Iron homeostasis governs erythroid phenotype in polycythemia vera.

Autor:	Bennett C; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Jackson VE; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Pettikiriarachchi A; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Hayman T; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Schaeper U; Silence Therapeutics GmbH, Berlin, Germany., Moir-Meyer G; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Fielding K; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Diagnostic Haematology, The Royal Melbourne Hospital, Parkville, VIC, Australia., Ataide R; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Infectious Diseases, Peter Doherty Institute, University of Melbourne, Parkville, VIC, Australia., Clucas D; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Diagnostic Haematology, The Royal Melbourne Hospital, Parkville, VIC, Australia., Baldi A; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Garnham AL; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Li-Wai-Suen CSN; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Loughran SJ; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom.; Department of Haematology, University of Cambridge, Cambridge, United Kingdom., Baxter EJ; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom.; Department of Haematology, University of Cambridge, Cambridge, United Kingdom., Green AR; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom.; Department of Haematology, University of Cambridge, Cambridge, United Kingdom., Alexander WS; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Bahlo M; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Burbury K; Clinical Haematology at the Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia., Ng AP; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Clinical Haematology at the Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia., Pasricha SR; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Diagnostic Haematology, The Royal Melbourne Hospital, Parkville, VIC, Australia.; Clinical Haematology at the Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Jun 29; Vol. 141 (26), pp. 3199-3214.
DOI:	10.1182/blood.2022016779
Abstrakt:	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. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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