Clinical Features and MicroRNA Expression Patterns Between AML Patients With DNMT3A R882 and Frameshift Mutations.

Li Yang,Ke'Feng Shen,Jian'Feng Zhou,Xiao'Lu Long,Shu'Gang Xing,Wei Zhang,Min Xiao,Yang Tang,Deng'Ju Li,Mei'Lan Zhang,Jia'Chen Wang,Hao'Dong Cai,Li'Man Lin,Jie Xiong

doi:10.3389/fonc.2019.01133

Abstract

Background: DNA methyltransferase 3A (DNMT3A) plays a unique role in hematopoiesis and acute myeloid leukemia (AML) pathogenesis. While the influences of DNMT3A mutation subtypes are still under debate.Purpose: Exploration of the clinical and molecular differences between AML patients carrying DNMT3A R882 mutations and DNMT3A frameshift mutations.Methods: Next generation of sequencing (NGS) and clinical data of 118 AML patients in our center were analyzed and compared. NGS, mRNA and miRNA profiling and clinical data from 12 patients in TCGA database were integrative analyzed.Results: Among all patients enrolled, 113 patients were positive for the variants of interest. Overall, a total of 295 variants were discovered, among which 24 DNMT3A mutations were detected, including 1 non-sense, 20 missense, 3 frameshift mutations. And 7 DNMT3A R882 mutations (3 R882H, 2 R882C, and 2 R882P) were found. Clinical analysis from our cohort and TCGA database indicated that patients carrying DNMT3A R882 mutation exhibited significantly higher levels of peripheral blood hemoglobin and non-significantly inferior prognosis compared with patients with DNMT3A frameshift mutations. Integrative analysis indicated that miR-10b, miR-143, and miR-30a were significantly decreased in the DNMT3A R882 group. High miR-143 expression is significantly associated with better prognosis in AML patients with DNMT3A mutations.Conclusion: Different molecular and clinical characteristics existed between patients with DNMT3A variant subtypes. The distinct microRNA expression pattern for DNMT3A R882 AML patients might not only act as markers to predict disease prognosis, but also could be further investigated to develop novel therapeutic targets for patients with DNMT3A mutations.

Highlights

Acute myeloid leukemia (AML) is a kind of disease with heterogeneous pathogenic mechanisms
In 17 AML-related gene-coding regions, we identified a total of 295 rare variants, which were defined as gene variants with minor allele frequency (MAF)
By comparing the clinical parameters between the two groups, we found that AML patients carrying DNA methyltransferase 3A (DNMT3A) R882 mutations exhibited higher peripheral blood cell levels (WBC 46.9∗109/L vs. 13∗109/L, 99 g/L vs. 80 g/L, and Plt 113.2∗109/L vs. 43∗109/L) compared with those in the DNMT3A frameshift group

Summary

Introduction

Acute myeloid leukemia (AML) is a kind of disease with heterogeneous pathogenic mechanisms. Among a series of gene mutations that present as inferior prognostic markers for AML patients, mutations in the DNMT3A gene have drawn great attention from researchers globally because these mutations play a unique role in normal hematopoiesis and in AML pathogenesis [4]. In this study, through the analysis of NGS sequencing data and the clinical features of AML patients at our center and in the TCGA database, we aimed to explore the molecular and biological differences between AML patients with DNMT3A frameshift mutations and those with DNMT3A R882 mutations. DNA methyltransferase 3A (DNMT3A) plays a unique role in hematopoiesis and acute myeloid leukemia (AML) pathogenesis. Purpose: Exploration of the clinical and molecular differences between AML patients carrying DNMT3A R882 mutations and DNMT3A frameshift mutations

Objectives

Methods

Results

Discussion

Conclusion