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

Bajalica‐Lagercrantz, Svetlana; Piehl, Fredrik; Lagercrantz, Jacob; Lindahl, J; Weber, Günther; Kerckeart, JP; Porwit‐MacDonald, Anna; Nordenskjöld, Magnus

doi:10.1038/sj.leu.2400577

Cited by 19 publications

(18 citation statements)

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“…Although BCL6 is highly expressed in germinal center B-cells, it is also expressed in diverse tissues including skeletal muscle, breast, prostate and olfactory sensory neurons (Bajalica-Lagercrantz et al, 1997;Logarajah et al, 2003;Otaki et al, 2005). BCL6 is not expressed in terminally differentiated plasma cells; however, forced expression of BCL6 in plasma cells causes a loss of terminal differentiation markers and reversion to a less differentiated state.…”

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confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high interspecies homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

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Section: Introductionmentioning

confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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“…1,2 BCL-6 protein expression is required for germinal center (GC) formation and is highly regulated during B cell differentiation, expressed in centrocytes and centroblasts and conversely down-regulated in pre-or post-GC cells. [3][4][5] Several target genes down-regulated by BCL-6 have been identified, which are implicated in B cell terminal differentiation (Blimp-1, STAT3), Th2 immunity and inflammatory response (IP-10, MIP␣), cell cycle control (p27, cyclin D2) or apoptosis (BCL-XL). [6][7][8] BCL-6 translocations, identified by cytogenetic or Southern blot analysis, can occur in a broad spectrum of B cell lymphomas.…”

Section: Introductionmentioning

confidence: 99%

Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements

Jardin¹,

Buchonnet²,

Parmentier

et al. 2002

Leukemia

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The BCL-6 gene, located on chromosome 3q27, is implicated in the normal germinal center formation and is frequently rearranged in a wide spectrum of lymphomas. However the links between genetic alterations and expression of the gene are not clearly determined. We established a quantitative RT-PCR assay based on TaqMan technology to quantify BCL-6 mRNA expression in different subtypes of lymphomas and to compare the level of expression in lymphomas characterized by the presence or absence of BCL-6 translocation. Total RNA was extracted from 105 nodes biopsies (35 diffuse large B cell lymphomas (DLBCL); 26 follicle center lymphomas (FCL); 7 marginal zone lymphomas (MZL); 6 mantle cell lymphomas (MCL); 6 chronic lymphocytic leukemia (CLL); 5 T cell lymphomas (TCL); 7 classical Hodgkin diseases (HD); 6 nodal metastasis (NM); and 7 reactive hyperplasia (RH)). BCL-6 gene rearrangement was assessed by Southern blot analysis in 75% of 3q27 + DLBCL (n = 20) cases and 67% of 3q27 + cases (n = 10). The highest level of relative BCL-6 expression was observed in FCL (9.12 ± 7.28) comparatively to the other lymphoma subtypes including DLBCL (2.53 ± 1.82; P Ͻ 0.001), MCL (1.23 ± 0.73), MZL (1.49 ± 1.3), HD (1.60 ± 1.00), TCL (1.75 ± 1.64), but also RH (3.91 ± 3.12) or NM (1.95 ± 2.6). Among the 26 FCL cases, we observed a lower expression in grade 3 (n = 8) than in grade 1/2 (P Ͻ 0.001). Conversely, we failed to show any difference between 3q27 + DLBCL and 3q27 − DLBCL cases (P = 0.42). Paradoxically BCL-6 expression in 3q27 + FCL (n = 10) was significantly lower than in 3q27 − FCL cases (P = 0.035). Finally, this study showed that BCL-6 expression in lymphoma is largely independent of chromosome 3q27 rearrangement and is more related to the histological subtype. Clinical implication and alternative deregulation pathways of BCL-6 expression remain to be determined.

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“…Infact, expression of BCL-6 occurs immediately after a B cell enters the GC and is maintained until GC exit, whereas MUM1 positivity begins only at the centrocyte stage and is maintained during post-GC maturation. [8][9][10][11]15 Consequently, the histogenetic value of MUM1 may be to provide a marker for the identification of the transition from BCL-6 positivity (GC B cells) to CD138 expression (immunoblasts and plasmacells).…”

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“…Available phenotypic markers of histogenesis include expression of the BCL-6 protein, which is restricted to B cells reflecting a GC stage of differentiation, and CD138/syndecan-1, a proteoglycan clustering with late stages of B cell maturation. 3,[8][9][10][11] On this basis, lymphomas may be histogenetically distinguished into: (1) lymphomas devoid of somatic Ig and BCL-6 mutations, which derive from naive, pre-GC B cells; (2) lymphomas associated with somatic Ig and/or BCL-6 mutations as well as BCL-6 protein expression, and thus closely reflecting GC B cells; and (3) lymphomas associated with somatic Ig and/or BCL-6 mutations as well as CD138/syndecan-1 positivity, which conceivably represent lymphomas of post-GC B cells. [2][3][4][5][6][7][8][9][10][11][12] According to this model, mantle cell lymphoma and a fraction of B cell chronic lymphocytic leukemia/small lymphocytic lymphoma are considered as lymphomas deriving from naive B cells 2,4 ( Figure 2).…”

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MUM1: a step ahead toward the understanding of lymphoma histogenesis

Gaïdano

Carbone

2000

Leukemia

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Lymphomagenesis is a complex process involving a panoplia of molecular pathways causing transformation of mature lymphoid cells. 1 Each of these pathways is characterized by molecular lesions of cancer related genes and targets a specific stage of lymphoid differentiation 1 (Figure 1). Because each molecular pathway selectively associates with a given clinico-pathologic category of lymphoma, it is assumed that the genetic heterogeneity of lymphoma drives the histological, phenotypical and clinical heterogeneity of these diseases. Research performed during the last decade has been most intense in the field of lymphoma pathogenesis, and has led to the characterization of many cancer-related genes involved in the molecular pathways of lymphoma. 1 Conversely, investigations of lymphoma histogenesis have been lagging behind compared to studies of lymphoma pathogenesis and, therefore, comprehension of the precise cellular counterpart from which a given lymphoma derives is less advanced than knowledge of the genetic lesions associated with the tumor clone.In recent times, however, the field of B cell lymphoma his- (Figure 2). Because these histogenetic markers are also retained upon neoplastic transformation, the origin and differentiation stage of a given lymphoma may be temptatively assigned based on the combination of histogenetic markers associated with the tumor clone ( Figure 2). To date, welldefined histogenetic markers of B cell lymphoma include mutations of immunoglobulin (Ig) and BCL-6 genes, expression of the BCL-6 protein, and, at least in the context of immunodeficiency-related lymphoma, expression of the CD138/syndecan-1 antigen. 2-7 Mutations of Ig genes are accumulated at the time of B cell transit through the germinal center (GC) and are maintained thereafter upon B cell exit from the GC. 2,4 Similarly, recent evidence has shown that normal GC B cells also accumulate mutations of the noncoding regions of the BCL-6 proto-oncogene, which therefore parallel Ig mutations as markers of GC transit. [5][6][7] Because both Ig and BCL-6 mutations are maintained by B cells upon GC exit and further differentiation, they cannot discriminate between GC and post-GC B cells. Such distinction can be eased by phenotypic markers of histogenesis. Available phenotypic markers of histogenesis include expression of the BCL-6 protein, which is restricted to B cells reflecting a GC stage of differentiation, and CD138/syndecan-1, a proteoglycan clustering with late stages of B cell maturation. 3,[8][9][10][11]

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

Abstract: Chromosomal translocation resulting in abnormal expressionThus the expression is not confined to malignant B cells but

Cited by 19 publications

References 1 publication

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements

MUM1: a step ahead toward the understanding of lymphoma histogenesis

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