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 journalArticle

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 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
Volume128
Issue number1
DOIs
StatePublished - Jan 2 2018

Fingerprint

Blood Vessels
Neoplasms
Erythrocyte Volume
Thrombocytosis
Philadelphia Chromosome
Polycythemia
Erythroid Cells
Splenomegaly
Myeloid Cells
platelet protein P47
Thrombosis
Erythrocytes
Morbidity
Phenotype
Mutation
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhao, Baobing ; Mei, Yang ; Cao, Lan ; Zhang, Jingxin ; Sumagin, Ronen ; Yang, Jing ; Gao, Juehua ; Schipma, Matthew J. ; Wang, Yanfeng ; Thorsheim, Chelsea ; Zhao, Liang ; Stalker, Timothy ; Stein, Brady ; Wen, Qiang Jeremy ; Crispino, John D. ; Abrams, Charles S. ; Ji, Peng. / Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 V617F -positive myeloproliferative neoplasms In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 1. pp. 125-140.
@article{544cbfbdf9164479b4f9932257f5e59e,
title = "Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 V617F -positive myeloproliferative neoplasms",
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 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.",
author = "Baobing Zhao and Yang Mei and Lan Cao and Jingxin Zhang and Ronen Sumagin and Jing Yang and Juehua Gao and Schipma, {Matthew J.} and Yanfeng Wang and Chelsea Thorsheim and Liang Zhao and Timothy Stalker and Brady Stein and Wen, {Qiang Jeremy} and Crispino, {John D.} and Abrams, {Charles S.} and Peng Ji",
year = "2018",
month = "1",
day = "2",
doi = "10.1172/JCI94518",
language = "English (US)",
volume = "128",
pages = "125--140",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 V617F -positive myeloproliferative neoplasms . / Zhao, Baobing; Mei, Yang; Cao, Lan; Zhang, Jingxin; Sumagin, Ronen; Yang, Jing; Gao, Juehua; Schipma, Matthew J.; Wang, Yanfeng; Thorsheim, Chelsea; Zhao, Liang; Stalker, Timothy; Stein, Brady; Wen, Qiang Jeremy; Crispino, John D.; Abrams, Charles S.; Ji, Peng.

In: Journal of Clinical Investigation, Vol. 128, No. 1, 02.01.2018, p. 125-140.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 V617F -positive myeloproliferative neoplasms

AU - Zhao, Baobing

AU - Mei, Yang

AU - Cao, Lan

AU - Zhang, Jingxin

AU - Sumagin, Ronen

AU - Yang, Jing

AU - Gao, Juehua

AU - Schipma, Matthew J.

AU - Wang, Yanfeng

AU - Thorsheim, Chelsea

AU - Zhao, Liang

AU - Stalker, Timothy

AU - Stein, Brady

AU - Wen, Qiang Jeremy

AU - Crispino, John D.

AU - Abrams, Charles S.

AU - Ji, Peng

PY - 2018/1/2

Y1 - 2018/1/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040173951&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040173951&partnerID=8YFLogxK

U2 - 10.1172/JCI94518

DO - 10.1172/JCI94518

M3 - Article

VL - 128

SP - 125

EP - 140

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -