DIS3 (DIS3 Homolog, Exosome Endoribonuclease And 3'-5' Exoribonuclease)

We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.

These results demonstrated that ssDNA derived from JAK2V617F+ cells can alter RNA-exosome complex gene expression and nucleic acid-sensing pathways, contributing to chronic inflammation in MPNs. This study provides novel insights into the interplay between ssDNA, exosome complex, and inflammatory signaling and offers potential therapeutic targets to modulate inflammation and genomic instability in MPNs.

These results indicate that only Dis3 deficiency and the combination of c-Maf overexpression and Dis3 deficiency do not develop plasma cell neoplasm and suggest that additional oncogenic events are necessary for myelomagenesis. Further investigations are required for elucidating the mechanisms of how loss-of-function of DIS3 is involved in the development of MM.

We showed superior prognostic value of CTC and MRD kinetics over single assessments. Tumor dissemination seems to be driven by transcriptional priming rather than acquired secondary genetic events, while on-treatment resistance is linked to genomic and transcriptional evolution, without recurrent genetic alterations and with common molecular signatures of resistance.

In MM, centrosome amplification is present in about a third of patients and may represent a mechanism leading to genomic instability. These findings strongly prompt further studies investigating the relevance of DIS3 in the centrosome duplication process; indeed, a combination of DIS3 defects and deficient spindle-assembly checkpoint, can allow cells to progress through the cell cycle without proper chromosome segregation generating aneuploid cells which finally lead to the development of MM.

A complementary biochemical approach revealed that Rrp4 M68T shows decreased interaction with Mtr4, consistent with these genetic results. This study suggests that the EXOSC2 mutation identified in a multiple myeloma patient impacts the function of the RNA exosome and provides functional insight into a critical interface between the RNA exosome and Mtr4.

Herein, we summarize the molecular and physiological functions of DIS3, focusing on hematopoiesis, and discuss the characteristics and potential roles of DIS3 mutations in MM. Recent findings highlight the essential roles of DIS3 in RNA homeostasis and normal hematopoiesis and suggest that the reduced activity of DIS3 may be involved in myelomagenesis by increasing genome instability.

We propose DIS3 loss in myeloma to be a driving force for tumorigenesis via DNA:RNA hybrid-dependent enhanced genome instability and increased mutational rate. At the same time, DIS3 loss represents a liability that might be therapeutically exploited in patients whose cancer cells harbor DIS3 mutations.

The results of in vivo experiments indicated that miR-125a/b-5p promoted tumor growth by downregulating DIS3. Overall, miR-125a/b-5p promotes MM cellular processes and xenograft tumor growth by targeting DIS3.