Treatment-related mutagenic processes in acute lymphoblastic leukemia

Karyotyping, SNP arrays, fluorescence in situ hybridization and next-generation sequencing techniques have greatly improved our understanding of the genetic drivers of acute lymphoblastic leukemia (ALL). In the past years, another layer of genetic data has been added by the study of mutational signatures, patterns of somatic mutations that represent specific mutational mechanisms. Mutational signatures can give insight into tumor development, but also reveal mutagenic side-effects of treatment in relapse samples. Multiple treatment-related mutational signatures have been detected in relapsed ALL that could play a role in therapy resistance and relapse development. In fact, multiple pathogenic driver mutations have been attributed to these treatment-related mutational processes, including a recurrent TP53 mutation. Studies in childhood ALL revealed that thiopurine exposure is the most common source of therapy-related mutagenicity in ALL and presents differently when patients are DNA mismatch repair deficient. Thiopurine-induced DNA damage indicates that leukemic cells were able to survive thiopurine exposure. This could be due to metabolic defects, acquired mutations that induce thiopurine resistance during treatment, or resistance to drugs synergizing with thiopurines. In this review, we discuss the types and prevalence of treatment-related mutational signatures in ALL, and explore mechanisms of thiopurine cytotoxicity and mutagenicity.