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

doi:10.1172/JCI94518

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 journal › Article › peer-review

35 Scopus citations

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 language	English (US)
Pages (from-to)	125-140
Number of pages	16
Journal	Journal of Clinical Investigation
Volume	128
Issue number	1
DOIs	https://doi.org/10.1172/JCI94518
State	Published - Jan 2 2018

Funding

We thank Benjamin Ebert and Ann Mullally (Harvard Medical School) for the gift of the JAK2V617F-knockin mice and SET-2 cell line, Lily Huang (University of Texas Southwestern Medical Center) for JAK2 constructs, and Merav Socolovsky (University of Massachusetts Medical School) for STAT5 constructs. We also thank Lin Li of the mouse histology and phenotyping laboratory at Northwestern University for the help with mouse phenotyping analyses. This work was supported by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) grant DK102718, Department of Defense grant CA140119, and a Dixon Translational Research Grant (all to PJ). This work was also supported by National Heart, Lung, and Blood Institute (NHLBI) grants HL112792 (to JDC), HL120846 (to CSA), and HL40387 (to CSA).

ASJC Scopus subject areas

General Medicine

Access to Document

10.1172/JCI94518

Cite this

Zhao, B., Mei, Y., Cao, L., Zhang, J., Sumagin, R., Yang, J., Gao, J., Schipma, M. J., Wang, Y., Thorsheim, C., Zhao, L., Stalker, T., Stein, B., Wen, Q. J., Crispino, J. D., Abrams, C. S., & Ji, P. (2018). Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 ^V617F -positive myeloproliferative neoplasms Journal of Clinical Investigation, 128(1), 125-140. https://doi.org/10.1172/JCI94518

@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",

note = "Funding Information: We thank Benjamin Ebert and Ann Mullally (Harvard Medical School) for the gift of the JAK2V617F-knockin mice and SET-2 cell line, Lily Huang (University of Texas Southwestern Medical Center) for JAK2 constructs, and Merav Socolovsky (University of Massachusetts Medical School) for STAT5 constructs. We also thank Lin Li of the mouse histology and phenotyping laboratory at Northwestern University for the help with mouse phenotyping analyses. This work was supported by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) grant DK102718, Department of Defense grant CA140119, and a Dixon Translational Research Grant (all to PJ). This work was also supported by National Heart, Lung, and Blood Institute (NHLBI) grants HL112792 (to JDC), HL120846 (to CSA), and HL40387 (to CSA).",

year = "2018",

month = jan,

day = "2",

doi = "10.1172/JCI94518",

language = "English (US)",

volume = "128",

pages = "125--140",

journal = "Journal of Clinical Investigation",

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Zhao, B, Mei, Y, Cao, L, Zhang, J, Sumagin, R, Yang, J, Gao, J , Schipma, MJ, Wang, Y, Thorsheim, C, Zhao, L, Stalker, T, Stein, B, Wen, QJ, Crispino, JD, Abrams, CS & Ji, P 2018, ' Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 ^V617F -positive myeloproliferative neoplasms ', Journal of Clinical Investigation, vol. 128, no. 1, pp. 125-140. https://doi.org/10.1172/JCI94518

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2 ^V617F -positive myeloproliferative neoplasms . / Zhao, Baobing; Mei, Yang; Cao, Lan et al.
In: Journal of Clinical Investigation, Vol. 128, No. 1, 02.01.2018, p. 125-140.

Research output: Contribution to journal › Article › peer-review

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

N1 - Funding Information: We thank Benjamin Ebert and Ann Mullally (Harvard Medical School) for the gift of the JAK2V617F-knockin mice and SET-2 cell line, Lily Huang (University of Texas Southwestern Medical Center) for JAK2 constructs, and Merav Socolovsky (University of Massachusetts Medical School) for STAT5 constructs. We also thank Lin Li of the mouse histology and phenotyping laboratory at Northwestern University for the help with mouse phenotyping analyses. This work was supported by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) grant DK102718, Department of Defense grant CA140119, and a Dixon Translational Research Grant (all to PJ). This work was also supported by National Heart, Lung, and Blood Institute (NHLBI) grants HL112792 (to JDC), HL120846 (to CSA), and HL40387 (to CSA).

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.

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