Format

Send to

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

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, New York.
5
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, New York. Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
8
Incyte Corporation, Wilmington, Delaware.
9
Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
10
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
11
Department of Biomedical Engineering, Yale University, New Haven, Connecticut. Yale Comprehensive Cancer Center, New Haven, Connecticut. leviner@mskcc.org rong.fan@yale.edu.
12
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. leviner@mskcc.org rong.fan@yale.edu.

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.

PMID:
25572172
PMCID:
PMC4355105
DOI:
10.1158/2159-8290.CD-14-0736
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center