Targeting APOBEC3 enzymes as novel metabolic regulators in multiple myeloma

APOBEC3 are a family of molecules which mutate specific genes in the white blood cells of our immune system to boost immune function and defend against viruses. Unfortunately, they frequently make mistakes and target thousands of other bystander genes which are not their normal targets. These undesirable collateral mutations play a major role in both cancer initiation and progression. Multiple myeloma (MM) is an incurable disease whose progression depends especially on acquiring genetic modification, and indeed APOBEC3-mediated mutations have been shown to correlate with worst clinical outcomes. Beyond this association, it is unclear how APOBEC3 expression drives MM progression. Based on emerging hints in the literature, we hypothesize that APOBEC3s play at least two distinct roles in MM: first, they can cause mutations that impact the energy management of MM cells, and, second, that APOBEC3s can cause drug resistance mutations through which MM cells escape treatment. The goal of this proposal is to study the role of APOBEC3s in drug resistance and energy management of MM cells as well as to test if inhibiting APOBEC3s in MM may be of therapeutic benefit in cell-based and mouse model preclinical experiments.