Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas

Ding, Bin; Yu, Jingwei; Yu, Raymond; Mendez, Lourdes M.; Shaknovich, Rita; Zhang, Yonghui; Cattoretti, Giorgio; Ye, B. Hilda

doi:10.1182/blood-2007-04-087734

Cited by 277 publications

(296 citation statements)

References 54 publications

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“…40 In our FL collective, the expression of pSTAT5 correlated with higher amounts of tumor-infiltrating regulatory T cells, which are also known to be associated with favorable outcomes. 25 Finally, we confirmed the prognostic importance of pSTAT3 in activated B-cell-like DLBCL, which was recently observed by others, 18 as our own nongerminal center DLBCL expressing pSTAT3 had also an inferior disease-specific survival, again indicating the oncogenic potential of pSTAT3.…”

Section: Discussionsupporting

confidence: 89%

“…Similar to others, we observed preferential expression of pSTAT3 in ALCL, 16,17 HL 35 (but not in NLPHL) and nongerminal center DLBCL. 18 Our PTCLs also preferentially expressed pSTAT3. As in ALK1 þ ALCL, NPM-ALK constitutively activates STAT3 by increased protein phosphorylation and increased transcription/stabilization of STAT3 mRNA and ALCLs overexpress JAK3, 16 our observed high predominance of pSTAT3, despite low expression of pJAK2 was expected.…”

Section: Discussionmentioning

confidence: 66%

“…Nongerminal center-like DLBCL expressing pSTAT3 above the ROC-determined prognostic cutoff of 12.5% positive tumor cells (pSTAT3-positive cases) had a worse prognosis, with 8/8 lymphoma-related deaths (mean survival 25, median survival 8 months) compared with 12/21 in pSTAT3-negative cases 18 (mean survival 74, median survival 27 months, P ¼ 0.054; Figure 4b). Presence of 9p24 gains did not influence survival.…”

Section: Prognostic Significancementioning

confidence: 99%

“…15 Constitutive STAT3 activation is a highly consistent finding in ALK1 þ anaplastic large cell lymphomas (ALCLs) 16,17 and, recently, STAT3 was shown to be an important prognostic factor in activated B-cell-like diffuse large B-cell lymphomas (DLBCLs). 18 The JAK2-STAT pathways seem to be of particular oncogenic significance in cHL and PMBCL, as they are targeted by multiple genetic aberrations (JAK2 locus gains, point mutations and deletions of SOCS1). [19][20][21] Although the presence of JAK2 mutations in lymphomas has been addressed in larger cohorts, 22,23 there are little systemic data on the presence of numerical and structural aberrations of JAK2.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 66%

Section: Prognostic Significancementioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2009

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“…12,13 Recently, it has been reported that STAT3 is overexpressed in ABC-type DLBCL human cell lines. 14,15 The role of pSTAT3 as a prognostic factor in DLBCL patients treated with R-CHOP-based therapies is unknown.Translocations involving the MYC gene at 8q24 are associated with Burkitt lymphoma. 16 Moreover, MYC translocations have been reported to occur in DLBCL with a frequency of 5%-10%.…”

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confidence: 99%

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

Gupta¹,

Maurer²,

Wellik³

et al. 2012

Blood

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35% of cases were pSTAT3-positive, and pSTAT3 positivity was more frequent in the non-GCB (P ‫؍‬ .06) type but did not correlate with event-free survival (EFS). Myc expression was observed in 50% of cases and was more frequent in non-GCB type (P ‫؍‬ .07). Myc-positive cases had inferior EFS in all patients, including the GCB and pSTAT3-positive cases, were more likely to express Myc (P ‫؍‬ .06). Myc translocations involving the major breakpoint regions were found in 10% (3 of 29) of cases, and all 3 cases were GCB and had an inferior EFS (P ‫؍‬ .09). pSTAT3, but not Myc expression, was correlated with elevated pretreatment serum cytokines, such as IL-10 (P ‫؍‬ .05), G-CSF (P ‫؍‬ .03), and TNF-␣ (P ‫؍‬ .04). pSTAT3 IHC in DLBCL tumors has the potential to identify patients for STAT3 pathway-directed therapy; Myc IHC is a potential marker for inferior EFS in GCB patients. (Blood. 2012; 120(22):4400-4406) IntroductionThe most significant advance in the treatment of diffuse large B-cell lymphoma (DLBCL) over the past 15 years has been the addition of rituximab to standard CHOP chemotherapy (R-CHOP). [1][2][3] We recently demonstrated in a phase 2 study (N0489; www.clinicaltrials.gov, #NCT00301821) that the anti-CD22 monoclonal antibody epratuzumab can be successfully added to R-CHOP (ER-CHOP) without additional toxicity and with potentially improved survival parameters. 4 Despite these advances, 30%-40% of patients still relapse and die of disease. Current pathology practice classifies DLBCL into at least 3 distinct subtypes: germinal center B cell-like (GCB), activated B cell-like (ABC), and primary mediastinal B-cell lymphoma by gene expression profiling or immunohistochemistry (IHC). 5,6 These classifications are being evaluated in new DLBCL trials, and there have been some reports suggesting that agents, such as bortezomib and lenalidomide, are more effective in non-GCB type DLBCL. 7,8 To improve outcomes for DLBCL patients, it is necessary to identify additional novel targets within GCB and non-GCB classifications to further stratify patients for prognosis and assist in choosing therapy for the individual patient.Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor that resides in the cytoplasm. 9 Phosphorylation of STAT3 (pSTAT3) at its Tyr-705 residue (pSTAT3 Tyr705 ) leads to activation and translocation to the nucleus where pSTAT3 regulates several target genes, such as MYC. 10,11 Constitutively active STATs (particularly STAT3 and STAT5) contribute to the malignant phenotype in both human cancer cell lines and primary tumors. 12,13 Recently, it has been reported that STAT3 is overexpressed in ABC-type DLBCL human cell lines. 14,15 The role of pSTAT3 as a prognostic factor in DLBCL patients treated with R-CHOP-based therapies is unknown.Translocations involving the MYC gene at 8q24 are associated with Burkitt lymphoma. 16 Moreover, MYC translocations have been reported to occur in DLBCL with a frequency of 5%-10%. [17][18][19] Myc protein can be expressed ...

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JAK/STATSignalling and Haematological Malignancies

Constantinescu

Vainchenker

2015

Encyclopedia of Life Sciences

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A major focus of investigation and drug screening efforts started with the discovery of JAK2V617F as a major driver of the BCR‐ABL‐negative myeloproliferative neoplasms (MPNs). An acquired somatic mutation, JAK2V617F , drives 65% of MPNs. Further studies established that these diseases almost always exhibit mutations leading to persistent JAK2‐STAT5 activation. Sequencing of the four mammalian JAKs (Janus kinases) ( JAK1 , JAK2 , JAK3 and TYK2 ) and of the seven STATs (signal transducers and activators of transcriptions) in a variety of cancers identified the pathologic activation of these JAKs and STATs, by mutations in the genes themselves or in upstream or downstream regulators as significant contributors to several haematological and solid malignancies. The development of JAK2, JAK1, JAK3 and TYK2 kinase inhibitors is unfolding with JAK2, JAK1 and JAK3 inhibitors being approved in certain conditions. Altogether, the JAK/STAT pathway became a new gold mine for discovery and therapy in haematological cancers. Key Concepts The JAK/STAT pathway has a central role in cytokine signalling in normal haematopoiesis. The JAK/STAT pathway is frequently pathologically activated by several mechanisms in many types of haematological malignancies. The JAK/STAT pathway can be targeted by small molecules. The JAK/STAT pathway can be pathologically activated by down‐modulation of negative regulators such as phosphatases. Constitutive STAT activation in blood cancers can be the result of several activated kinases, not only JAKs. JAK2 activation is the main mechanismresponsible of the poorprognosis of mostpediatric B‐cell acute lymphoblasticleukemia.

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Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas

Cited by 277 publications

References 54 publications

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

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

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

JAK/STATSignalling and Haematological Malignancies

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