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


Authors: Kleppe, M.; Kwak, M.; Koppikar, P.; Riester, M.; Keller, M.; Bastian, L.; Hricik, T.; Bhagwat, N.; McKenney, A. S.; Papalexi, E.; Abdel-Wahab, O.; Rampal, R.; Marubayashi, S.; Chen, J. J.; Romanet, V.; Fridman, J. S.; Bromberg, J.; Teruya-Feldstein, J.; Murakami, M.; Radimerski, T.; Michor, F.; Fan, R.; Levine, R. L.
Article Title: JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response
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. © 2015 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 5
Issue: 3
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2015-03-01
Start Page: 316
End Page: 331
Language: English
DOI: 10.1158/2159-8290.cd-14-0736
PROVIDER: scopus
PMCID: PMC4355105
PUBMED: 25572172
DOI/URL:
Notes: Export Date: 2 April 2015 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Jacqueline Bromberg
    105 Bromberg
  2. Julie T Feldstein
    288 Feldstein
  3. Raajit Kumar Rampal
    139 Rampal
  4. Ross Levine
    490 Levine
  5. Neha Bhagwat
    21 Bhagwat
  6. Maria Kleppe
    30 Kleppe
  7. Todd Raymond Hricik
    26 Hricik
  8. Matthew D Keller
    24 Keller