Multiple Myeloma associated DIS3 mutations drive AID-dependent IgH Translocations

Abstract

AbstractDIS3 is mutated in multiple myeloma (MM), but the mechanism by which oncogenesis occurs specifically in B cell lineage remains to be established. Somatic DIS3 variants have substitutions enriched around its RNB domain, which in a dominant negative way, inactivate or reduce the exoribonucleolytic activity of this enzyme responsible for nuclear RNA degradation. Here using knock-in mice with a clinical Dis3 G766R variant, we demonstrate a B cell-specific mutagenic effect that induces aberrant chromosomal translocations, increasing the incidence of plasmacytoma, a mouse model of early-stage MM. Dis3 G766R-dependent translocations display characteristics typical to aberrant activation-induced deaminase (AID) activity sites. Indeed, analysis of MM clinical samples revealed that in MM driver genes, DIS3 alleles lead to increased AID-dependent DNA lesions. Mechanistically, mutated DIS3 accumulates on chromatin-associated RNA substrates, including aberrant AID action sites, fostering oncogenic chromosomal rearrangements during immunoglobulin class switch recombination. In conclusion, MM DIS3 mutations lead to a gain-of-function phenotype and drive MM development, enhancing driver translocations.