JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response

Maria Kleppe, Minsuk Kwak, Priya Koppikar, Markus Riester, Matthew Keller, Lennart Bastian, Todd Hricik, Neha Bhagwat, Anna Sophia McKenney, Efthymia Papalexi, Omar Abdel-Wahab, Raajit Rampal, Sachie Marubayashi, Jonathan J. Chen, Vincent Romanet, Jordan S. Fridman, Jacqueline Bromberg, Julie Teruya-Feldstein, Masato Murakami, Thomas RadimerskiFranziska Michor, Rong Fan, Ross L. Levine

Research output: Contribution to journalArticlepeer-review

143 Citations (Scopus)

Abstract

The identifi cation of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofi brosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve effi cacy has not been delineated. Patients with MPN present with increased levels of circulating proinfl ammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profi ling demonstrated that hematopoietic cells from myelofi brosis models and patient samples aberrantly secrete infl ammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar effi cacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations.

Original languageEnglish
Pages (from-to)316-331
Number of pages16
JournalCancer Discovery
Volume5
Issue number3
DOIs
Publication statusPublished - 2015

Bibliographical note

Publisher Copyright:
© 2015 American Association for Cancer Research.

All Science Journal Classification (ASJC) codes

  • Oncology

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