The JAK2-V617F Mutant Found in Myeloproliferative Disorders and Acute Myeloid Leukemia Cooperates with the EpoR, but Not with FLT3 To Promote Proliferation of IL-3 Dependent Cells.

The Janus Kinase (JAK) 2 mutation V617F can be detected in patients with polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) as well as at low percentages in other myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDS) and in 5–6% of de novo AML. Moreover, a recent study showed that JAK2 complemented by an additional signal of KIT or FLT3 confers self renewal capacity to hematopoietic cells. Since the JAK2V617F mutation is found in AML, we asked whether JAK2 might cooperate with FLT3, a receptor tyrosine kinase that is overexpressed in most patients with AML to induce proliferation.

JAK2-WT and JAK2V617F did not confer factor independent growth when expressed in IL-3 dependent Ba/F3 cells. Further, exploring the coordination of JAK2 and its mutant with the type I cytokine receptor EpoR, Ba/F3 cells co-expressing both JAK2 and EpoR showed proliferation in the presence of Epo but not in the absence of Epo. In contrast Ba/F3 cells co-expressing JAK2V617F and EpoR have a profound proliferation advantage and are able to grow in the absence of Epo. These data provide strong evidence that JAK2V617F has transforming potential in the presence of a type I cytokine receptor. The coexpression of the JAK2V617F mutant with a class III cytokine receptor like FLT3, which is involved in the pathogenesis of acute myeloid leukemia (AML), does not result in an increased proliferative response. Both, JAK2-WT and JAK2V617F expressing Ba/F3 cells were able to survive in the presence of the FLT3 receptor, but did not show autonomous growth.

Analysis of signaling pathways showed that the JAK2-V617F mutant, but not JAK2-WT is able to activate STAT5 in cooperation with the EpoR and FLT3.

Our data show that the JAK2-V617F mutant which is found in 5–6% of AML patients cooperates with the EpoR, but not with FLT3 to promote proliferation in IL-3 dependent cells.