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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 8

Loss of Plek2 reverts the vascular occlusions in the JAK2V617F-knockin mice.

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Loss of Plek2 reverts the vascular occlusions in the JAK2V617F-knockin m...
(A) Histologic examination of the lungs and kidneys of the indicated mice. The histologic images are representative of 5 mice in each group analyzed. Arrows indicate vascular occlusions with diameters larger than 50 μm in the lungs (top panels) and numerous small occlusions in the kidneys (bottom panels). Scale bars: 100 μm. (B) Quantification of the number of vascular clots (>50 μm in diameter per ×4 field) in the lungs from JAK2VF/+ Plek2+/+ and JAK2VF/+ Plek2–/– mice. Fifteen fields were analyzed from 5 mice in each group. P value was determined by multiple 2-tailed t tests. (C) Histologic examination (H&E) and immunohistochemical stains of Gr1 to reveal granulocytes of the representative occlusions from the lungs of the indicated mice. Images are representative of 5 mice in each group analyzed. Scale bars: 20 μm. (D) Intravital imaging was performed on vasculature of the small intestine to examine platelet aggregation. Blood vessels and platelets were immunofluorescently stained for PECAM-1 (red) and CD41 (green), respectively. Scale bar: 100 μm. (E) Platelet velocity in the non-occluded area was quantified. Data were obtained from 3 independent experiments. P value was determined by multiple 2-tailed t tests.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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