TY  - JOUR
AU  - Diamond, Benjamin
AU  - Chahar, Dhanvantri
AU  - Jain, Michael D
AU  - Poos, Alexandra
AU  - Durante, Michael A
AU  - Ziccheddu, Bachisio
AU  - Kaddoura, Marcella
AU  - Papadimitriou, Marios
AU  - Maclachlan, Kylee H
AU  - Jelinek, Tomas
AU  - Davies, Faith E
AU  - Figura, Nicholas B
AU  - Morgan, Gareth J
AU  - Mai, Elias K
AU  - Weisel, Katja
AU  - Fenk, Roland
AU  - Raab, Marc-Steffen
AU  - Usmani, Saad
AU  - Landgren, Ola
AU  - Locke, Frederick L
AU  - Goldschmidt, Hartmut
AU  - Schatz, Jonathan Harry
AU  - Weinhold, Niels
AU  - Maura, Francesco
TI  - Mutagenic impact and evolutionary influence of chemo-radiotherapy in hematologic malignancies.
JO  - Blood cancer discovery
VL  - 6
IS  - 5
SN  - 2643-3230
CY  - Philadelphia, PA
PB  - American Association for Cancer Research
M1  - DKFZ-2025-01067
SP  - 450-463
PY  - 2025
N1  - 2025 Sep 3;6(5):450-463 / #EA:A360#LA:A360#
AB  - Ionizing radiotherapy (RT) is a widely used 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 surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole-genome sequence samples (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). 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-surviving cell may seed distant relapse.
LB  - PUB:(DE-HGF)16
C6  - pmid:40402512
DO  - DOI:10.1158/2643-3230.BCD-24-0328
UR  - https://inrepo02.dkfz.de/record/301546
ER  -