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Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms
Baobing Zhao, … , Charles S. Abrams, Peng Ji
Baobing Zhao, … , Charles S. Abrams, Peng Ji
Published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):125-140. https://doi.org/10.1172/JCI94518.
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Research Article Hematology

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

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Abstract

V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombosis is a leading cause of mortality and morbidity in MPNs, the mechanisms underlying their pathogenesis are unclear. Here, we identified pleckstrin-2 (Plek2) as a downstream target of the JAK2/STAT5 pathway in erythroid and myeloid cells, and showed that it is upregulated in a JAK2V617F-positive MPN mouse model and in patients with MPNs. Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality in JAK2V617F-knockin mice. Additionally, we demonstrated that a reduction in red blood cell mass was the main contributing factor in the reversion of vascular occlusions. Thus, our study identifies Plek2 as an effector of the JAK2/STAT5 pathway and a key factor in the pathogenesis of JAK2V617F-induced MPNs, pointing to Plek2 as a viable target for the treatment of MPNs.

Authors

Baobing Zhao, Yang Mei, Lan Cao, Jingxin Zhang, Ronen Sumagin, Jing Yang, Juehua Gao, Matthew J. Schipma, Yanfeng Wang, Chelsea Thorsheim, Liang Zhao, Timothy Stalker, Brady Stein, Qiang Jeremy Wen, John D. Crispino, Charles S. Abrams, Peng Ji

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Figure 7

Loss of Plek2 rescues the lethality of the JAK2V617F-knockin mice.

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Loss of Plek2 rescues the lethality of the JAK2V617F-knockin mice.
(A) K...
(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; JAK2VF/+ Plek2+/+ mice, N = 36; JAK2VF/+ Plek2–/– mice, N = 36. (B) Total bone marrow cells from the indicated mice (CD45.2+, 6 weeks old) were transplanted into lethally irradiated recipient mice (CD45.1+, 6 weeks old). Complete blood counts were performed 3 months after transplantation. Each data point represents 1 mouse. The data are shown as the mean ± SD. *P < 0.05, **P < 0.01, and ****P < 0.0001; all P values were determined by 1-way ANOVA with Tukey’s multiple comparisons test. M, millions; K, thousands. (C) Kaplan-Meier survival analysis of the transplanted mice. JAK2+/+ Plek2+/+ mice, N = 10; JAK2+/+ Plek2–/– mice, N = 10; JAK2VF/+ Plek2+/+ mice, N = 17; JAK2VF/+ Plek2–/– mice, N = 17.
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