Identification of FUBP1 as a long tail driver and widespread regulator of tumor suppressor and oncogene alternative splicing

Comprehensive sequencing approaches have allowed for the identification of the most frequent contributors to cancer, known as drivers. They have also revealed a class of mutations in understudied, infrequently altered genes, referred to as “long tail” (LT) drivers. A key challenge has been to find clinically relevant LT drivers and understand how they cooperate to drive disease. Here, we identified Far Upstream Binding Protein 1 (FUBP1) as a LT driver using an in vivo CRISPR screen. FUBP1 cooperates with other tumor suppressor genes to transform mammary epithelial cells by disrupting cellular differentiation and tissue architecture. Mechanistically, FUBP1 participates in regulating m6A RNA methylation, and its loss leads to global changes in RNA splicing and widespread expression of aberrant driver isoforms. These findings suggest that somatic alteration of a single gene involved in RNA splicing and m6A methylation can produce the necessary panoply of contributors for neoplastic transformation. Examination of gene expression profile of normal mammary epithelial cells with loss of FUBP1