Hematologic neoplasms including myelodysplastic syndromes (MDSs), chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia, and acute myeloid leukemia have recently been reported to contain heterozygous hotspot mutations in splicing factor genes involved with 3′ splice site (ss) recognition (SF3B1, U2AF1, SRSF2, and ZRSR2).1-4 In contrast to other disorders, CLL is unique in that only SF3B1 is recurrently mutated.2 The spliceosome machinery directs the removal of introns from transcripts followed by ligation of coding exons during RNA splicing.5 The recently solved eukaryotic spliceosome structures indicate that SF3B1 HEAT domains interact with the branch site and polypyrimidine (Py) tract.6-8 Although the majority of SF3B1 hotspot mutations are located in the Py tract interacting region, the reason for inducing aberrant 3′ ss selection through reduced branch site fidelity remains unclear.9-13