Pleckstrin-2 Plays an Essential Role in the Pathogenesis of JAK2^V617F-Induced Myeloproliferative Neoplasms

V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Studies on the pathogenesis of JAK2^V617F positive MPNs have primarily focused on deregulation of JAK2 and STAT activities. It remains unclear exactly how JAK2-STAT downstream targets are involved in the development of the MPNs. We previously reported that pleckstrin-2 (Plek2) plays an important role in terminal erythropoiesis in vitro. Here we show that Plek2 is a downstream target of the JAK2-STAT5 pathway in erythroid, megakaryocytic, and granulocytic cells. Plek2 is significantly upregulated by JAK2^V617F in both transduced primary mouse hematopoietic cells and in patients with JAK2^V617F positive MPNs. Using a JAK2^V617F knockin mouse model, we demonstrated that loss of Plek2 ameliorated JAK2^V617F-induced myeloproliferative phenotypes including reticulocytosis, thrombocytosis, neutrophilia, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality of JAK2^V617F knockin mice (Figure 1A). These phenotypes were also transplantable indicating the role of Plek2 in mediating the pathogenesis of JAK2V617F-induced MPNs is cell-intrinsic (Figure 1B). Our study identifies Plek2 as a novel effector of JAK2-STAT5 pathway and a key factor in the pathogenesis of JAK2^V617F-induced MPNs.

Figure 1.

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Loss of Plek2 Rescues The Lethality of JAK2^V617F Knockin Mice. (A) Kaplan-Meier survival analysis of indicated mice. Both males and females were included in each group. JAK2^+/+Plek2^+/+mice, n=34; JAK2^+/+Plek2^-/-mice, n=34;JAK2^VF/+Plek2^+/+ mice, n=36; JAK2^VF/+Plek2^-/- mice, n=36. (B) Kaplan-Meier survival analysis of the transplanted mice. JAK2^+/+Plek2^+/+mice, n=10; JAK2^+/+Plek2^-/-mice, n=10;JAK2^VF/+Plek2^+/+ mice, n=17; JAK2^VF/+Plek2^-/- mice, n=17.

Figure 1.

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Loss of Plek2 Rescues The Lethality of JAK2^V617F Knockin Mice. (A) Kaplan-Meier survival analysis of indicated mice. Both males and females were included in each group. JAK2^+/+Plek2^+/+mice, n=34; JAK2^+/+Plek2^-/-mice, n=34;JAK2^VF/+Plek2^+/+ mice, n=36; JAK2^VF/+Plek2^-/- mice, n=36. (B) Kaplan-Meier survival analysis of the transplanted mice. JAK2^+/+Plek2^+/+mice, n=10; JAK2^+/+Plek2^-/-mice, n=10;JAK2^VF/+Plek2^+/+ mice, n=17; JAK2^VF/+Plek2^-/- mice, n=17.

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