title: Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents.
abstract: Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Results from a phase 2 study for the treatment of MF with the Janus kinase 1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, which was unexpected for a JAK1/2 inhibitor, because erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease, we demonstrated that MMB treatment can normalize hemoglobin and red blood cell numbers. We found that this positive effect is driven by direct inhibition of the bone morphogenic protein receptor kinase activin A receptor, type I (ACVR1), and the subsequent reduction of hepatocyte hepcidin production. Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatment of MF, had no inhibitory activity on this pathway. Further, we demonstrated the effect of MMB is not mediated by direct inhibition of JAK2-mediated ferroportin (FPN1) degradation, because neither MMB treatment nor myeloid-specific deletion of JAK2 affected FPN1 expression. Our data support the hypothesis that the improvement of inflammatory anemia by MMB results from inhibition of ACVR1-mediated hepcidin expression in the liver, which leads to increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis.
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Malte
authors.initials: M
authors.lastname: Asshoff
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Petzer
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Warr
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Haschka
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Piotr
authors.initials: P
authors.lastname: Tymoszuk
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Egon
authors.initials: E
authors.lastname: Demetz
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Posch
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA.
authors.forename: Pat
authors.initials: P
authors.lastname: Maciejewski
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA.
authors.forename: Peter
authors.initials: P
authors.lastname: Fowles
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA.|The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA.
authors.forename: Gregg
authors.initials: G
authors.lastname: Smith
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Foster City, CA.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Whitney
authors.affiliation: Department of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors; D000740:Anemia / Q000188:drug therapy*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors*; D002908:Chronic Disease; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins / Q000096:biosynthesis*; D007501:Iron / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000150:complications; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats
chemical_list: D001549:Benzamides; D064451:Hepcidins; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; D007501:Iron; D030201:Activin Receptors, Type I; C000610415:Acvr1 protein, rat; D052005:Bone Morphogenetic Protein Receptors, Type I