Mutations in SF3B1 and SRSF2 common in myelodysplastic syndrome (MDS) are synthetic lethal.

  • Major finding: Mutations in SF3B1 and SRSF2 common in myelodysplastic syndrome (MDS) are synthetic lethal.

  • Concept: SF3B1 and SRSF2 mutations have distinct effects on splicing that result in hyperactivation of NF-κB.

  • Impact: The convergence on NF-κB explains the mutual exclusivity of splicing factor mutations observed in MDS.

Mutations in RNA splicing factor genes occur frequently in patients with myelodysplastic syndrome (MDS). The mutations are generally heterozygous point mutations that occur in a mutually exclusive manner, but the basis of the mutual exclusivity and the contribution to MDS have not been fully elucidated. Lee, North, Kim, and colleagues generated mice with inducible heterozygous expression of two splicing factor mutations common in MDS, SF3B1K700E and SRSF2P95H. Co-expression of these mutations blocked hematopoiesis in vivo, and increased apoptosis and reduced quiescence in hematopoietic stem and progenitor cells (HSPC). RNA-sequencing of single- and double-mutant cells revealed that Srsf2 and Sf3b1 have largely distinct effects on gene expression and splicing. Srsf2 predominantly affected cassette exon recognition, whereas Sf3b1 preferentially altered 3′ splice site recognition. Comutation downregulated key genes in HSPC survival and rendered cells hypersensitive to inflammatory simuli. Despite distinct effects on splicing, Sf3b1 and Srsf2 mutations converged to hyperactivate downstream NF-κB signaling. Sf3b1K700E hyperactivated NF-κB in part through mis-splicing of MAP3K7 via an intron-proximal 3′ splice site promoted by SF3B1. Srsf2P95H activated NF-κB via aberrant splicing of Caspase-8, which resulted in a truncated protein. Taken together, these findings show that SF3B1K700E and SRSF2P95H mutations target distinct pre-mRNAs for splicing, but both result in downstream activation of NF-κB to produce a synthetic lethality. This mechanism explains the mutual exclusivity of splicing factor mutations observed in patients with MDS.

Lee SC, North K, Kim E, Jang E, Obeng E, Lu SX, et al. Synthetic lethal and convergent biological effects of cancer-associated spliceosomal gene mutations. Cancer Cell 2018;34:225–41.

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©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.