The results of our RNA-seq and splicing analyses suggest that a major function of MBNL1 in MLL-rearranged leukemia is through alternative splicing, and a number of alternatively spliced genes identified using our approach have been implicated in leukemogenesis, including a subset of epigenetic regulators such as the H3K79 methyltransferase DOT1L and the SET1 histone methyltransferase complex member and cyclin K regulator SETD1A. A frequent splicing outcome following MBNL1 knockdown was intron retention, and MBNL1 knockdown appears generally to reverse intron exclusion. This evidence concerns the gene DOT1L and leukemia.