Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling

Mutations in splice factor (SF) genes occurmore frequently inmyelodysplastic syndromes (MDS) than in acute myeloid leukemias (AML). We sequenced complementary DNA from bonemarrowof 47 refractory anemiawithexcess blasts (RAEB) patients, 29AML cases with low marrow blast cell count, and 325 other AML patients and determined the presence of SFhotspot mutations in SF3B1, U2AF35, and SRSF2. SFmutations were found in 10 RAEB, 12 AML cases with low marrow blast cell count, and 25 other AML cases. Our study provides evidence that SF-mutant RAEB and SF-mutant AML are clinically, cytologically, and molecularly highly similar. An integrated analysis of genomewidemessenger RNA (mRNA) expression profiling and DNA-methylation profiling data revealed 2 unique patient clusters highly enriched for SF-mutant RAEB/AML. The combined genomewide mRNA expression profiling/DNA-methylation profiling signatures revealed 1 SF-mutant patient clusterwith an erythroid signature. The other SF-mutant patient cluster was enriched for NRAS/KRAS mutations and showed an inferior survival.We conclude that SF-mutant RAEB/AML constitutes a related disorder overriding the artificial separation between AML and MDS, and that SF-mutant RAEB/AML is composed of 2 molecularly and clinically distinct subgroups.We conclude that SF-mutant disorders should be considered as myeloid malignancies that transcend the boundaries of AML and MDS.