DIS3 depletion in multiple myeloma causes extensive perturbation in cell cycle progression and centrosome amplification.

DIS3 gene mutations occur in approximately 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), found in roughly 40% of MM cases. Despite the high incidence of DIS3 mutations and deletions, the biological significance of DIS3 and its contribution to MM pathogenesis remains poorly understood. Herein, we investigated the functional role of DIS3 in MM, by exploiting a loss of function approach in human MM cell lines. We found that DIS3 knockdown inhibits proliferation in MM cell lines and largely affects MM plasma cells (PC) cell cycle progression, finally inducing a significant increase of the percentage of cells in the G0/G1 phase and a decrease in the S and G2/M phases. DIS3 plays an important role not only in the control of MM PCs cell cycle, but also in the centrosome duplication cycle, which are strictly coregulated in physiological condition in the G1 phase. Indeed, DIS3 silencing leads to the formation of supernumerary centrosomes accompanied by the assembing of multipolar spindles during mitosis. 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.

Citation

Vanessa K Favasuli, Domenica Ronchetti, Ilaria Silvestris, Noemi Puccio, Giuseppina Fabbiano, Valentina Traini, Katia Todoerti, Silvia Erratico, Alessia Ciarrocchi, Valentina Fragliasso, Domenica Giannandrea, Francesca Tumiatti, Raffaella Chiaramonte, Yvan Torrente, Palma Finelli, Eugenio Morelli, Nikhil C Munshi, Niccolò Bolli, Antonino Neri, Elisa Taìana. DIS3 depletion in multiple myeloma causes extensive perturbation in cell cycle progression and centrosome amplification. Haematologica. 2023 Jul 13

PMID: 37439377

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