SDF1α-induced chemotaxis of JAK2-V617F positive cells is dependent on Bruton's Tyrosine Kinase and its downstream targets PI3K/AKT, PLCγ1 and RhoA

Nimmagadda, S.C., Frey, S., Müller, P., Wolleschak, D., Weinert, S., Keller, U., Edelmann, B., Fischer, T. (2019). Haematologica 104, e288-e292.

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JAK2-V617F is present in nearly 95% of patients with polycythemia vera and 50-60% of those with essential thrombocythemia or primary myelofibrosis. In addition to erythrocytosis, thrombocytosis and bone marrow fibrosis (as in polycythemia vera, essential thrombocythemia, and primary myelofibrosis, respectively), the clinical course of patients with myeloproliferative neoplasia (MPN) is characterized by increased risks of thrombosis, splenomegaly and an inflammatory response syndrome. Clinical studies of JAK kinase inhibitors have shown that these agents can produce considerable improvements of splenomegaly, constitutive symptoms, and overall survival in MPN patients. However, the therapeutic response is often limited and short-lived. In addition, transformation to acute leukemia remains a major problem. It is, therefore, essential to identify novel nodes of constitutive JAK2-V617F signaling and to develop better approaches to the therapy of these neoplasias. Downstream of JAK2-V617F, NFκB signaling (p65) is constitutively active and regulates expression of CXCL10 in MPN. In bortezomib-resistant multiple myeloma cells and in acute myeloid leukemia cells with MLL-AF9 rearrangements, constitutively active NFκB drives the expression of Bruton tyrosine kinase (BTK). Of note, it was found that BTK interacted with erythropoietin receptor-JAK2 and was tyrosine phosphorylated in response to treatment with erythropoietin. These observations led us to investigate whether JAK2-V617F kinase also induces BTK expression (via p65) and activation and to characterize its physiological relevance in JAK2-V617F-positive cells.