Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 V617F -positive myeloproliferative neoplasms

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 JAK2 V617F -positive MPN mouse model and in patients with MPNs. Loss of Plek2 ameliorated JAK2 V617F -induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality in JAK2 V617F -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 JAK2 V617F -induced MPNs, pointing to Plek2 as a viable target for the treatment of MPNs.

Original languageEnglish (US)
Pages (from-to)125-140
Number of pages16
JournalJournal of Clinical Investigation
Issue number1
StatePublished - Jan 2 2018

ASJC Scopus subject areas

  • Medicine(all)


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