The long-term effects of chemotherapy on normal blood cells

Emily Mitchell; My H Pham; Anna Clay; Rashesh Sanghvi; Nicholas Williams; Sandra Pietsch; Joanne I Hsu; Hyunchul Jung; Aditi Vedi; Sarah Moody; Jingwei Wang; Daniel Leonganmornlert; Michael Spencer Chapman; Ellie Dunstone; Anna Santarsieri; Alex Cagan; Heather E Machado; E Joanna Baxter; George Follows; Daniel J Hodson; Ultan McDermott; Gary J Doherty; Inigo Martincorena; Laura Humphreys; Krishnaa Mahbubani; Kourosh Saeb Parsy; Koichi Takahashi; Margaret A Goodell; David Kent; Elisa Laurenti; Peter J Campbell; Raheleh Rahbari; Jyoti Nangalia; Michael R Stratton

doi:10.1038/s41588-025-02234-x

The long-term effects of chemotherapy on normal blood cells

Nat Genet. 2025 Jul 1. doi: 10.1038/s41588-025-02234-x. Online ahead of print.

Authors

Emily Mitchell^#^{1

2

3}, My H Pham^#¹, Anna Clay^#^{2

4}, Rashesh Sanghvi¹, Nicholas Williams¹, Sandra Pietsch^{2

3}, Joanne I Hsu⁵, Hyunchul Jung¹, Aditi Vedi^{2

6}, Sarah Moody¹, Jingwei Wang¹, Daniel Leonganmornlert¹, Michael Spencer Chapman¹, Ellie Dunstone¹, Anna Santarsieri^{2

3}, Alex Cagan¹, Heather E Machado¹, E Joanna Baxter³, George Follows³, Daniel J Hodson^{2

3}, Ultan McDermott^{1

7

8}, Gary J Doherty⁷, Inigo Martincorena¹, Laura Humphreys¹, Krishnaa Mahbubani^{9

10}, Kourosh Saeb Parsy^{9

10}, Koichi Takahashi¹¹, Margaret A Goodell⁵, David Kent¹², Elisa Laurenti^{2

3}, Peter J Campbell¹, Raheleh Rahbari¹, Jyoti Nangalia^#^{13

14

15}, Michael R Stratton^#¹⁶

Affiliations

¹ Wellcome Sanger Institute, Hinxton, UK.
² Wellcome-MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus, Cambridge, UK.
³ Department of Haematology, University of Cambridge, Cambridge, UK.
⁴ Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
⁵ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Paediatrics, Cambridge University Hospitals Foundation Trust, Cambridge, UK.
⁷ Department of Oncology, Cambridge University Hospitals Foundation Trust, Cambridge, UK.
⁸ Oncology R&D, AstraZeneca, Cambridge, UK.
⁹ Department of Surgery, University of Cambridge, Cambridge, UK.
¹⁰ Cambridge Biorepository for Translational Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹¹ Department of Leukemia, Division of Cancer Medicine, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
¹² York Biomedical Research Institute, Department of Biology, University of York, York, UK.
¹³ Wellcome Sanger Institute, Hinxton, UK. jn5@sanger.ac.uk.
¹⁴ Wellcome-MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus, Cambridge, UK. jn5@sanger.ac.uk.
¹⁵ Department of Haematology, University of Cambridge, Cambridge, UK. jn5@sanger.ac.uk.
¹⁶ Wellcome Sanger Institute, Hinxton, UK. mrs@sanger.ac.uk.

^# Contributed equally.

PMID: 40596443
DOI: 10.1038/s41588-025-02234-x

Abstract

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects.