MMB ameliorates anemia in a rodent anemia of chronic disease model by inhibiting ALK2 activity.
Hepcidin dependent ferroportin degratation is independent of Jak2 phosphorylation.
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 kinase1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, unexpected for a JAK1/2 inhibitor, as erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease (ACD), we now demonstrate 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 (BMPR) kinase Activin A receptor, type I (ACVR1) and the subsequent reduction of hepatocyte hepcidin production. Of note, ruxolitinib (RUX), a JAK1/2 inhibitor approved for the treatment of MF, had no inhibitory activity on this pathway. Further, we demonstrate the effect of MMB is not mediated by direct inhibition of JAK2-mediated ferroportin (FPN1) degradation, as 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.
- Submitted September 16, 2016.
- Accepted January 27, 2017.
- Copyright © 2017 American Society of Hematology
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