Clonal hematopoiesis landscape in frequent blood donors

Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 lifetime donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FDs) compared with sporadic donors (<10 lifetime donations; 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex-matched control donor cohorts. Functional analysis of FD-enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone that increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with interferon gamma. Through concurrent mutational and immunophenotypic profiling of primary samples at single-cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, whereas no significant lineage bias was observed in HSCs harboring EPO-responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced, ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations.

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Publication Details

Journal
Blood
Published
2025-03-11
DOI
https://doi.org/10.1182/blood.2024027999
Citations
8
Primary Topic
Myeloproliferative Neoplasms: Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
13.00
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article

Clonal hematopoiesis landscape in frequent blood donors

Miriam Llorian, Jasper Panten, Elisa Donato, Dominique A. Bonnet et al.
8 citations
Blood
Myeloproliferative Neoplasms: Diagnosis and Treatment
13.00
article

Clonal hematopoiesis landscape in frequent blood donors

Miriam Llorian, Jasper Panten, Elisa Donato, Dominique A. Bonnet, Sabine Harenkamp, Aino‐Maija Leppä, Hector Huerga Encabo, Torsten Tonn, Kai Zimmer, Terrence Wong, Lars Velten, Iuliia Kotova, Darja Karpova, John F. DiPersio, Silvia Calderazzo, Dominik Wolf, Annette Kopp‐Schneider, Michael Scherer, Steven Ngo, Andreas Trumpp, Despoina Papazoglou, Halvard Bönig, Patrick Stelmach, Roberto Würth, Adriana Przybylla, Alessandra Ferrelli, John C. Reed
article en
8 citations

Abstract

Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 lifetime donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FDs) compared with sporadic donors (<10 lifetime donations; 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex-matched control donor cohorts. Functional analysis of FD-enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone that increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with interferon gamma. Through concurrent mutational and immunophenotypic profiling of primary samples at single-cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, whereas no significant lineage bias was observed in HSCs harboring EPO-responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced, ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations.

BloodVol. 145(21)
Goethe University Frankfurt (DE), Innsbruck Medical University (AT), German Cancer Research Center (DE), Universität Innsbruck (AT), Washington University in St. Louis (US), Heidelberg University (DE), University of Michigan (US), The Francis Crick Institute (GB), German Red Cross (DE), Michigan United (US), VASCage (AT), Centre for Genomic Regulation (ES), European Molecular Biology Laboratory (DE), Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE), Epigenomics (Germany) (DE)
Openalex Percentile: Top 1%
Myeloproliferative Neoplasms: Diagnosis and Treatment
13.00
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