Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples

Abstract The transformation biology of sAML from MDS is still not fully understood. Here, we performed a big cohort of paired sequences including target, whole-exome and single cell sequencing to search AML transformation-related last events. The results showed that fifty-five out of the 64 (85.9%) patients presented presumptive last mutation events involving activated signaling, transcription factors, or tumor suppressors. Most last mutation events (63.6%, 35 cases) emerged at the leukemia transformation point. All five of the remaining nine patients analyzed by paired whole exome sequencing showed transformation-related mutations which are not included in the reference targets. Single-cell sequencing indicated that the activated cell signaling route was related to last gene mutation events which take place prior to phenotypic development. Of note, last gene mutation events defined using target sequencing was limited to a small set of genes (less than ten, in the order: NRAS/KRAS, CEBPA, TP53, FLT3, RUNX1, CBL, PTPN11 and WT1, accounted for 91.0% of the mutations). In conclusion, somatic mutations involving in activated signaling, transcription factors, or tumor suppressors appeared to be a precondition for AML transformation from myelodysplastic syndromes. The transformation-related gene mutations may be considered as new therapy targets.