Iron is a modifier of the phenotypes of JAK2-mutant myeloproliferative neoplasms

Abstract

JAK2-V617F mutation causes myeloproliferative neoplasms (MPN) that can manifest as polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF). PV patients at diagnosis already exhibited iron deficiency, whereas ET patients 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 a N542-E543del mutation in exon 12 (E12). At baseline on control diet, all JAK2-mutant mouse models with 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 to wildtype (WT) mice. On low-iron diet, JAK2-mutant mice and WT controls increased platelet production at the expense of erythrocytes. Mice with 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 pre-megakaryocyte erythrocyte progenitors (pre-MegE), 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 of PV patients.