Ionizing radiotherapy (RT) is a widely used palliative and curative treatment strategy for malignancies. In solid tumors, RT-induced double strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in resistant cells. However, the extent of RT-induced DNA damage in hematologic malignancies and its impact on their evolution and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole genome sequencing (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, it was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode we demonstrate that a single RT-resistant cell may seed systemic relapse.

Clinical Cooperation Unit Molecular Hematology Oncology Department of Internal Medicine 5 Heidelberg University Hospital Heidelberg University and German Cancer Research Center Heidelberg Germany

Department of Hemato Oncology University Hospital Ostrava and Faculty of Medicine University of Ostrava Czech Republic

Department of Hematology Oncology and Clinical Immunology University Hospital Duesseldorf Duesseldorf Germany

Department of Oncology Hematology and Blood and Marrow Transplant University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Radiation Oncology Moffitt Cancer Center Tampa FL USA

Heidelberg Myeloma Center Department of Internal Medicine 5 Heidelberg University Hospital Medical Faculty Heidelberg University Heidelberg Germany

Lymphoma Service Moffitt Cancer Center Tampa FL USA

Lymphoma Service Sylvester Comprehensive Cancer Center Miami FL USA

Myeloma Institute Sylvester Comprehensive Cancer Center University of Miami Miami FL USA

Myeloma Research Program NYU Langone Perlmutter Cancer Center New York NY USA

Myeloma Service Memorial Sloan Kettering Cancer Center New York NY USA

Aktualizováno

Blood Cancer Discov. 2025 May 22. doi: 10.1158/2643-3230.BCD-24-0328. PubMed

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