Cutting Edge: Polycomb Gene Expression Patterns Reflect Distinct B Cell Differentiation Stages in Human Germinal Centers

Raaphorst, Frank M.; Kemenade, Folkert J. van; Fieret, Elly; Hamer, Karien M.; Satijn, David; Otte, Arie P.; Meijer, Chris J.L.M.

doi:10.4049/jimmunol.164.1.1

Cited by 88 publications

(97 citation statements)

References 22 publications

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“…Polycomb gene complexes were recently identified as novel regulators of hematopoiesis, and they appear to be expressed differently in a nonoverlapping pattern in follicular B cells (8,26). Thus, their expression profile reflects distinct B cell differentiation stages in human GC.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells

Caron

Gallou

Lamy

et al. 2009

The Journal of Immunology

101

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The human germinal center is a highly dynamic structure where B cells conduct their terminal differentiation and traffic following chemokine gradients. The rapidly dividing centroblasts and the nondividing centrocytes represent the two major B cell subsets present in germinal center and also the most common normal counterparts for a majority of lymphomas. CD77 expression was previously associated to proliferating centroblasts undergoing somatic hypermutation, but data from transcriptional studies demonstrate that CD77 is not a reliable marker to discriminate human centroblasts from centrocytes. Herein we were able for the first time to separate these two subpopulations based on the expression of the chemokine receptor CXCR4 allowing their characterization. Phenotypic and functional features were especially explored, giving an accurate definition of CXCR4+ centroblasts compared with CXCR4− centrocytes. We show that CXCR4+ and CXCR4− germinal center B cells present a clear dichotomy in terms of proliferation, transcription factor expression, Ig production, and somatic hypermutation regulation. Microarray analysis identified an extensive gene list segregating these B cells, including highly relevant genes according to previous knowledge. By gene set enrichment analysis we demonstrated that the centroblastic gene expression signature was significantly enriched in Burkitt’s lymphomas. Collectively, our findings show that CXCR4 expression can properly separate human centroblasts from centrocytes and offer now the possibility to have purified normal counterparts of mature B cell-derived malignancies.

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Section: Discussionmentioning

confidence: 99%

CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells

Caron

Gallou

Lamy

et al. 2009

The Journal of Immunology

101

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“…EZH2 expression is rapidly upregulated in hematopoietic cells upon mitogen stimulation. In addition, the transition of resting mantle B cells to proliferating follicular centroblasts coincides with the appearance of both EZH2 and EED expression (Raaphorst et al, 2000b). Furthermore, downregulation of EZH2 protein expression was shown to retard cell proliferation in some tumor cells (Fukuyama et al, 2000;Jacobs and van Lohuizen, 2002).…”

Section: Introductionmentioning

confidence: 96%

Activated p53 suppresses the histone methyltransferase EZH2 gene

et al. 2004

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Replicative senescence is an irreversible cell cycle arrest that limits the proliferation of damaged cells and may be an important tumor suppression mechanism in vivo. This process is regulated at critical steps by the tumor suppressor p53. To identify genes that may regulate the senescence process, we performed cDNA microarray analysis of gene expression in senescent, young proliferating, and hTERT-immortalized primary human fibroblasts. The histone methyltransferase (HMTase), EZH2, was specifically downregulated in senescent cells. Activated p53 suppressed EZH2 gene expression through repression of the EZH2 gene promoter. This activity of p53 requires intact p53 transactivation and DNA binding domains. Furthermore, the repression of EZH2 promoter by p53 is dependent on p53 transcriptional target p21 Waf1 inactivating RB/E2F pathways. In addition, the knockdown of EZH2 expression retards cell proliferation and induces G2/M arrest. We suggest that the p53-dependent suppression of EZH2 expression is a novel pathway that contributes to p53-mediated G2/M arrest. EZH2 associated complex possesses HMTase activity and is involved in epigenetic regulation. Activated p53 suppresses EZH2 expression, suggesting a further role for p53 in epigenetic regulation and in the maintenance of genetic stability. Suppression of EZH2 expression in tumors by p53 may lead to novel approaches to control cancer progression.

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“…6 PcG complexes play an important role in B-cell development and the germinal center reaction, and increased or decreased activity of PcG proteins is thought to contribute to lymphomagenesis. [8][9][10] The precise interplay between the various epigenetic mechanisms is very complex and not fully understood. 1,11,12 Classical Hodgkin's lymphoma (cHL) is a monoclonal lymphoid neoplasm derived from (post-) germinal center B cells in almost all instances.…”

Section: Introductionmentioning

confidence: 99%

Classical Hodgkin's lymphoma shows epigenetic features of abortive plasma cell differentiation

Seitz¹,

Thomas²,

Zimmermann³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundEpigenetic changes are involved in the extinction of the B-cell gene expression program of classical Hodgkin's lymphoma. However, little is known regarding epigenetic similarities between cells of classical Hodgkin's lymphoma and plasma cell myeloma, both of which share extinction of the gene expression program of mature B cells. Design and MethodsGlobal histone H3 acetylation patterns were determined in cell lines derived from classical Hodgkin's lymphoma, plasma cell myeloma and B-cell lymphoma by chromatin immunoprecipitation and subsequent hybridization onto promoter tiling arrays. H3K27 trimethylation was analyzed by chromatin immunoprecipitation and real-time DNA polymerase chain reaction for selected genes. Epigenetic modifications were compared to gene expression data. ResultsCharacteristic B-cell genes were hypoacetylated in classical Hodgkin's lymphoma and plasma cell myeloma cell lines as demonstrated by comparison of their histone H3 acetylation patterns to those of B-cell lines. However, the number of genes jointly hyperacetylated and expressed in classical Hodgkin' lymphoma and plasma cell myeloma cell lines, such as IRF4/MUM1 and RYBP, is limited. Moreover, H3K27 trimethylation for selected characteristic B-cell genes revealed that this additional epigenetic silencing is much more prevalent in classical Hodgkin's lymphoma than in plasma cell myeloma. ConclusionsOur epigenetic data support the view that classical Hodgkin's lymphoma is characterized by abortive plasma cell differentiation with a down-regulation of characteristic B-cell genes but without activation of most genes typical of plasma cells.

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Cutting Edge: Polycomb Gene Expression Patterns Reflect Distinct B Cell Differentiation Stages in Human Germinal Centers

Cited by 88 publications

References 22 publications

CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells

CXCR4 Expression Functionally Discriminates Centroblasts versus Centrocytes within Human Germinal Center B Cells

Activated p53 suppresses the histone methyltransferase EZH2 gene

Classical Hodgkin's lymphoma shows epigenetic features of abortive plasma cell differentiation

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