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

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 mechan...

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Bibliographic Details
Published in:Cancer discovery 2015-03, Vol.5 (3), p.316-331
Main Authors: Kleppe, Maria, Kwak, Minsuk, Koppikar, Priya, Riester, Markus, Keller, Matthew, Bastian, Lennart, Hricik, Todd, Bhagwat, Neha, McKenney, Anna Sophia, Papalexi, Efthymia, Abdel-Wahab, Omar, Rampal, Raajit, Marubayashi, Sachie, Chen, Jonathan J, Romanet, Vincent, Fridman, Jordan S, Bromberg, Jacqueline, Teruya-Feldstein, Julie, Murakami, Masato, Radimerski, Thomas, Michor, Franziska, Fan, Rong, Levine, Ross L
Format: Article
Language:English
Subjects:
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
Signal Transduction - drug effects
STAT Transcription Factors - genetics
STAT Transcription Factors - metabolism
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Summary: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. 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.
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-14-0736