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

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.

Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation

“…Yang et al indicated that there were different clinical features and disease prognoses in AML patients with different DNMT3A mutation types, which were related to unique miRNA expression patterns. Moreover, the expression level of three miRNAs (miR-10b, miR-143, and miR-30b) was decreased in the DNMT3A R882 group [ 29 ]. In the present study, DNMT3A mutation was obviously associated with age, blast in peripheral blood, and FLT3 mutation.…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Multiple researchers have confirmed that DNMT3A is frequently mutated in AML patients (13.5-23%) [3,93,94]. DNMT3A plays a unique role in hematopoiesis and AML pathogenesis as the inferior prognostic markers for AML patients [6,95]. For other non-R882 mutations, especially for DNMT3A frameshift mutations, the occurrence is much less frequent and its prognostic significance is poorly understood [6].…”

“…DNMT3A plays a unique role in hematopoiesis and AML pathogenesis as the inferior prognostic markers for AML patients [6,95]. For other non-R882 mutations, especially for DNMT3A frameshift mutations, the occurrence is much less frequent and its prognostic significance is poorly understood [6]. AML patients with DNMT3A truncating mutations have comparable prognoses to those of DNMT3A wild type patients [96].…”

“…AML patients with DNMT3A truncating mutations have comparable prognoses to those of DNMT3A wild type patients [96]. 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 [6].…”

“…Six genes, including FMSlike tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), CCAAT/enhancer binding protein alpha (CEBPA), Runtrelated transcription factor 1 (RUNX1), additional sex combs-like 1 (ASXL1), and tumor protein p53 (TP53), have already been incorporated into the risk categories proposed by the European Leukemia Net (ELN) [2]. Other recurrent gene mutations have been reported in AML patients [3][4][5][6][7][8]. Furthermore, the important roles of recurrent gene mutation in AML pathogenesis had been explored and gene mutation-targeted therapies had been developed [8][9][10][11][12][13][14][15].…”