Clonal evolution of hematopoietic stem cells after cancer chemotherapy

Abstract Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies1. The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as TET2 and PPM1D. Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as TP53 and PPM1D. Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy. Competing Interest Statement CDD receives research support (to institution) from Abbvie, Agios, Bayer, Calithera, Cleave, BMS/Celgene, Daiichi-Sankyo and ImmuneOnc, and is among the Consultant/Advisory Boards at Abbvie, Agios, Celgene/BMS, Daiichi Sankyo, ImmuneOnc, Novartis, Takeda and Notable Labs. HK receives research grants from AbbVie, Amgen, Ascentage, BMS, Daiichi Sankyo, Immunogen, Jazz, Novartis, Pfizer and Sanofi, and honoraria from Abbvie, Actinium, Adaptive Biotechnologies, Amgen, Apptitude Health, BioAscend, Daiichi-Sankyo, Delta Fly, Janssen Global, Novartis, Oxford Biomedical, Pfizer and Takeda. KT has received consulting fees from Celgene, GSK, and Novartis. He is on the scientific advisory board for Symbio Pharmaceuticals.