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

• Published in: Blood 2023-04, Vol.141 (17), p.2127-2140
• Main Authors: Stetka, Jan, Usart, Marc, Kubovcakova, Lucia, Rai, Shivam, Rao, Tata Nageswara, Sutter, Joshua, Hao-Shen, Hui, Dirnhofer, Stefan, Geier, Florian, Bader, Michael S., Passweg, Jakob R., Manolova, Vania, Dürrenberger, Franz, Ahmed, Nouraiz, Schroeder, Timm, Ganz, Tomas, Nemeth, Elizabeta, Silvestri, Laura, Nai, Antonella, Camaschella, Clara, Skoda, Radek C.
• Format: Article
• Language: English
• Subjects: Animals; Hemoglobins - genetics; Iron; Iron Deficiencies; Janus Kinase 2 - genetics; Mice; Mutation; Myeloproliferative Disorders - diagnosis; Myeloproliferative Disorders - drug therapy; Myeloproliferative Disorders - genetics; Phenotype; Polycythemia Vera - genetics; Thrombocythemia, Essential - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022017976

•Iron availability alters the phenotype of MPN mouse models by affecting the lineage bias of bipotent megakaryocyte-erythroid progenitors.•The ferroportin inhibitor vamifeport and the minihepcidin PR73–normalized hematocrit and hemoglobin levels in mouse models of PV. [Display omitted] JAK2-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. Stetka and colleagues elucidate a major role for iron trafficking in determining the red cell and platelet mass in polycythemia vera (PV). In JAK2-V617F mutant mice, PV phenotype mice were iron deficient, whereas those with essential thrombocythemia were not. PV phenotype mice increased their red cells in response to parenteral iron. Impeding iron availability with a ferroportin inhibitor or a minihepcidin normalized red cell mass, suggesting a novel therapy for controlling red cell mass in PV.