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 the SETD2 gene in MDS. In this study, we investigated the roles of SETD2 gene 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 of SETD2 mutation on Wnt/β-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 included TET2, DNMT3A, and ASXL1 mutations/variants. 37 patients had SETD2 gene mutations/variants, and these patients exhibited a significantly increased frequency of TP53 mutations. Multivariate survival analyses indicated that SETD2 mutations/variants were closely associated with overall survival (OS), and they were identified as risk factors for progression-free survival (PFS), especially with low expression of SETD2 gene. Further, we found that SETD2 loss could promote MDS progression via upregulation DVL3 mRNA level in BM cells and it could also cause genomic instability. Secondary mutations, such as TP53 and FLT3 mutations, were acquired at the time of progression to AML. In conclusion, we showed that SETD2 deficiency was associated with poor outcomes in patients with MDS. Moreover, SETD2 deficiency may upregulate DVL3 expression and modulate genomic stability that caused AML transformation.

最近的研究表明，骨髓增生异常综合症（MDS）演变为急性髓细胞性白血病（AML）与基因突变有关。SET域包含2（SETD2）变异被报道为AML患者预后不良的危险因素。但是，人们对这种技术的潜在贡献知之甚少。SETD2MDS中的基因。在这项研究中，我们调查了SETD2MDS患者临床特征和预后的基因突变/变体。43基因组用于203例原发性MDS患者的下一代测序，SETD2在MDS的不同阶段研究了Wnt /β-catenin信号转导的突变。在中位随访33个月后，记录了65例（32.0％）死亡和94例（46.3％）白血病转化。最常见的突变/变异包括TET2， DNMT3A和 ASXL1突变/变体。37例患者SETD2 基因突变/变体，并且这些患者表现出明显增加的频率 TP53突变。多元生存分析表明SETD2 突变/变体与总生存期（OS）密切相关，它们被确定为无进展生存期（PFS）的危险因素，尤其是在低 SETD2基因。此外，我们发现SETD2 丢失可能通过上调促进MDS进展 DVL3BM细胞中的mRNA水平也可能导致基因组不稳定。次生突变，例如TP53 和 FLT3突变是在发展为AML时获得的。总之，我们表明SETD2缺乏与MDS患者预后不良有关。此外，SETD2 缺乏可能会上调 DVL3 表达并调节导致AML转化的基因组稳定性。