Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents

Malte Asshoff, Verena Petzer, Matthew R. Warr, David Haschka, Piotr Tymoszuk, Egon Demetz, Markus Seifert, Wilfried Posch, Manfred Nairz, Pat Maciejewski, Peter Fowles, Christopher J. Burns, Gregg Smith, Kay Uwe Wagner, Guenter Weiss, J. Andrew Whitney, Igor Theurl

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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.

Original languageEnglish (US)
Pages (from-to)1823-1830
Number of pages8
JournalBlood
Volume129
Issue number13
DOIs
StatePublished - Mar 30 2017

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Hepcidins
Anemia
Rodentia
Janus Kinase 1
Chronic Disease
Janus Kinase 2
Primary Myelofibrosis
Erythropoiesis
Blood
Cells
Activin Receptors
Therapeutics
Erythrocyte Transfusion
Blood Cell Count
Erythropoietin
Liver
Protein Kinases
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
Rats
Hepatocytes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Asshoff, M., Petzer, V., Warr, M. R., Haschka, D., Tymoszuk, P., Demetz, E., ... Theurl, I. (2017). Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood, 129(13), 1823-1830. https://doi.org/10.1182/blood-2016-09-740092

Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. / Asshoff, Malte; Petzer, Verena; Warr, Matthew R.; Haschka, David; Tymoszuk, Piotr; Demetz, Egon; Seifert, Markus; Posch, Wilfried; Nairz, Manfred; Maciejewski, Pat; Fowles, Peter; Burns, Christopher J.; Smith, Gregg; Wagner, Kay Uwe; Weiss, Guenter; Whitney, J. Andrew; Theurl, Igor.

In: Blood, Vol. 129, No. 13, 30.03.2017, p. 1823-1830.

Research output: Contribution to journalArticle

Asshoff, M, Petzer, V, Warr, MR, Haschka, D, Tymoszuk, P, Demetz, E, Seifert, M, Posch, W, Nairz, M, Maciejewski, P, Fowles, P, Burns, CJ, Smith, G, Wagner, KU, Weiss, G, Whitney, JA & Theurl, I 2017, 'Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents', Blood, vol. 129, no. 13, pp. 1823-1830. https://doi.org/10.1182/blood-2016-09-740092
Asshoff, Malte ; Petzer, Verena ; Warr, Matthew R. ; Haschka, David ; Tymoszuk, Piotr ; Demetz, Egon ; Seifert, Markus ; Posch, Wilfried ; Nairz, Manfred ; Maciejewski, Pat ; Fowles, Peter ; Burns, Christopher J. ; Smith, Gregg ; Wagner, Kay Uwe ; Weiss, Guenter ; Whitney, J. Andrew ; Theurl, Igor. / Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. In: Blood. 2017 ; Vol. 129, No. 13. pp. 1823-1830.
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AU - Tymoszuk, Piotr

AU - Demetz, Egon

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AU - Fowles, Peter

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