SF3B1 mutations increase telomerase activity, Notch signaling, and DNA damage via alternative splicing.

  • Major finding: SF3B1 mutations increase telomerase activity, Notch signaling, and DNA damage via alternative splicing.

  • Concept: Transcriptomic profiling shows that SF3B1K700E promotes the use of alternative 3′ splice sites.

  • Impact: Mutant SF3B1 regulates diverse processes via alternative splicing that may promote leukemogenesis.

The spliceosomal protein SF3B1 is commonly mutated in patients with chronic lymphocytic leukemia (CLL). These mutations are associated with a poor outcome, but the role of SF3B1 mutations in leukemogenesis is unclear. Wang and colleagues analyzed RNA-sequencing (RNA-seq) data from 37 patients with CLL, 13 with SF3B1 mutations, and found that alternative 3′ splice site selection was increased in SF3B1-mutant CLL. SF3B1K700E retained its ability to bind components of the U2 small nuclear ribonucleoprotein (snRNP), and its overexpression increased the use of alternative 3′ splice sites, resulting in increased expression of splice variants and indicating that mutant SF3B1 promotes alternative splicing. Analysis of mutation status and splice variants in single cells further established the link between SF3B1 mutations and altered splicing. Moreover, SF3B1 mutations induced subtle but broad changes in gene expression and splicing, and were associated with differential expression of a number of genes including increased expression of TERC, which encodes a telomerase component. Accordingly, ectopic expression of SF3B1K700E enhanced telomerase activity. In addition, single-cell analysis from 4 primary CLLs revealed that SF3B1 mutations were linked to differential expression of genes associated with a poor CLL prognosis, DNA damage, and Notch signaling. Consistent with these findings, overexpression of mutant SF3B1 resulted in increased DNA damage. Further, mutant SF3B1 promoted alternative splicing of DVL2, a negative regulator of Notch signaling, thereby activating Notch signaling. Taken together, these results demonstrate that SF3B1 mutations promote alternative splicing in CLL cells, thereby deregulating multiple cancer-related pathways to potentially induce leukemogenesis.

Wang L, Brooks AN, Fan J, Wan Y,Gambe R, Li S, et al. Transcriptomic characterization of SF3B1 mutation reveals its pleiotropic effects in chronic lymphocytic leukemia. Cancer Cell 2016 Nov 3 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.