Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation
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.
Authors
- Farhad Ravandi (ORCID: https://orcid.org/0000-0002-7621-377X)
- Tomoyuki Tanaka (ORCID: https://orcid.org/0000-0003-3790-4364)
- Ken Furudate
- Li Zhao (ORCID: https://orcid.org/0000-0001-7374-3348)
- Michael Spencer Chapman (ORCID: https://orcid.org/0000-0002-5320-8193)
- Carlos E. Bueso‐Ramos (ORCID: https://orcid.org/0000-0003-0180-7124)
- Courtney Denton Dinardo (ORCID: https://orcid.org/0000-0001-9003-0390)
- Koichi Saeki (ORCID: https://orcid.org/0000-0003-1886-8302)
- Satoko Ogata (ORCID: https://orcid.org/0000-0002-0169-3959)
- Muzaffar H. Qazilbash (ORCID: https://orcid.org/0000-0003-2876-2886)
- Shujuan Chen (ORCID: https://orcid.org/0000-0002-1068-195X)
- Nitin Jain (ORCID: https://orcid.org/0000-0003-0114-8384)
- Hidetaka Uryu (ORCID: https://orcid.org/0000-0001-7167-895X)
- Xingzhi Song (ORCID: https://orcid.org/0000-0002-9436-2728)
- Gheath Alatrash (ORCID: https://orcid.org/0000-0002-7648-4377)
- Elizabeth Shpall
- Naval Guastad Daver (ORCID: https://orcid.org/0000-0001-7103-373X)
- Robert Zygmunt Orlowski (ORCID: https://orcid.org/0000-0002-5723-4129)
- Erika J. Thompson
- Hui Yang
- Chiraag D. Kapadia (ORCID: https://orcid.org/0000-0003-1805-8879)
- Koichi Takahashi (ORCID: https://orcid.org/0000-0002-8027-9659)
- Simona Colla (ORCID: https://orcid.org/0000-0001-6583-8910)
- Hongli Tang (ORCID: https://orcid.org/0000-0003-2215-2294)
- Jeffery Molldrem
- Daisuke Nakada (ORCID: https://orcid.org/0000-0001-6010-7094)
- Rashmi Kanagal‐Shamanna (ORCID: https://orcid.org/0000-0001-7829-5249)
- Guillermo Garcia‐Manero (ORCID: https://orcid.org/0000-0002-3631-2482)
- P. Andrew Futreal (ORCID: https://orcid.org/0000-0001-8663-2671)
- Joanne I. Hsu (ORCID: https://orcid.org/0000-0002-1194-0650)
- Sarah Hanache (ORCID: https://orcid.org/0000-0003-0166-3757)
- Margaret A. Goodell (ORCID: https://orcid.org/0000-0003-1111-2932)
- Kapil N. Bhalla (ORCID: https://orcid.org/0000-0001-5209-5126)
- Zongrui Li (ORCID: https://orcid.org/0000-0001-5888-4222)
- Hiroshi Haeno (ORCID: https://orcid.org/0000-0002-6211-0649)
- Jyoti Nangalia (ORCID: https://orcid.org/0000-0001-7122-4608)
- Chong Zhao (ORCID: https://orcid.org/0000-0003-3271-5783)
- Naveen Pemmaraju (ORCID: https://orcid.org/0000-0002-1670-6513)
- Curtis Gumbs (ORCID: https://orcid.org/0000-0001-8026-0897)
- Hagop M. Kantarjian (ORCID: https://orcid.org/0000-0002-1908-3307)
- Latasha Little (ORCID: https://orcid.org/0000-0001-9690-6314)
- Jianhua Zhang (ORCID: https://orcid.org/0000-0001-5412-9860)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Tokyo University of Science (JP)
- Queen Mary University of London (GB)
- Baylor College of Medicine (US)
- Wellcome Sanger Institute (GB)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1038/s41588-025-02235-w
- Citations
- 7
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 6.55
Funders
- Leukemia and Lymphoma Society
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Andrew Sabin Family Foundation
- Break Through Cancer
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute