Exploring the role of APOBEC3B cytosine deaminase in high-risk multiple myeloma

APOBEC3B (A3B), a cytosine deaminase, has emerged as a critical driver of multiple myeloma (MM) progression due to its role in inducing APOBEC mutation signatures. However, the prognostic significance of A3B expression and its functional impact on MM cellular characteristics remain poorly understood. This study investigated the prognostic significance of A3B expression and its downstream cellular effects. Using patient-derived data from the MMRF CoMMpass dataset, elevated A3B mRNA expression levels were shown to correlate with poor prognosis, identifying A3B as a potential biomarker for high-risk MM. Functional studies reveal that A3B not only induces replication stress but also that replication stress itself increases A3B expression levels. This creates a feed-forward loop that amplifies A3B expression, exacerbates replication stress, generates more single-stranded DNA (ssDNA) substrates for its activity, and contributes to genomic instability and the generation of APOBEC mutation signatures. These effects are particularly pronounced in del(17p) MM cells with TP53 inactivation. The project addresses three key aims: (1) assessing the prognostic significance of APOBEC expression in newly diagnosed MM patients (NDMM) and developing an APOBEC-based risk score, (2) evaluating the impact of A3B expression levels on MM cell lines, and (3) examining the role of A3B expression in del(17p) MM, where genomic instability is most pronounced. These findings highlight A3B as a promising prognostic marker, particularly in del(17p) MM, offering novel strategies to mitigate replication stress and improve outcomes for high-risk MM patients.