Katia Todoerti, Domenica Ronchetti, Vanessa Favasuli, Francesco Maura, Fortunato Morabito, Niccolò Bolli, Elisa Taiana, Antonino Neri

DIS3 gene mutations (DIS3mts) occur in roughly 10% of multiple myeloma (MM) patients; furthermore, DIS3 expression could be affected by monosomy 13 or del(13q), which occur in approximately 40% of MM cases. Despite several reports on the prevalence of DIS3mts, their contribution to the pathobiology of MM remains largely unknown. We took advantage of the large public CoMMpass dataset to investigate the spectrum of DIS3mts in MM and its impact on the transcriptome and clinical outcome. We found that DIS3mts clinical relevance strictly depended on del(13q) co-occurrence. In particular, bi-allelic DIS3 lesions significantly affected PFS, independently from other predictors of poor clinical outcome, while mono-allelic events mostly impacted OS. As expected, DIS3mts affect MM transcriptome involving cellular processes and signaling pathways associated with RNA metabolism, and the deregulation of a large number of lncRNAs, among which we identified five distinct transcripts as independent predictors of poorer OS and nine of worse PFS, some of which (AC015982.2 and AL445228.3) predicting both. These findings strongly prompt further studies investigating the relevance of these lncRNAs in MM.