Survival differences and associated molecular signatures of DNMT3A-mutant acute myeloid leukemia patients

Abstract

Acute myeloid leukemia (AML) is a very heterogeneous and highly malignant blood cancer. Mutations of the DNA methyltransferase DNMT3A are among the most frequent recurrent genetic lesions in AML. The majority of DNMT3A-mutant AML patients shows fast relapse and poor survival, but also patients with long survival or long-term remission have been reported. Underlying molecular signatures and mechanisms that contribute to these survival differences are only poorly understood and have not been studied in detail so far. We applied hierarchical clustering to somatic gene mutation profiles of 51 DNMT3A-mutant patients from The Cancer Genome Atlas (TCGA) AML cohort revealing two robust patient subgroups with profound differences in survival. We further determined molecular signatures that distinguish both subgroups. Our results suggest that FLT3 and/or NPM1 mutations contribute to survival differences of DNMT3A-mutant patients. We observed an upregulation of genes of the p53, VEGF and DNA replication pathway and a downregulation of genes of the PI3K-Akt pathway in short-compared to long-lived patients. We identified that the majority of measured miRNAs was downregulated in the short-lived group and we found differentially expressed microRNAs between both subgroups that have not been reported for AML so far (miR-153-2, miR-3065, miR-95, miR-6718) suggesting that miRNAs could be important for prognosis. In addition, we learned gene regulatory networks to predict potential major regulators and found several genes and miRNAs with known roles in AML pathogenesis, but also interesting novel candidates involved in the regulation of hematopoiesis, cell cycle, cell differentiation, and immunity that may contribute to the observed survival differences of both subgroups and could therefore be important for prognosis. Moreover, the characteristic gene mutation and expression signatures that distinguished short-from long-lived patients were also predictive for independent DNMT3A-mutant AML patients from other cohorts and could also contribute to further improve the European LeukemiaNet (ELN) prognostic scoring system. Our study represents the first in-depth computational approach to identify molecular factors associated with survival differences of DNMT3A-mutant AML patients and could trigger additional studies to develop robust molecular markers for a better stratification of AML patients with DNMT3A mutations. Acute myeloid leukemia (AML) is a highly malignant cancer of myeloid blood cells affecting about one million people globally in 2015 1,2. It most frequently occurs in older adults and shows a relatively poor five-year survival rate of about 25%, which is worsening with increasing age of a patient at diagnosis 3. AML is characterized by a rapid growth of abnormal, immature myeloblasts that lost their ability to differentiate, which replace normal

miR‐6718‐5p and miR‐4329 can be used as potential biomarkers for acute myocardial infarction

“…Lauber et al believed that the expression of miR-6718 in patients with acute myeloid leukemia was significantly different from that of normal individuals, so the prognosis of patients with acute myeloid leukemia could be determined by the difference in miR-6718 expression. 17 However, no relevant studies on miR-6718 and patients with AMI have been conducted thus far. In this study, it was found that the expression of miR-6718 in patients with AMI was significantly lower than that in normal individuals.…”

Comparative Gene Expression Analysis Reveals Similarities and Differences of Chronic Myeloid Leukemia Phases

“…More details to the underlying concept are provided in [ 24 , 68 ]. Following [ 71 ], this network inference was repeated 100 times based on randomly created training sets that comprised 75% of all 87 CML gene expression samples (i.e., 65 randomly selected CML samples). The other 25% of samples (i.e., the remaining 22 CML samples), which were not in the corresponding specific training set, were considered as independent network-specific test set.…”

Gene Transcription as a Therapeutic Target in Leukemia

“…Chromatin regulators have been identified as drivers of transformation in various blood malignancies. Chromosomal rearrangements (e.g., MLL rearrangements ( MLL -r) in acute myelogenous leukemia (AML) or BCR–ABL1 in chronic myelogenous leukemia (CML)) and mutations (point mutations in EZH2 in acute lymphocytic leukemia (ALL)) can affect chromatin state [ 19 , 20 , 21 , 22 , 23 ] and/or activity of the enzymes involved in methylation/demethylation or acetylation/deacetylation of chromatin. These modifications are important for the activation or suppression of transcription ( Table 1 ).…”