Evolution of clonal hematopoiesis during cancer treatment and its impact on outcomes
Clonal hematopoiesis (CH) is the age-related expansion of mutated hematopoietic stem cells without hematologic abnormalities. In patients with solid tumors, CH is associated with higher mortality and may evolve to therapy-related myeloid neoplasms; however, the mechanisms by which cancer treatments promote CH dynamics remain largely unknown. Here, we analyzed 392 serial samples from a prospective cohort of breast cancer patients and showed that cytotoxic treatments led to strong therapeutic bottlenecks, resulting in significant reductions in hematopoietic allelic populations and differential clonal selection. Positively selected CH that expanded through dose-dependent therapeutic bottlenecks harbored mutations in TP53, PPM1D, SRCAP, DNMT3A, and YLPM1. Patients with positively selected CH during treatment had the shortest progression-free and overall survival compared to patients with unchanging or negatively selected CH across all therapies. These findings, validated in independent breast cancer and pan-cancer cohorts, provide strong evidence for clinical relevance of monitoring CH during cancer treatment.
Authors
- Hossein Khiabanian (ORCID: https://orcid.org/0000-0003-1446-4394)
- Yi-Han Tang (ORCID: https://orcid.org/0009-0006-2248-1978)
- Erika Harper
- Sadegh Marzban (ORCID: https://orcid.org/0000-0002-9435-017X)
- Mingxiang Teng (ORCID: https://orcid.org/0000-0002-8536-8941)
- Stefania Morganti (ORCID: https://orcid.org/0000-0001-5284-9944)
- Shridar Ganesan (ORCID: https://orcid.org/0000-0002-5404-3044)
- Vaidhyanathan Mahaganapathy (ORCID: https://orcid.org/0000-0003-0577-2870)
- Mona Arabzadeh
- H. A. Parsons
- Christelle Colin‐Leitzinger
- Nancy Gillis
- Iman Washington
- Jacob K. Kresovich (ORCID: https://orcid.org/0000-0002-9577-226X)
- Daniel Walgenbach
- Judy E. Garber (ORCID: https://orcid.org/0000-0001-9449-3982)
- Jeffrey West
Institutions
- Rutgers, The State University of New Jersey (US)
- University of South Florida (US)
- Moffitt Cancer Center (US)
- Rutgers Sexual and Reproductive Health and Rights (NL)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-06-09
- DOI
- https://doi.org/10.1172/jci204429
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Breast Cancer Research Foundation
- Moffitt Cancer Center
- National Institutes of Health
- National Cancer Institute
- New Jersey Commission on Cancer Research