Abstract
Deregulated JAK2 signaling plays an important role in the pathogenesis of myeloproliferative neoplasms (MPN). We and others have shown constitutive activation of JAK2 and STAT3 in diffuse large B cell lymphomas (DLBCL). We sought to determine the mechanism of JAK2 signaling in DLBCL tumors with a genetic approach. The most common JAK2 activating mutation present in most MPNs is V617F (exon 14 within the pseudokinase-domain); however, this mutation is absent in lymphoid malignancies. We bi-directionally sequenced all the domains of the JAK2 gene and performed mutational analysis. No novel non-synonymous mutations were detected in the 40 DLBCL tumors tested. However synonymous and non-synonymous single nucleotide polymorphism (SNPs) were detected within the exons 6, 9 and 19 in the majority of patients. Taken together, these data suggest that other mechanisms for altered JAK2 signaling aside from activating JAK2 mutations are present in DLBCL. Targeting JAK2 activation could be an important therapeutic target for DLBCL. Indeed, the JAK2 inhibitor ruxolitinib is now approved for the treatment of MPN. Our study indicates that JAK2 targeted clinical trials in lymphoma should not be confined to only JAK2 mutation cases but rather based on pathway activation.