Faculty, Staff and Student Publications

Publication Date

7-1-2025

Journal

Nature Genetics

DOI

10.1038/s41588-025-02235-w

PMID

40596442

PMCID

PMC12283406

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated phylogenetic analysis of matched therapy-related myeloid neoplasm samples traced their clonal origin to a single-HSPC clone among multiple competing clones, supporting a model of oligoclonal to monoclonal transformation. These findings underscore the need for further systematic research on the long-term hematological consequences of cancer chemotherapy.

Keywords

Humans, Hematopoietic Stem Cells, Clonal Evolution, Hematopoietic Stem Cell Transplantation, Multiple Myeloma, Transplantation, Autologous, Mutation, Melphalan, Whole Genome Sequencing, Male, Female, Middle Aged, Phylogeny, Aged, Genetics research, Acute myeloid leukaemia

Published Open-Access

yes

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