title: Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition.
abstract: Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-β. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis. Here we show through pharmacologic and genetic studies that aurora kinase A (AURKA) represents a new therapeutic target in PMF. Treatment with MLN8237, a selective AURKA inhibitor, promoted polyploidization and differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF. Moreover, heterozygous deletion of Aurka was sufficient to ameliorate fibrosis and other PMF features in vivo. Our data suggest that megakaryocytes drive fibrosis in PMF and that targeting them with AURKA inhibitors has the potential to provide therapeutic benefit.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Qiang Jeremy
authors.initials: QJ
authors.lastname: Wen
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goldenson
authors.affiliation: Institut Gustave Roussy, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Malinge
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Terra
authors.initials: T
authors.lastname: Lasho
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Breyfogle
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Schultz
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Gilles
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Koppikar
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Brady
authors.initials: B
authors.lastname: Stein
authors.affiliation: Section of Hematopathology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017281:Cost of Illness; D004195:Disease Models, Animal; D004357:Drug Synergism; D006579:Heterozygote; D020128:Inhibitory Concentration 50; D053614:Janus Kinase 2 / Q000235:genetics; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009570:Nitriles; D011123:Polyploidy; D055728:Primary Myelofibrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D053628:Receptors, Thrombopoietin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018952:Antigens, CD34; D001381:Azepines; C550258:MLN 8237; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011720:Pyrazoles; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C540383:ruxolitinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D064096:Aurora Kinase A