Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms

Eline J. M. Bertrums, Jurrian K. Kanter, Lucca L. M. Derks, Mark Verheul, Laurianne Trabut, Markus J. Roosmalen, Henrik Hasle, Evangelia Antoniou, Dirk Reinhardt, Michael N. Dworzak, Nora Mühlegger, Marry M. Heuvel-Eibrink, C. Michel Zwaan, Bianca F. Goemans and Ruben Boxtel ()
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Eline J. M. Bertrums: Princess Máxima Centrum for pediatric oncology
Jurrian K. Kanter: Princess Máxima Centrum for pediatric oncology
Lucca L. M. Derks: Princess Máxima Centrum for pediatric oncology
Mark Verheul: Princess Máxima Centrum for pediatric oncology
Laurianne Trabut: Princess Máxima Centrum for pediatric oncology
Markus J. Roosmalen: Princess Máxima Centrum for pediatric oncology
Henrik Hasle: Aarhus University Hospital
Evangelia Antoniou: University Hospital of Essen
Dirk Reinhardt: University Hospital of Essen
Michael N. Dworzak: St. Anna Children’s Cancer Research Institute
Nora Mühlegger: St. Anna Children’s Cancer Research Institute
Marry M. Heuvel-Eibrink: Princess Máxima Centrum for pediatric oncology
C. Michel Zwaan: Princess Máxima Centrum for pediatric oncology
Bianca F. Goemans: Princess Máxima Centrum for pediatric oncology
Ruben Boxtel: Princess Máxima Centrum for pediatric oncology

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.

Date: 2024
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DOI: 10.1038/s41467-024-50384-z

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