Journal Article

DKFZ-2025-00550

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Clonal Hematopoiesis Landscape in Frequent Blood Donors.

Karpova, D. (First author)DKFZ* ; Huerga Encabo, H. ; Donato, E.DKFZ* ; Calderazzo, S.DKFZ* ; Scherer, M.DKFZ* ; Llorian-Sopena, M. ; Leppä, A.-M.DKFZ* ; Würth, R.DKFZ* ; Stelmach, P.DKFZ* ; Papazoglou, D. ; Ferrelli, A. ; Ngo, S. ; Kotova, I. ; Harenkamp, S. ; Zimmer, K. ; Wolf, D. ; Panten, J.DKFZ* ; Reed, J. ; Przybylla, A.DKFZ* ; Tonn, T. ; Kopp-Schneider, A.DKFZ* ; Velten, L. ; DiPersio, J. F. ; Wong, T. N. ; Bonnet, D. ; Bonig, H. ; Trumpp, A. (Last author)DKFZ*

2025
American Society of Hematology Washington, DC

This record in other databases:  

Please use a persistent id in citations: doi:10.1182/blood.2024027999

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 life-time donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FD) compared to sporadic donors (<10 life-time 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 (CD) 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 which increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with IFNy. Through concurrent mutational and immunophenotypic profiling of primary samples at single cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, while 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.

Note: DKFZ- ZMBH Alliance / #EA:A010#LA:A010# / 2025 May 22;145(21):2411-2423

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Contributing Institute(s):

1. A010 Stammzellen und Krebs (A010)
2. C060 Biostatistik (C060)
3. Epigenomik (B370)
4. B270 Regulatorische Genomik und Evolution von Tumoren (B270)
5. DKTK HD zentral (HD01)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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