SET Domain Containing 2 Deficiency in Myelodysplastic Syndrome

Jiaming Li,Yu Chen,Fangxiu Luo,Zhenping Peng

doi:10.3389/fgene.2020.00794

Jiaming Li, Yu Chen + Show 2 more

Open Access

https://doi.org/10.3389/fgene.2020.00794

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Abstract

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.

Highlights

Myelodysplastic syndrome (MDS) is a clonal myeloproliferative disorder of hematopoietic stem cells (HSCs) and can evolve into aggressive forms of acute myeloid leukemia (AML) (Greenberg et al, 2017)
overall survival (OS) and progression-free survival (PFS) were evaluated as disease outcomes, and events were defined as any AML transformation or death
We found that Tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3A (DNMT3A), ASXL1, and TP53 were commonly mutated in 203 patients with myelodysplastic syndrome (MDS), consistent with a previous study (Yu et al, 2020)

Summary

INTRODUCTION

Myelodysplastic syndrome (MDS) is a clonal myeloproliferative disorder of hematopoietic stem cells (HSCs) and can evolve into aggressive forms of acute myeloid leukemia (AML) (Greenberg et al, 2017). Illumina multi-PE-adaptors were bound to terminal genes and target enrichment was performed by probe capture, amplicons were purified using VAHTS DNA Clean Beads and captured on the Illumina Hiseq Xten instrument. Both VarScan and GATK software were adopted for data analysis, including quality assessment, reading comparison, variant identification, variant annotation, visualization, and prioritization. The following antibodies were used in this study: anti-SETD2 Cells were incubated overnight at 4◦C with anti-SETD2 antibodies A P-value of less than 0.05 was considered significant

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT