Activation of JAK/STAT signaling in megakaryocytes sustains myeloproliferation in vivo

Brittany Woods, Wei Chen, Sophia Chiu, Christian Marinaccio, Chunling Fu, Lilly Gu, Marinka Bulic, Qiong Yang, Anouar Zouak, Shengxian Jia, Praveen Kumar Suraneni, Kailin Xu, Ross L. Levine, John D. Crispino, Qiang Jeremy Wen*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: The myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by the expansion of the erythroid, megakaryocytic, and granulocytic lineages. A common feature of these disorders is the presence of abnormal megakaryocytes, which have been implicated as causative agents in the development of bone marrow fibrosis. However, the specific contributions of megakaryocytes to MPN pathogenesis remain unclear. Experimental Design: We used Pf4-Cre transgenic mice to drive expression of JAK2V617F in megakaryocyte lineage-committed hematopoietic cells. We also assessed the critical role of mutant megakaryocytes in MPN maintenance through cell ablation studies in JAK2V617F and MPLW515L BMT models of MPN. Results: JAK2V617F-mutant presence in megakaryocytes was sufficient to induce enhanced erythropoiesis and promote fibrosis, which leads to a myeloproliferative state with expansion of mutant and nonmutant hematopoietic cells. The increased erythropoiesis was associated with elevated IL6 level, which was also required for aberrant erythropoiesis in vivo. Furthermore, depletion of megakaryocytes in the JAK2V617F and MPLW515L BMT models ameliorated polycythemia and leukocytosis in addition to expected effects on megakaryopoiesis. Conclusions: Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance in vivo. These observations indicate that MPN clone can influence the behavior of the wild-type hematopoietic milieu, at least, in part, via altered production of proinflammatory cytokines and chemokines. Our findings resonate with patients who present with a clinical MPN and a low JAK2V617F allele burden, and support the development of MPN therapies aimed at targeting megakaryocytes.

Original languageEnglish (US)
Pages (from-to)5901-5912
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2019

Fingerprint

Megakaryocytes
Erythropoiesis
Neoplasms
Primary Myelofibrosis
Maintenance
Essential Thrombocythemia
Polycythemia Vera
Polycythemia
Leukocytosis
Chemokines
Transgenic Mice
Interleukin-6
Fibrosis
Research Design
Clone Cells
Alleles
Cytokines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Woods, Brittany ; Chen, Wei ; Chiu, Sophia ; Marinaccio, Christian ; Fu, Chunling ; Gu, Lilly ; Bulic, Marinka ; Yang, Qiong ; Zouak, Anouar ; Jia, Shengxian ; Suraneni, Praveen Kumar ; Xu, Kailin ; Levine, Ross L. ; Crispino, John D. ; Wen, Qiang Jeremy. / Activation of JAK/STAT signaling in megakaryocytes sustains myeloproliferation in vivo. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 19. pp. 5901-5912.
@article{b2659abc773440a599437de9f9cac25a,
title = "Activation of JAK/STAT signaling in megakaryocytes sustains myeloproliferation in vivo",
abstract = "Purpose: The myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by the expansion of the erythroid, megakaryocytic, and granulocytic lineages. A common feature of these disorders is the presence of abnormal megakaryocytes, which have been implicated as causative agents in the development of bone marrow fibrosis. However, the specific contributions of megakaryocytes to MPN pathogenesis remain unclear. Experimental Design: We used Pf4-Cre transgenic mice to drive expression of JAK2V617F in megakaryocyte lineage-committed hematopoietic cells. We also assessed the critical role of mutant megakaryocytes in MPN maintenance through cell ablation studies in JAK2V617F and MPLW515L BMT models of MPN. Results: JAK2V617F-mutant presence in megakaryocytes was sufficient to induce enhanced erythropoiesis and promote fibrosis, which leads to a myeloproliferative state with expansion of mutant and nonmutant hematopoietic cells. The increased erythropoiesis was associated with elevated IL6 level, which was also required for aberrant erythropoiesis in vivo. Furthermore, depletion of megakaryocytes in the JAK2V617F and MPLW515L BMT models ameliorated polycythemia and leukocytosis in addition to expected effects on megakaryopoiesis. Conclusions: Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance in vivo. These observations indicate that MPN clone can influence the behavior of the wild-type hematopoietic milieu, at least, in part, via altered production of proinflammatory cytokines and chemokines. Our findings resonate with patients who present with a clinical MPN and a low JAK2V617F allele burden, and support the development of MPN therapies aimed at targeting megakaryocytes.",
author = "Brittany Woods and Wei Chen and Sophia Chiu and Christian Marinaccio and Chunling Fu and Lilly Gu and Marinka Bulic and Qiong Yang and Anouar Zouak and Shengxian Jia and Suraneni, {Praveen Kumar} and Kailin Xu and Levine, {Ross L.} and Crispino, {John D.} and Wen, {Qiang Jeremy}",
year = "2019",
month = "10",
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doi = "10.1158/1078-0432.CCR-18-4089",
language = "English (US)",
volume = "25",
pages = "5901--5912",
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Woods, B, Chen, W, Chiu, S, Marinaccio, C, Fu, C, Gu, L, Bulic, M, Yang, Q, Zouak, A, Jia, S, Suraneni, PK, Xu, K, Levine, RL, Crispino, JD & Wen, QJ 2019, 'Activation of JAK/STAT signaling in megakaryocytes sustains myeloproliferation in vivo', Clinical Cancer Research, vol. 25, no. 19, pp. 5901-5912. https://doi.org/10.1158/1078-0432.CCR-18-4089

Activation of JAK/STAT signaling in megakaryocytes sustains myeloproliferation in vivo. / Woods, Brittany; Chen, Wei; Chiu, Sophia; Marinaccio, Christian; Fu, Chunling; Gu, Lilly; Bulic, Marinka; Yang, Qiong; Zouak, Anouar; Jia, Shengxian; Suraneni, Praveen Kumar; Xu, Kailin; Levine, Ross L.; Crispino, John D.; Wen, Qiang Jeremy.

In: Clinical Cancer Research, Vol. 25, No. 19, 01.10.2019, p. 5901-5912.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of JAK/STAT signaling in megakaryocytes sustains myeloproliferation in vivo

AU - Woods, Brittany

AU - Chen, Wei

AU - Chiu, Sophia

AU - Marinaccio, Christian

AU - Fu, Chunling

AU - Gu, Lilly

AU - Bulic, Marinka

AU - Yang, Qiong

AU - Zouak, Anouar

AU - Jia, Shengxian

AU - Suraneni, Praveen Kumar

AU - Xu, Kailin

AU - Levine, Ross L.

AU - Crispino, John D.

AU - Wen, Qiang Jeremy

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Purpose: The myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by the expansion of the erythroid, megakaryocytic, and granulocytic lineages. A common feature of these disorders is the presence of abnormal megakaryocytes, which have been implicated as causative agents in the development of bone marrow fibrosis. However, the specific contributions of megakaryocytes to MPN pathogenesis remain unclear. Experimental Design: We used Pf4-Cre transgenic mice to drive expression of JAK2V617F in megakaryocyte lineage-committed hematopoietic cells. We also assessed the critical role of mutant megakaryocytes in MPN maintenance through cell ablation studies in JAK2V617F and MPLW515L BMT models of MPN. Results: JAK2V617F-mutant presence in megakaryocytes was sufficient to induce enhanced erythropoiesis and promote fibrosis, which leads to a myeloproliferative state with expansion of mutant and nonmutant hematopoietic cells. The increased erythropoiesis was associated with elevated IL6 level, which was also required for aberrant erythropoiesis in vivo. Furthermore, depletion of megakaryocytes in the JAK2V617F and MPLW515L BMT models ameliorated polycythemia and leukocytosis in addition to expected effects on megakaryopoiesis. Conclusions: Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance in vivo. These observations indicate that MPN clone can influence the behavior of the wild-type hematopoietic milieu, at least, in part, via altered production of proinflammatory cytokines and chemokines. Our findings resonate with patients who present with a clinical MPN and a low JAK2V617F allele burden, and support the development of MPN therapies aimed at targeting megakaryocytes.

AB - Purpose: The myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by the expansion of the erythroid, megakaryocytic, and granulocytic lineages. A common feature of these disorders is the presence of abnormal megakaryocytes, which have been implicated as causative agents in the development of bone marrow fibrosis. However, the specific contributions of megakaryocytes to MPN pathogenesis remain unclear. Experimental Design: We used Pf4-Cre transgenic mice to drive expression of JAK2V617F in megakaryocyte lineage-committed hematopoietic cells. We also assessed the critical role of mutant megakaryocytes in MPN maintenance through cell ablation studies in JAK2V617F and MPLW515L BMT models of MPN. Results: JAK2V617F-mutant presence in megakaryocytes was sufficient to induce enhanced erythropoiesis and promote fibrosis, which leads to a myeloproliferative state with expansion of mutant and nonmutant hematopoietic cells. The increased erythropoiesis was associated with elevated IL6 level, which was also required for aberrant erythropoiesis in vivo. Furthermore, depletion of megakaryocytes in the JAK2V617F and MPLW515L BMT models ameliorated polycythemia and leukocytosis in addition to expected effects on megakaryopoiesis. Conclusions: Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance in vivo. These observations indicate that MPN clone can influence the behavior of the wild-type hematopoietic milieu, at least, in part, via altered production of proinflammatory cytokines and chemokines. Our findings resonate with patients who present with a clinical MPN and a low JAK2V617F allele burden, and support the development of MPN therapies aimed at targeting megakaryocytes.

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U2 - 10.1158/1078-0432.CCR-18-4089

DO - 10.1158/1078-0432.CCR-18-4089

M3 - Article

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