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Oncogenic mechanisms of DIS3 mutations in Multiple Myeloma

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE155631 | GEO | 2026/02/11

REPOSITORIES: GEO

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Effect of Dis3 depletion on gene expression in hematopoietic stem cells of C57BL/6 mice

Project description:Multiple myeloma (MM) is a plasma cell neoplasm that remains incurable regardless of the introduction of novel agents. Therefore, it is of necessity to decode the molecular mechanisms of myelomagenesis to identify novel therapeutic strategies. Recent advances in next-generation sequencing technologies have not only reconfirmed the significance of known driver events in MM but also have identified novel genetic alterations in MM. Importantly, mutations of DIS3 genes have been identified in ~10% of MM patients, and loss of heterozygosity at chromosome 13q that leads to deletion of one allele of DIS3 has been observed in ~ 40% of MM patients. However, the roles of DIS3 in hematopoiesis and myelomagenesis remain incompletely understood. Here we show that Dis3 prevents accumulation of DNA damage in hematopoietic cells, thereby supporting hematopoiesis. We also show that loss of Dis3 alone and in combination with c-MAF transgene in GC B cells do not exhibit plasma cell neoplasm in mice.

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Human DIS3 shapes the RNA polymerase II transcriptome degrading variety of unwanted transcripts.

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