistochemistry and in situ hybridization. Molecular analysis, performed in 45 cases, showed novel findings. More than half of the cases displayed BCL-6 gene mutations, which usually occurred along with functioning somatic IgV(H) gene mutations and Bcl-6 and/or MUM1/IRF4 expression. The present study supports the concept that a sizable fraction of cases of this lymphoma are from activated germinal center or postgerminal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective immunoglobulin production despite the expression of OCT-2, BOB.1, and PU.1 transcription factors and the lack of IgV(H) gene crippling mutations.
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PMID:Primary mediastinal B-cell lymphoma: high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, BOB.1, and PU.1 in the absence of immunoglobulins. 1250 7

Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H) gene crippling mutations.
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PMID:Pathobiology of primary mediastinal B-cell lymphoma. 1520 21

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin's lymphoma (cHL) are thought to be derived from germinal centre B-cells in almost all cases. However, expression profiling has revealed that HRS cells do not show a germinal centre B-cell-like phenotype. Although the nature of this aberrant phenotype and the underlying molecular mechanisms remain largely unknown, it has been reported that the activity of NOTCH1 plays an important role in the growth and survival of HRS cells. In some leukaemic cell lines, the effect of Notch signalling is mediated by the early transcription factor GATA-2. This and the fact that HRS cells lack expression of PU.1, which can repress Gata-2, led to an investigation of GATA-2 expression in HRS cells. GATA-2 expression was found in all the cHL-derived cell lines studied, but not in a Burkitt lymphoma-derived cell line. In addition, 50% of biopsies from patients with cHL contained GATA-2-expressing HRS cells. In contrast, neither normal germinal centre B-cells nor malignant cells of nodular lymphocyte-predominant Hodgkin's lymphoma, Burkitt lymphoma or diffuse large B-cell lymphoma expressed GATA-2. Thus, GATA-2 expression was found specifically in HRS cells of cHL, suggesting that GATA-2 is important in establishing the abnormal B-cell phenotype of HRS cells.
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PMID:The early transcription factor GATA-2 is expressed in classical Hodgkin's lymphoma. 1553 55

Primary mediastinal B-cell lymphoma (PMBL) is a highly aggressive tumour with a unique pattern of clinical, morphological, immunological and genetic features distinct from other diffuse large B-cell lymphomas. PMBLs are characterized by a mature B-cell phenotype, but they typically lack immunoglobulin (Ig) gene expression. The PMBL cell line MedB-1 shares many characteristic properties of the primary tumour, including low-level Ig production despite a functionally rearranged IgVH gene and absence of 'crippling' mutations. In this study, a search was undertaken for reasons for downregulated Ig expression. Similar levels of the B-cell-specific transcription factors BOB.1/OBF.1 and PU.1 were found in MedB-1 cells to those in the Ig-producing UM-1 lymphoblastoid cell line. However, MedB-1 lacked the Oct2 transcription factor. Reporter assays showed that Ig-type promoters were active in MedB-1 cells. In contrast, activity of the intronic heavy chain enhancer was dramatically reduced. Ectopic expression of Oct2 was able partially to restore enhancer activity but transcription from the endogenous IgVH gene could not be rescued. Therefore, the role of epigenetic factors in the downregulation of Ig was investigated. Methylated histone 3 lysine 9, a reliable marker of chromatin silencing, was not detected in MedB-1 promoter and enhancer regions. Inhibition of DNA methyltransferase and of histone deacetylases also did not reactivate Ig production. These data suggest the existence of alternative mechanisms of Ig inhibition in MedB-1 cells, different from chromatin silencing and the lack of Oct2.
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PMID:Downregulation of internal enhancer activity contributes to abnormally low immunoglobulin expression in the MedB-1 mediastinal B-cell lymphoma cell line. 1568 41

The transcription factor PU.1 has been shown to be crucial for the early stages of B cell development but its function at later stages of B cell development is less well known. We observed previously that PU.1 is expressed uniformly throughout the mature pre-plasma cell B cell population, the only exception being a subpopulation of germinal centre (GC) cells which showed exceptionally high expression of PU.1. This suggested that PU.1 may also have a role in GC B cell biology. To test this hypothesis and to screen for possible genes regulated by PU.1, we first evaluated semi-quantitatively the possible co-expression of PU.1 with proteins known to be upregulated or downregulated during GC B cell development. Normal lymphoid tissues and 255 B cell non-Hodgkin lymphomas of putative GC B cell origin were evaluated. PU.1 expression was positively associated with CD10 (p < 0.0001), CD20 (p = 0.043), CD22 (p = 0.005), CD79a (p = 0.024) and Bcl-6 (p < 0.0001) and negatively associated with cytoplasmic immunoglobulin light-chain expression (p = 0.036) in diffuse large B cell lymphoma. Identical or nearly identical associations were found in follicular lymphoma. Since CD20 is known to be partly regulated by PU.1 and putative PU.1-binding sites have been described in the regulatory regions of the CD22, CD79a and CD10 genes, we looked for putative PU.1 binding sites in the BCL6 promotor. Four such putative PU.1 binding sites were identified. Further analysis by gel-shift electromobility essay showed that PU.1 protein binds to three of the four putative binding sites in the BCL6 promotor. PU.1 and Bcl-6 were also found to be upregulated in centroblasts in the normal GC, but jointly downregulated in a subpopulation of centrocytes. Our findings support the contention that PU.1 may also have an important role in GC B cell development.
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PMID:PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor. 1684 70

MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by interferon-gamma(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG. Leukemia (2005) 19, 1471-1478. doi:10.1038/sj.leu.2403833; published online 16 June 2005.
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PMID:Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma (MIG) gene expression in B-cell malignancy. 1595 30

Very few prognostic factors are known in follicular lymphoma (FL), a common malignancy of germinal centre (GC) B-cells. The Follicular Lymphoma International Prognostic Index (FLIPI) thus far appears to be the most important predictor of clinical outcome. This study explores the predictive power of the degree of GC differentiation for outcome in FL. Samples from 73 patients with FL were evaluated by immunohistochemistry for expression of GC markers. Strong PU.1, CD20, and CD75 expression were significantly associated with longer progression-free survival (PFS) and overall survival (OS). Results for PFS were independent of the International Prognostic Index or the Italian Lymphoma Intergroup prognostic index for CD75 and PU.1, but only PU.1 expression was independent of FLIPI for PFS and OS. Oct-2 was weakly expressed overall, but more strongly in higher grades of FL; it had a trend for negative linear association with PU.1 and strong positive linear association with CD27, which possibly reflects its role in terminal B-cell differentiation. We show that the level of GC differentiation, as determined by the levels of PU.1, CD75, CD20, Bcl-6, and CD10 expression, has an association with outcome in patients with FL. While this is determined qualitatively in most studies of diffuse large B-cell lymphoma, in FL there is a quantitative positive association between a high level of expression of GC antigens and longer OS and PFS even when data are stratified by the FLIPI score.
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PMID:Prognostic significance of PU.1 in follicular lymphoma. 1663 93

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare B-cell lymphoma considered to be of germinal center (GC) derivation. Studies on immunoglobulin expression have been few, and post-switch immunoglobulin (IgG) has been identified in the majority of cases examined thus far. We reviewed 180 cases of NLPHL and observed the unexpected expression of IgD in 27% of cases. IgD is usually coexpressed with IgM in naive B cells but can also be seen as IgD-only in centroblasts (CD38-positive) or memory B cells (CD27-positive). We asked whether IgD-positive NLPHL differed from cases of NLPHL negative for IgD. Clinically, the IgD-positive cases presented at a younger median age (21 vs. 44 years) and had a striking male predominance (male-to-female ratio, 23:1 vs. 1.5:1). Cervical lymph nodes were more frequently involved (56% vs. 18.2%). L&H cells were localized in a predominantly extrafollicular distribution in the majority of IgD-positive cases (69%). The IgD-positive cases did not coexpress IgM or CD27 (a marker associated with memory B cells), and nearly all (93%) were weakly positive for CD38, supporting a GC derivation. The expression of Bcl-6, BOB.1, Oct2, and SWAP-70 was similar in the two groups. However, PU.1 expression was seen in 60% of the IgD-positive cases in contrast to 86% of the IgD-negative cases. The absence of PU.1 staining correlated with more L&H cells in an extrafollicular distribution, weakening the use of this marker in the differential diagnosis with T-cell rich/histiocyte rich B-cell lymphomas. To study IgD expression in "de-novo" T-cell rich/histiocyte rich B-cell lymphomas, we analyzed 20 cases and all but one were negative. In conclusion, cases of IgD-positive NLPHL do not differ from IgD-negative cases regarding cellular derivation and most other immunophenotypic characteristics. However, IgD-positive NLPHL exhibits distinctive clinical features, and more often involves the interfollicular region in a background relatively rich in T cells. IgD positivity may represent an additional useful marker in the diagnosis of NLPHL.
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PMID:IgD positive L&H cells identify a unique subset of nodular lymphocyte predominant Hodgkin lymphoma. 1669 12

Expression patterns of eight transcription factors involved in different stages of B-cell development were investigated in a large group of primary cutaneous B-cell lymphomas and compared with expression patterns during normal B-cell development. The following transcription factors were investigated: Pax-5, PU.1, Oct2, BOB.1, Bcl-6, Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous large B-cell lymphomas, leg type showed aberrant coexpression of Bcl-6 and Mum1/IRF4 and in addition strong expression of FOXP1. Expression of FOXP1 and Mum1/IRF4 strongly suggests an activated B-cell type of origin. In contrast, primary cutaneous follicle center lymphomas showed expression of Bcl-6, Pax-5, PU.1, Oct2 and BOB.1, but not of Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous marginal zone B-cell lymphoma showed expression of Pax-5, PU.1, Oct2 and BOB.1, but not Bcl-6 by the neoplastic B-cells, and Mum1/IRF4 and Blimp-1 by the neoplastic plasma cells. In conclusion, in primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma expression patterns were observed similar to their supposed benign counterparts, germinal center B-cells and postgerminal center B-cells, respectively, which might reflect their indolent clinical behaviour and excellent prognosis. In contrast, the activated B-cell expression pattern in the group of primary cutaneous large B-cell lymphoma, leg type may contribute to its poor prognosis and Mum1/IRF4 and FOXP1 may serve as additional diagnostic markers for this type of primary cutaneous B-cell lymphoma.
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PMID:Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma. 1677 25

The transit of T cell-activated B cells through the germinal center (GC) is controlled by sequential activation and repression of key transcription factors, executing the pre- and post-GC B cell program. B cell lymphoma (BCL) 6 and IFN regulatory factor (IRF) 8 are necessary for GC formation and for its molecular activity in Pax5+PU.1+ B cells. IRF4, which is highly expressed in BCL6- GC B cells, is necessary for class switch recombination and the plasma cell differentiation at exit from the GC. In this study, we show at the single-cell level broad coexpression of IRF4 with BCL6, Pax5, IRF8, and PU.1 in pre- and post-GC B cells in human and mouse. IRF4 is down-regulated in BCL6+ human GC founder cells (IgD+CD38+), is absent in GC centroblasts, and is re-expressed in positive regulatory domain 1-positive centrocytes, which are negative for all the B cell transcription factors. Activated (CD30+) and activation-induced cytidine deaminase-positive extrafollicular blasts coexpress Pax5 and IRF4. PU.1-negative plasma cells and CD30+ blasts uniquely display the conformational epitope of IRF4 recognized by the MUM1 Ab, an epitope that is absent from any other IRF4+PU.1+ lymphoid and hemopoietic subsets. Low grade B cell lymphomas, representing the malignant counterpart of pre- and post-GC B cells, accordingly express IRF4. However, a fraction of BCL6+ diffuse large B cell lymphomas express IRF4 bearing the MUM1 epitope, indicative of a posttranscriptional modification of IRF4 not seen in the normal counterpart.
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PMID:Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. 1708 8


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