Oncogenic mechanisms of DIS3 mutations in Multiple Myeloma

DIS3 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. Translocations occur during immunoglobulin class switch recombination, which otherwise proceeds unaffected both MM and the mouse model. In conclusion, MM DIS3 mutations lead to a gain-of-function phenotype and drive MM development, enhancing driver translocations. Overall design: Examination of total transcriptome by RNA-seq in Human Multiple Myeloma PE2 (DIS3 A507P/A507P) with lentiviral reconstitution of DIS3 WT expression and in primary mouse embryonic fibroblast cells and B-cells isolated from DIS3 G766R/+ heterozygous mice and their litter counterparts. Examination of genomic structural variants in pristan induced plasmocytoma cells from DIS3 G766R/+ and DIS3 WT mice. Examination of the global chromatin architecture in B-cells isolated from DIS3 G766R/+ heterozygous mice and their WT litter counterparts by MicroC. Examination of RNA/DNA hybrid accumulation in B-cells isolated from DIS3 G766R/+ heterozygous mice and their WT, litter counterparts by DRIPc-seq.