biostudies-literaturevan der Ham CGKWF Kankerbestrijding (Dutch Cancer Society)KWF Kankerbestrijding2366-2375https://www.ebi.ac.uk/biostudies/studies/S-EPMC11518985biostudies-literatureUnknown38(11)Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the reLeukemiaMutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia.PMC1151898512482van der Ham CGvan Leeuwen FNAntic ZHoogerbrugge PMKuiper RPKleisman MMvan der Velden VHJYeong MWestera LLelieveld SHSuurenbroek LCSonneveld EfalseMutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia.Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the re2024-01-01T00:00:00Z2024 Nov2025-04-05T09:12:37.762Z2025-04-05T09:12:37.762ZS-EPMC115189853923220610.1038/s41375-024-02403-7