Mutant Sf3b1 Promotes Akt- And Nf-Kappa B Driven Mammary Tumorigenesis

Mutations in the core RNA splicing factor SF381 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF381 alter hematopoietic differentiation, whether SF381 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF381 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kappa B, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1(K70DE/WT) mice, and isogenic mutant cell lines identified hundreds of aberrant 3' splice sites (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kappa B. Coordinate activation of NF-kappa B and AKT signaling was observed in the Icnockin models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify hotspot mutations in SF381 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.