TY  - JOUR
AU  - Karpova, Darja
AU  - Huerga Encabo, Hector
AU  - Donato, Elisa
AU  - Calderazzo, Silvia
AU  - Scherer, Michael
AU  - Llorian-Sopena, Miriam
AU  - Leppä, Aino-Maija
AU  - Würth, Roberto
AU  - Stelmach, Patrick
AU  - Papazoglou, Desponia
AU  - Ferrelli, Alessandra
AU  - Ngo, Steven
AU  - Kotova, Iuliia
AU  - Harenkamp, Sabine
AU  - Zimmer, Kai
AU  - Wolf, Dominik
AU  - Panten, Jasper
AU  - Reed, John
AU  - Przybylla, Adriana
AU  - Tonn, Torsten
AU  - Kopp-Schneider, Annette
AU  - Velten, Lars
AU  - DiPersio, John F
AU  - Wong, Terrence N
AU  - Bonnet, Dominique
AU  - Bonig, Halvard
AU  - Trumpp, Andreas
TI  - Clonal Hematopoiesis Landscape in Frequent Blood Donors.
JO  - Blood
VL  - 145
IS  - 21
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2025-00550
SP  - 2411-2423
PY  - 2025
N1  - DKFZ- ZMBH Alliance / #EA:A010#LA:A010# / 2025 May 22;145(21):2411-2423
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40067117
DO  - DOI:10.1182/blood.2024027999
UR  - https://inrepo02.dkfz.de/record/299795
ER  -