JAK 2-V617F mutation causes myeloproliferative neoplasms (MPNs) that can manifest as polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis. At diagnosis, patients with PV already exhibited iron deficiency, whereas patients with ET had normal iron stores. We examined the influence of iron availability on MPN phenotype in mice expressing JAK2-V617F and in mice expressing JAK2 with an N542-E543del mutation in exon 12 (E12). At baseline, on a control diet, all JAK2-mutant mouse models with a PV-like phenotype displayed iron deficiency, although E12 mice maintained more iron for augmented erythropoiesis than JAK2-V617F mutant mice. In contrast, JAK2-V617F mutant mice with an ET-like phenotype had normal iron stores comparable with that of wild-type (WT) mice. On a low-iron diet, JAK2-mutant mice and WT controls increased platelet production at the expense of erythrocytes. Mice with a PV phenotype responded to parenteral iron injections by decreasing platelet counts and further increasing hemoglobin and hematocrit, whereas no changes were observed in WT controls. Alterations of iron availability primarily affected the premegakaryocyte-erythrocyte progenitors, which constitute the iron-responsive stage of hematopoiesis in JAK2-mutant mice. The orally administered ferroportin inhibitor vamifeport and the minihepcidin PR73 normalized hematocrit and hemoglobin levels in JAK2-V617F and E12 mutant mouse models of PV, suggesting that ferroportin inhibitors and minihepcidins could be used in the treatment for patients with PV.

CSL Vifor St Gallen Switzerland

David Geffen School of Medicine University of California Los Angeles Los Angeles CA

Department of Biology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Biosystems Science and Engineering Eidgenössische Technische Hochschule Zurich Basel Switzerland

Division of Genetics and Cell Biology San Raffaele Scientific Institute Milan Italy

Division of Hematology University Hospital Basel Basel Switzerland

Experimental Hematology Department of Biomedicine University Hospital Basel and University of Basel Basel Switzerland

Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Swiss Institute of Bioinformatics Basel Switzerland

Vita Salute San Raffaele University Milan Italy

Blood. 2023 Apr 27;141(17):2042-2044. doi: 10.1182/blood.2023020065. PubMed

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