Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation
Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag D. Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Linda Zhang, Jennifer Padilla, Li Zhao, Joanne I. Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney D. DiNardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika J. Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z. Orlowski, Muzaffar H. Qazilbash, Kapil N. Bhalla, Simona Colla, Hagop M. Kantarjian, Rashmi Kanagal‐Shamanna, Carlos E. Bueso‐Ramos, Daisuke Nakada, Gheath Alatrash, Jeffery Molldrem, P. Andrew Futreal, Elizabeth Shpall, Margaret A. Goodell, Guillermo Garcia‐Manero, Koichi Takahashi
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.