STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression

Scheeren, Ferenc A.; Naspetti, Marianne; Diehl, Sean A.; Schotte, Remko; Nagasawa, Maho; Wijnands, Erwin; Gimeno, Ramón; Vyth‐Dreese, Florry A.; Blom, Bianca; Spits, Hergen

doi:10.1038/ni1172

Cited by 145 publications

(181 citation statements)

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“…Recently, it has been demonstrated that STAT5 upregulates BCL6 in a subset of germinal center cells (Scheeren et al, 2005). Using reporter assays, it was demonstrated that the STAT5-binding site was located at À526 to À534 according to the þ 1 nucleotide defined by Ohashi et al (1995).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, we utilized this site in our ChIP experiments as the control region (Figure 6a), and in NKL cells stimulated with IL-2, STAT5 does not bind to that site (Figure 6c). It is possible that the site identified by Scheeren et al (2005) is a STAT5-binding site specific to germinal center cells in which STAT5 upregulates BCL6 expression. Therefore, STAT5 may be upregulating BCL6 in some cell types and downregulating BCL6 expression in other cell types.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

2006

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“…The combination of cytokines stimulation and antigendriven BCR activity may drive specific B-cell fate in the germinal center. There, STAT5 may play a special role in the self-renewal of B cells (Scheeren et al, 2005). The delayed activation of STAT after BCR engagement could be secondary to interleukin (IL)-6 or CD40L production, because neutralizing antibodies to IL-6 or CD40 inhibited STAT3 activation following BCR engagement (Fan and Rothstein, 2001).…”

Section: Discussionmentioning

confidence: 99%

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

2006

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Engagement of the B-cell antigen receptor (BCR) initiated by the Src kinase Lyn triggers rapid signaling cascades, leading to proliferation, differentiation or growth arrest of B cells. The Janus kinase (JAK)-STAT (signal transducer and activator of transcription) pathway, activated through cytokine receptors, mediates similar responses. Hypothesizing that Src and JAK pathways engage in crosstalk in B-cell signaling, we studied wild-type and Lyn-null B-cell lines, which express BCR. We found that activated BCR results in tyrosine phosphorylation of JAK-STAT, which required Lyn. To confirm that STAT activation is not due to JAK, we cloned the chicken homologs of JAK1 and JAK2 and made their antisense constructs. In cells expressing antisense JAK1 and JAK2, tyrosine phosphorylation of STAT was not inhibited following BCR stimulation. Using activation loop-specific phosphotyrosine antibodies, we did not detect phospho-JAK1 and phospho-JAK2 after BCR stimulation. The JAK inhibitor AG490 did not inhibit the tyrosine phosphorylation of Lyn or STAT after BCR simulation. An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3. In an electrophoretic mobility shift assay, BCR stimulation led to enhanced DNA binding of the STAT3 in DT40, but not in the Lynnull cells. We conclude that BCR engagement activates the STAT pathway via Lyn, independent of JAK.

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“…In this regard, a subpopulation of germinal center B cells that is characterized by pSTAT5 expression with an activated centrocyte phenotype has been identified recently. 31 Nuclear expression of pSTAT5 was detected in all megakaryocytes of myeloproliferative disorders with high JAK2 mutated/wild-type ratios, in all nuclei of the K562 pellets, and in erythroid precursors of myeloid disorders without JAK2 mutations (Figure 2d and e).…”

Section: Immunohistochemistrymentioning

confidence: 92%

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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STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression

Cited by 145 publications

References 49 publications

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

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

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

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