Abstract

Abstract SCI-15

A major challenge in the treatment of chronic lymphocytic leukemia (CLL) is the tremendous clinical heterogeneity of this disease, ranging from indolent disease kinetics to a rapidly fatal course despite aggressive therapy. While some prognostic markers have been established, the advent of deep-sequencing technologies has enabled identification of most or all genetic alterations underlying malignancy, which is leading to new genetic prognostic markers across cancers. We recently sequenced the exomes of 91 CLLs with matched germline controls and identified nine recurrently mutated genes, six pathways involved in CLL pathogenesis (1), as well as new prognostic factors. From this study, a striking finding was the high frequency of mutations in SF3B1, part of the catalytic core of the spliceosome. We found that 14 independent SF3B1 mutations (15% of 91 CLL samples) localized to a single region of the gene (with unknown function) with 50 percent being identical K700E mutations. This finding has been since verified by other investigators. SF3B1 mutations were significantly associated with del(11q), a cytogenetic abnormality that is associated with aggressive disease, and whose minimally deleted region contains the critical DNA damage response gene ATM. Importantly, a Cox multivariate regression model identified mutated SF3B1 as an independent predictive marker of poor prognosis. Mechanistically, CLL samples harboring SF3B1 mutation demonstrated altered pre-mRNA splicing, with increased intron retention in known spliceosome target genes. Finally, SF3B1-K700E was also identified as a recurring mutation in myelodysplasia. In short, mutations in SF3B1 are positively selected in CLL, alter splicing patterns, and represent a novel oncogenic mechanism in hematologic malignancies. Our genetic and clinical evidence suggests that altered pre-mRNA splicing is a novel cancer pathway of importance to CLL and to blood malignancies in general. An ongoing focus of investigation in our group is trying to understand the CLL-promoting activity of SF3B1 mutation by linking alterations in transcripts with functional changes in B-cell biology. Precise identification of driver transcripts and their functional characterization will enable the development of novel therapeutics that can target this pathway more efficaciously and with minimal toxicity. This is especially important in the treatment of a clinically aggressive subgroup of CLL for which effective therapies are presently unavailable. Spliceosome targeting drugs have been identified—discovered through medicinal screens of natural products with tumoricidal properties, and only later found to target the SF3b complex—and may have promise for this subset of patients. Elucidation of this novel cancer pathway has broad implications for cancer biology, from the vantage of both understanding disease mechanism and the potential for therapeutic targeting.

Disclosures:

No relevant conflicts of interest to declare.

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