Iron homeostasis governs erythroid phenotype in polycythemia vera. 2023

Cavan Bennett, and Victoria E Jackson, and Anne Pettikiriarachchi, and Thomas Hayman, and Ute Schaeper, and Gemma Moir-Meyer, and Katherine Fielding, and Ricardo Ataide, and Danielle Clucas, and Andrew Baldi, and Alexandra L Garnham, and Connie S N Li-Wai-Suen, and Stephen J Loughran, and E Joanna Baxter, and Anthony R Green, and Warren S Alexander, and Melanie Bahlo, and Kate Burbury, and Ashley P Ng, and Sant-Rayn Pasricha
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Polycythemia vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

UI MeSH Term Description Entries
D007501 Iron A metallic element with atomic symbol Fe, atomic number 26, and atomic weight 55.85. It is an essential constituent of HEMOGLOBINS; CYTOCHROMES; and IRON-BINDING PROTEINS. It plays a role in cellular redox reactions and in the transport of OXYGEN. Iron-56,Iron 56
D010641 Phenotype The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment. Phenotypes
D011087 Polycythemia Vera A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. Erythremia,Osler-Vaquez Disease,Polycythemia Rubra Vera,Polycythemia Ruba Vera,Primary Polycythemia,Disease, Osler-Vaquez,Erythremias,Osler Vaquez Disease,Polycythemia Ruba Veras,Polycythemia Rubra Veras,Polycythemia, Primary,Polycythemias, Primary,Primary Polycythemias,Ruba Vera, Polycythemia,Ruba Veras, Polycythemia,Vera, Polycythemia Ruba,Vera, Polycythemia Rubra,Veras, Polycythemia Ruba,Veras, Polycythemia Rubra
D006706 Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Autoregulation
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055106 Genome-Wide Association Study An analysis comparing the allele frequencies of all available (or a whole GENOME representative set of) polymorphic markers to identify gene candidates or quantitative trait loci associated with a specific organism trait or specific disease or condition. Genome Wide Association Analysis,Genome Wide Association Study,GWA Study,Genome Wide Association Scan,Genome Wide Association Studies,Whole Genome Association Analysis,Whole Genome Association Study,Association Studies, Genome-Wide,Association Study, Genome-Wide,GWA Studies,Genome-Wide Association Studies,Studies, GWA,Studies, Genome-Wide Association,Study, GWA,Study, Genome-Wide Association
D064451 Hepcidins Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hepcidin,Liver-Expressed Antimicrobial Peptide,Pro-Hepcidin,Prohepcidin,Antimicrobial Peptide, Liver-Expressed,Liver Expressed Antimicrobial Peptide,Peptide, Liver-Expressed Antimicrobial,Pro Hepcidin

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