Splicing May Be Therapeutically Targetable in Acute Myeloid Leukemia Free

Mutations in genes that encode splicing factors, including SRSF2, are common in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). These mutations occur early in myeloid malignancy, are always heterozygous, and are usually mutually exclusive, prompting Lee and colleagues to hypothesize that cells with spliceosomal gene mutations may be sensitive to further disruption of splicing. To test this hypothesis, mice expressing inducible mutant Srsf2 (Srsf2^P95H) in the hematopoietic cells were generated. Srsf2^P95H/− mice exhibited severe bone marrow aplasia due to loss of bone marrow hematopoietic stem/progenitor cells, and had reduced survival compared to Srsf2^P95H/+ mice. Srsf2^P95H/− cells exhibited more missplicing events, which was due to altered exon recognition. Cells expressing the leukemic fusion KMTA–MLLT3 and Srsf2^P95H/+ or Srsf2^P95H/− were transplanted into lethally irradiated mice. All of the Srsf2^P95H/+ mice developed leukemia, whereas only half of the Srsf2^P95H/− mice did, indicating that the wild-type Srsf2 allele is critical for survival. Analysis of RNA-sequencing (RNA-seq) data from patients with MLL-rearranged AML indicated that SRSF2-mutant AML transcriptomes were similar to the Srsf2-mutated mouse models, suggesting that SRSF2 mutations also alter exon recognition in humans. Further, in a mouse model of leukemia driven by the oncogenic fusion MLL–AF9, Srsf2^+/+ and Srsf2^P95H/+ bone marrow cells resulted in fully penetrant AML. Treatment with the splicing inhibitor E7107 reduced disease burden and increased survival in Srsf2^P95H/+ mice, but had no effect on survival in Srsf2^+/+ mice. Srsf2^P95H/+ mice exhibited more widespread intron retention and cassette exon skipping, and differentially spliced genes included those involved in leukemogenesis, such as Dot1l and Meis1. Treatment of patient-derived xenografts (PDX) from patients with AML with E7107 indicated that in spliceosome-mutant PDXs E7107 reduced the leukemic burden. Together, these data show that mutations in a splicing factor can sensitize leukemia cells to further disruption of splicing, and patients with AML may benefit from splicing inhibitors.

Lee SC, Dvinge H, Kim E, Cho H, Micol J-B, Chung YR, et al. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat Med 2016 May 2 [Epub ahead of print].