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.
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
Title and authors | Publication | Year |
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Pleckstrin-2 mediates the activation of AKT in prostate cancer and is repressed by AR
Peng Ji, Xu Han, Pan Wang, Kehan Ren, Ermin Li, Ximing Yang, Honghao Bi, Inci Aydemir, Sarki Abdulkadir, Jing Yang |
The American Journal of Pathology | 2024 |
Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms
Dunbar AJ, Bowman RL, Park YC, O'Connor K, Izzo F, Myers RM, Karzai A, Zaroogian Z, Kim WJ, Fernández-Maestre I, Waarts MR, Nazir A, Xiao W, Codilupi T, Brodsky M, Farina M, Cai L, Cai SF, Wang B, An W, Yang JL, Mowla S, Eisman SE, Hanasoge Somasundara AV, Glass JL, Mishra T, Houston R, Guzzardi E, Martinez Benitez AR, Viny AD, Koche RP, Meyer SC, Landau DA, Levine RL |
Cancer Discovery | 2024 |
Exacerbation of thromboinflammation by JAK2V617F mutation worsens the prognosis of cerebral venous sinus thrombosis
Bourrienne MC, Le Cam Duchez V, Faille D, Farkh C, Solo Nomenjanahary M, Gay J, Loyau S, Journé C, Dupont S, Ollivier V, Villeval JL, Plo I, Edmond V, Jandrot-Perrus M, Labrouche-Colomer S, Cassinat B, Verger E, Desilles JP, Ho-Tin-Noé B, Triquenot Bagan A, Mazighi M, Ajzenberg N |
Blood Advances | 2024 |
Development of iPSC-derived human bone marrow organoid for autonomous hematopoiesis and patient-derived HSPC engraftment
Ren K, Li E, Aydemir I, Liu Y, Han X, Bi H, Wang P, Tao K, Ji A, Chen YH, Yang J, Sukhanova M, Ji P |
Blood Advances | 2024 |