Clonal hematopoiesis landscape in frequent blood donors
Abstract
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.
Article Details
Authors (27)
Darja Karpova
Hector Huerga Encabo
6Hematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom
Elisa Donato
1German Cancer Research Center (DKFZ), Stem Cells and Cancer, Heidelberg, Germany
Silvia Calderazzo
Michael Scherer
Miriam Llorian-Sopena
10Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom
Aino-Maija Leppä
Roberto Würth
1Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
Patrick Stelmach
1German Cancer Research Center (DKFZ), Stem Cells and Cancer, Heidelberg, Germany
Despoina Papazoglou
1Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom
Alessandra Ferrelli
1Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom
Steven Ngo
1Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom
Iuliia Kotova
11European Molecular Biology Laboratory, Hamburg, Germany
Sabine Harenkamp
5Institute for Transfusion Medicine and Immunohematology, Goethe University Hospital Medical School, German Red Cross Blood Donor Service, Frankfurt, Germany
Kai Zimmer
12Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
Dominik Wolf
Jasper Panten
John Reed
4Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
Adriana Przybylla
1Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
Torsten Tonn
5Institute for Transfusion Medicine and Immunohematology, Goethe University Hospital Medical School, German Red Cross Blood Donor Service, Frankfurt, Germany
Annette Kopp-Schneider
Lars Velten
John F. DiPersio
Department of Medicine, Washington University School of Medicine, St. Louis
Terrence N. Wong
2Division of Hematology-Oncology, University of Michigan, Ann Arbor, MI
Dominique Bonnet
Halvard Bonig
Andreas Trumpp