STAT3-Mediated Up-Regulation of BLIMP1 Is Coordinated with BCL6 Down-Regulation to Control Human Plasma Cell Differentiation

Diehl, Sean A.; Schmidlin, Heike; Nagasawa, Maho; Haren, Simon D. van; Kwakkenbos, Mark J.; Yasuda, Etsuko; Beaumont, Tim; Scheeren, Ferenc A.; Spits, Hergen

doi:10.4049/jimmunol.180.7.4805

Cited by 211 publications

(268 citation statements)

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“…IL-21 is a potent inducer of Blimp-1 (21,29), the master regulator of PC differentiation (42). The differentiation of LCLs into PC in vivo (43) or in vitro (44,45) resulted in the down-regulation of EBNA expression, but only IL-21 treatment could maintain the expression of LMP-1 in the absence of EBNA-2 and result in the activation of Qp.…”

Section: Resultsmentioning

confidence: 99%

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

Kis

Salamon

Persson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Epstein-Barr virus (EBV) is associated with a variety of human tumors. Although the EBV-infected normal B cells in vitro and the EBV-carrying B cell lymphomas in immunodeficient patients express the full set of latent proteins (type III latency), the majority of EBVassociated malignancies express the restricted type I (EBNA-1 only) or type II (EBNA-1 and LMPs) viral program. The mechanisms responsible for these different latent viral gene expression patterns are only partially known. IL-21 is a potent B cell activator and plasma cell differentiation-inducer cytokine produced by CD4 + T cells. We studied its effect on EBV-carrying B cells. In type I Burkitt lymphoma (BL) cell lines and in the conditional lymphoblastoid cell line (LCL) ER/ EB2-5, IL-21 potently activated STAT3 and induced the expression of LMP-1, but not EBNA-2. The IL-21-treated type I Jijoye M13 BL line ceased to proliferate, and this was paralleled by the induction of IRF4 and the down-regulation of BCL6 expression. In the type III LCLs and BL lines, IL-21 repressed the C-promoter-derived and LMP-2A mRNAs, whereas it up-regulated the expression of LMP-1 mRNAs. The IL-21-treated type III cells underwent plasma cell differentiation with the induction of Blimp-1, and high levels of Ig and Oct-2. IL-21 might be involved in the EBNA-2-independent expression of LMP-1 in EBV-carrying type II cells. In light of the fact that IL-21 is already in clinical trials for the treatment of multiple malignancies, the in vivo modulation of EBV gene expression by IL-21 might have therapeutic benefits for the EBV-carrying malignancies.Epstein-Barr virus | IL-21 | lymphoma | STAT3

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Section: Resultsmentioning

confidence: 99%

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

Kis

Salamon

Persson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In controls, pJAK2 was detectable in the cytoplasm of centroblasts (1-5%) and marginal zone lymphocytes (1%) as well as in higher proportions in endothelial and dendritic cells (Figure 2a). Nuclear pSTAT3 was seen in follicular cells (1-5%), in lymphocytes surrounding the germinal centers (2%) and in plasmocytoid/monocytoid lymphocytes (up to 20%), corresponding to its important role in terminal B-cell differentiation, 30 as well as in endothelial and vascular smooth muscle cells (Figure 2b). Nuclear pSTAT5 was detectable in lymphocytes surrounding the germinal centers (1-5%) (Figure 2c).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

et al. 2009

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The Janus kinase 2 (JAK2)-signal transducers and activators of transcription (STAT) pathway plays an important role in hematological malignancies. Mutations and translocations of the JAK2 gene, mapped at 9p24, lead to constitutive activation of JAK2 and its downstream targets. The presence of JAK2 mutations in lymphomas has been addressed in larger cohorts, but there are little systemic data on numerical and structural JAK2 aberrations in lymphoid neoplasms. To study the molecular epidemiology of these aberrations and the consecutive activation of the JAK2-STAT pathway in lymphomas, we examined 527 cases, covering the most common entities, in a tissue microarray by fluorescent in situ hybridization with breakable JAK2 probes, and immunohistochemistry for phosphorylated JAK2 (pJAK2) and its preferred downstream pSTAT3 and pSTAT5. 9p24 gains were detected in 6/17 (35%) primary mediastinal B-cell lymphomas (PMBCLs), 25/77 (33%) Hodgkin's lymphomas (HLs), 3/16 (19%) angioimmunoblastic T-cell lymphomas (AILTs) and 1/5 ALK1 þ anaplastic large cell lymphomas (ALCLs); breaks were observed only in three cases. pJAK2 expression was most prevalent in PMBCL, peripheral T-cell lymphomas and HL. pSTAT3 predominated in ALCLs, HLs, AILTs, PMBCLs and peripheral T-cell lymphomas. pSTAT5 expression was detected frequently in follicular lymphomas, diffuse large B-cell lymphomas and AILTs. 9p24 gains correlated with increased proportions of tumor cells expressing pJAK2 (P ¼ 0.002) and pSTAT3 (P ¼ 0.001). In follicular lymphomas, concomitant expression of pJAK2 and pSTAT5 was linked to better prognosis, whereas expression of pSTAT3 in nongerminal center-like diffuse large B-cell lymphomas could identify a patient group with an inferior outcome. Our findings stress that despite the rarity of activating JAK2 mutations in lymphomas, JAK2 is recurrently targeted by numerical, and rarely by structural, genetic aberrations in distinct lymphoma subtypes and that JAK2-STAT pathway may play a role in lymphomagenesis. Modern Pathology (2009) 22, 476-487; doi:10.1038/modpathol.2008; published online 9 January 2009 Keywords: Janus kinase 2; pSTAT3; pSTAT5; FISH; gains 9p24; lymphoma Genetic alterations of tyrosine kinases play an important oncogenic role. 1 The V617F and the less common K539L mutations of the Janus kinase 2 (JAK2) gene have been shown to be key pathogenic players in chronic myeloproliferative diseases. [2][3][4] Recently, translocations involving the JAK2 locus such as t(9;12)(p24;p23), t(8;9)(p24;q11.2), t(3;9) (q21;p24) and t(8;9)(p22;p24) were suggested to be of oncogenic importance in various hematological neoplasms, such as acute lymphoblastic and myelogenous leukemias, atypical chronic myeloid leukemias, myelodysplastic/myeloproliferative diseases and peripheral T-cell lymphomas. [5][6][7][8][9][10][11] Gains of JAK2 gene dosage, particularly due to trisomy 9p24, which is recurrent in classical Hodgkin's lymphoma

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“…Bcl6 also represses genes that are involved in B-cell activation and in B-cell-T-cell interactions [17][18][19]. Importantly, several experiments have proposed a double-negative regulatory circuit between Bcl6 and Blimp-1 [18,[20][21][22][23][24]. PRDM1 (encoding Blimp-1) is directly repressed by Bcl6 in B cells [23,24] and, in contrast, enforced Blimp-1 expression in B cells is shown to downregulate the BCL6 gene [4,25].…”

Section: Introductionmentioning

confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. Supporting Information available online See accompanying Commentary by Tarlinton IntroductionThe transition of activated B cells into high-affinity antibodyproducing plasmablasts, plasma cells and memory B cells in the germinal centers (GCs) is a biologically unique process involving rapid B-cell proliferation coupled with a high rate of mutation in the variable regions of immunoglobulin (Ig) genes. Considering that the majority of B-cell lymphomas originate from the GC B cells [1], a comprehensive understanding of the transcriptional regulation controlling the transition of B cells to plasma cells is essential. The transcription factors Blimp-1, Xbp-1 and IRF4 have been identified to be critical regulators promoting the Ig secretion and plasma cell phenotype, whereas Pax5, Bcl6, MITF and Bach2 are the known inhibitors of plasma cell development [2].Previous studies have shown that the downregulation of B-cell identity factor Pax5 occurs before the induction of the plasma cell transcription program [3,4], and that the loss of Pax5 expression [4] leads to the downregulation of BCL6. Furthermore, B-cell receptor (BCR) signaling of sufficient affinity leads to rapid phosphorylation and degradation of Bcl6 protein [5], while Bcl6 can also be functionally inactivated by acetylation [6]. These features of Bcl6 make it a prominent molecular trigger that controls the plasma cell differentiation.The transcription factor Bcl6 has been demonstrated to be essential for GC B-cell development, as Bcl6 knockout mice fail to develop GCs and do not produce high-affinity antibodies [7][8][9]. Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16]. Thus, Bcl6 appears to function as a factor permitting rapid B-cell 2404proliferation and tolerance for DNA damage in GCs. Bcl6 also represses genes that are involve...

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STAT3-Mediated Up-Regulation of BLIMP1 Is Coordinated with BCL6 Down-Regulation to Control Human Plasma Cell Differentiation

Cited by 211 publications

References 73 publications

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

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