SET Domain Containing 2 Deficiency in Myelodysplastic Syndrome.

Recent studies have shown that myelodysplastic syndrome's (MDS) progression to acute myeloid leukemia (AML) is associated with gene mutations. SET domain containing 2 (SETD2) variants were reported as a risk factor of poor prognosis in patients with AML. However, little is known about the potential contribution of theSETD2gene in MDS. In this study, we investigated the roles ofSETD2gene mutations/variants on clinical features and prognosis in patients with MDS. A 43-gene panel was used for next-generation sequencing in 203 patients with primary MDS, and then the effects ofSETD2mutation on Wnt/beta-catenin signaling was investigated during the different stages of MDS. At a median follow up of 33 months, 65 (32.0%) deaths and 94 (46.3%) leukemic transformations were recorded. The most frequent mutations/variants includedTET2,DNMT3A, andASXL1mutations/variants. 37 patients hadSETD2gene mutations/variants, and these patients exhibited a significantly increased frequency ofTP53mutations. Multivariate survival analyses indicated thatSETD2mutations/variants were closely associated with overall survival (OS), and they were identified as risk factors for progression-free survival (PFS), especially with low expression ofSETD2gene. Further, we found thatSETD2loss could promote MDS progression via upregulationDVL3mRNA level in BM cells and it could also cause genomic instability. Secondary mutations, such asTP53andFLT3mutations, were acquired at the time of progression to AML. In conclusion, we showed thatSETD2deficiency was associated with poor outcomes in patients with MDS. Moreover,SETD2deficiency may upregulateDVL3expression and modulate genomic stability that caused AML transformation.