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We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that  U2AF1 S34F is expressed from one of the two endogenous  U2AF1  loci. By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor. Preferential recognition of specific 3′ splice sites in S34F-expressing cells is largely explained by differential  in vitro  RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3′ splice sites. Finally, we show that lung adenocarcinoma cell lines bearing  U2AF1  mutations do not require the mutant protein for growth  in vitro  or  in vivo . In contrast, wild-type U2AF1 is required for survival, regardless of whether cells carry the  U2AF1 S34F allele. Our results provide mechanistic explanations of the magnitude of splicing changes observed in  U2AF1 -mutant cells and why tumors harboring  U2AF1  mutations always retain an expressed copy of the wild-type allele.

Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival