title: JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
authors.forename: Minsuk
authors.initials: M
authors.lastname: Kwak
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Priya
authors.initials: P
authors.lastname: Koppikar
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Markus
authors.initials: M
authors.lastname: Riester
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Matthew
authors.initials: M
authors.lastname: Keller
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lennart
authors.initials: L
authors.lastname: Bastian
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.affiliation: 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.
authors.forename: Neha
authors.initials: N
authors.lastname: Bhagwat
authors.affiliation: 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.
authors.forename: Anna Sophia
authors.initials: AS
authors.lastname: McKenney
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Efthymia
authors.initials: E
authors.lastname: Papalexi
authors.affiliation: 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.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: 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.
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sachie
authors.initials: S
authors.lastname: Marubayashi
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.affiliation: Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut. Yale Comprehensive Cancer Center, New Haven, Connecticut. leviner@mskcc.org rong.fan@yale.edu.
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053612:Janus Kinases; D017493:Leukocyte Common Antigens