Unraveling mutational processes in acute lymphoblastic leukemia: Etiology, prevalence and consequences

Abstract

In this thesis, we studied mutational signatures in the most common childhood cancer, acute lymphoblastic leukemia (ALL). These patterns of mutations reflect the activity of specific mutational processes that give insight in disease development and progression, as well as treatment response. While ALL typically has a low mutational load, a subset of patients show increased mutational loads caused by various endogenous, exogenous and therapy-related processes. We investigated the prevalence, origin, and consequences of mutational signatures in ALL at diagnosis and relapse. Analysis of patients with multiple relapses revealed that most patients had low mutational loads at diagnosis, mainly caused by aging-related and oxidative DNA damage. A minority showed high mutational loads driven by APOBEC mutagenesis (SBS2 and SBS13) or the ultraviolet light–associated signature SBS7a. Treatment-related mutagenesis was also common, particularly the thiopurine-associated signature SBS87, which introduced pathogenic mutations contributing to relapse. We further investigated the origin of SBS7a and found that its molecular characteristics closely resemble UV-induced mutations in skin cancers, supporting a UV-induced origin. Our clonal analyses suggest that these mutations arise during early leukemic expansion at extramedullary sites before the leukemic cells expand and progress in the bone marrow. Additionally, we detected highly dynamic APOBEC mutagenesis in nearly 60% of the ETV6::RUNX1-positive ALL cases based on clonal, subclonal and transcriptomic activity. APOBEC3A expression strongly correlates with APOBEC mutagenesis, and single-cell transcriptomics revealed enrichment of APOBEC3A-expressing cells in affected cases. Overall, our findings highlight how endogenous and therapy-induced mutational processes drive mutation accumulation, disease progression, and relapse in ALL.