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

Abstract

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

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

“…26 Amplification of 9p.24 locus containing the JAK2 gene were detected in various lymphoma subtypes, including primary mediastinal B-cell lymphomas, Hodgkin's lymphomas and angioimmunoblastic T-cell lymphomas. 27,28 Our cellular data, combined with these published observations, provide a rationale for clinical trials with SB1518 in lymphoma and may account for some of the promising efficacy, including partial responses, observed in ongoing phase 1 trials. 5,29 Our animal model data provide further rationale for the clinical trials with SB1518 in patients with JAK2-driven disease.…”

Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays

“…'s 19 A case was classified as carrier of deletion or trisomy provided that a concomitant normal hybridization pattern was observed with the chromosome-10-centromeric probe. As previously described by Meiner et al 27 amplification was defined as the presence of tumor cell nuclei with three or more signals exceeding the mean plus 3 s.d. of tri-/polysome nuclei in the reference cases.…”

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

“…Interestingly, both STAT5A overexpression and STAT5 activation were recently reported in FL samples. 34,35 Besides its effect on STAT5 expression, our work reveals that CD40L cooperates with IL-15 to favor STAT5 activation through a transduction pathway involving Src tyrosine kinase. Several other mechanisms could support the interconnection between IL-15 and CD40L signals.…”