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

Cancer Discov. 2015 Mar;5(3):316-31. doi: 10.1158/2159-8290.CD-14-0736. Epub 2015 Jan 8.

Abstract

The identification 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 myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy 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.

Significance: Our results demonstrate that JAK-STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Transformation, Neoplastic / metabolism*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gene Deletion
  • Humans
  • Inflammation Mediators / metabolism
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinases / genetics
  • Janus Kinases / metabolism*
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / metabolism
  • Mice
  • Mice, Knockout
  • Mutation
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Myeloproliferative Disorders / drug therapy
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / metabolism*
  • Myeloproliferative Disorders / pathology
  • Primary Myelofibrosis / genetics
  • Primary Myelofibrosis / metabolism
  • Primary Myelofibrosis / pathology
  • Protein Kinase Inhibitors / pharmacology
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism*
  • Signal Transduction* / drug effects

Substances

  • Antineoplastic Agents
  • Cytokines
  • Inflammation Mediators
  • Protein Kinase Inhibitors
  • STAT Transcription Factors
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinases
  • Leukocyte Common Antigens