Multiple Myeloma associated DIS3 mutations drive AID-dependent IgH Translocations

Role of dominant DIS3 mutations in multiple myeloma (MM) remains elusive. These mutations decrease the exoribonucleolytic activity of DIS3, a key nuclear RNA-degrading enzyme. Utilizing knock-in mice with clinical Dis3 G766R variant, we demonstrate an increased frequency of aberrant chromosomal translocations in B-cells, leading to plasmacytoma, an early-stage MM model. DIS3-dependent translocations display characteristics of aberrant activation-induced deaminase (AID) activity. In clinical MM samples with DIS3 mutations, driver genes also show AID-dependent 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, a process otherwise unaffected in MM patients or mice with mutated DIS3. Dis3 G766R mutation does not alter chromatin architecture in activated B-cells but hijacks it to bring together enhancers with proto-oncogenes permanently. In conclusion, gain-of-function DIS3 mutations increase nuclear exosome and AID affinity to chromatin, facilitating IGH translocations and driving MM transformation.