JAK/STAT signal transduction: Regulators and implication in hematological malignancies

Valentino, Lyne; Pierre, Josiane

doi:10.1016/j.bcp.2005.12.017

Cited by 221 publications

(172 citation statements)

References 97 publications

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“…1,13,15 Mutations and translocations of the JAK2 gene, mapped at 9p24, lead to constitutive activation of the JAK2 kinase and its downstream targets in myeloid malignancies, 2-12 but little is known about the molecular epidemiology of numerical and structural JAK2 aberrations in lymphoid malignancies. Our FISH data confirm and substantially extend data from previous studies on numerical and structural JAK2 gene aberrations in lymphomas by taking advantage of a validated lymphoma TMA in a large cohort of cases covering a broad spectrum of disease entities currently recognized by the WHO.…”

Section: Discussionmentioning

confidence: 99%

“…13 A specific phosphotyrosine domain in these receptors works in association with a phosphorylated JAK (pJAK) as binding ligand for the SH2 domain of signal transducers and activators of transcription (STAT). In turn, STAT become phosphorylated, dimerize and subsequently migrate to the nucleus to induce transcription of target genes.…”

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confidence: 99%

“…14 STAT are regulated by protein inhibitors of activated STAT (PIAS), phosphotyrosine phosphatases and suppressors of cytokine signaling (SOCS). 13 STAT3 and, particularly, STAT5 are the preferred downstream targets of phosphorylated JAK2 (pJAK2). 1,12 Both STAT3 and STAT5 have been shown to be of functional importance in lymphomas.…”

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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: Discussionmentioning

confidence: 99%

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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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“…From the scientific standpoint, it is well known now that the cancer cell growth pathway is complicated, interrelated and multi-factorial (Valentino and Pierre, 2006). Identifying and overcoming one target has often proved fruitless until it is known that the whole pathway, can actually be blocked by doing so, or that the other integrated pathways do not surpass what is achieved by blocking one particular track.…”

Section: Molecular Targeting Agents In Cancer Therapy: Science and Somentioning

confidence: 99%

Molecular Targeting Agents in Cancer Therapy: Science and Society

Shaikh

2012

Asian Pacific Journal of Cancer Prevention

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“…Binding of cytokines results in cell surface receptor oligomerization and activation of the Jak family of tyrosine kinases (47). Activated Jaks phosphorylate the cytoplasmic domain of the receptor, thereby creating docking sites for STATs, which are phosphorylated by Jaks and consequently dimerize and migrate to the nucleus where they regulate gene transcription (47).…”

Section: Jak/statmentioning

confidence: 99%

Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

Cardoso

Gírio

Henriques

et al. 2008

Braz J Med Biol Res

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JAK/STAT signal transduction: Regulators and implication in hematological malignancies

Cited by 221 publications

References 97 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

Molecular Targeting Agents in Cancer Therapy: Science and Society

Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

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