AUTHOR=Li Jiaming , Peng Zhenping , Luo Fangxiu , Chen Yu 

TITLE=SET Domain Containing 2 Deficiency in Myelodysplastic Syndrome

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.00794

DOI=10.3389/fgene.2020.00794

ISSN=1664-8021

ABSTRACT=<p>Recent studies have shown that myelodysplastic syndrome’s (MDS) progression to acute myeloid leukemia (AML) is associated with gene mutations. SET domain containing 2 (<italic>SETD2</italic>) variants were reported as a risk factor of poor prognosis in patients with AML. However, little is known about the potential contribution of the <italic>SETD2</italic> gene in MDS. In this study, we investigated the roles of <italic>SETD2</italic> 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 <italic>SETD2</italic> 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 <italic>TET2</italic>, <italic>DNMT3A</italic>, and <italic>ASXL1</italic> mutations/variants. 37 patients had <italic>SETD2</italic> gene mutations/variants, and these patients exhibited a significantly increased frequency of <italic>TP53</italic> mutations. Multivariate survival analyses indicated that <italic>SETD2</italic> 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 <italic>SETD2</italic> gene. Further, we found that <italic>SETD2</italic> loss could promote MDS progression via upregulation <italic>DVL3</italic> mRNA level in BM cells and it could also cause genomic instability. Secondary mutations, such as <italic>TP53</italic> and <italic>FLT3</italic> mutations, were acquired at the time of progression to AML. In conclusion, we showed that <italic>SETD2</italic> deficiency was associated with poor outcomes in patients with MDS. Moreover, <italic>SETD2</italic> deficiency may upregulate <italic>DVL3</italic> expression and modulate genomic stability that caused AML transformation.</p>