Abstract
It has been recently shown that DNA methyl transferase overexpression is correlated with unfavourable prognosis in human malignancies while methylation deregulation remains a hallmark that defines acute myeloid leukemia (AML). The oncogenic transcription factor EVI1 is involved in methylation deregulation and its overexpression plays a major role for predicting an adverse outcome. Moreover, the identification of DNMT3A mutations in AML patients has recently been described as a poor prognostic indicator. In order to clarify relationship between these key actors in methylation mechanisms and their potential impact on patient outcomes, we analysed 195 de novo AML patients for the expression of DNMT3A, 3B (and its non-catalytic variant 3BNC) and their correlations with the outcome and the expression of other common prognostic genetic biomarkers (EVI1, NPM1, FLT3ITD/TKD and MLL) in adult AML. The overexpression of DNMT3B/3BNC is (i) significantly correlated with a shorter overall survival, and (ii) inversely significantly correlated with event-free survival and DNMT3A expression level. Moreover, multivariate analysis showed that a high expression level of DNMT3B/3BNC is statistically a significant independent poor prognostic indicator. This study represents the first report showing that the overexpression of DNMT3B/3BNC is an independent predictor of poor survival in AML. Its quantification should be implemented to the genetic profile used to stratify patients for therapeutical strategies and should be useful to identify patients who may benefit from therapy based on demethylating agents.
Highlights
Methylation-specific gene alteration is the major mechanism involved in inappropriate gene activation or silencing in leukemic cells and has been shown to be a universal feature occurring in all acute myeloid leukemia (AML) patients [1,2]
DNMT3B7, a truncated non catalytic DNMT3B isoform expressed in human tumors, has been shown to accelerate lymphomagenesis, increase chromosomal rearrangements and shows more locus specific perturbations in DNA methylation patterns in mice when Dnmt3b7 transgenic mice are bred with Em-Myc transgenic mice [14]
It should be noted that no correlation was observed at the transcriptional level between EVI1 and (i) DNMT3A (p = 0.38), (ii) DNMT3B (p = 0.5) or (iii) DNMT3BNC (p = 0.27)
Summary
Methylation-specific gene alteration is the major mechanism involved in inappropriate gene activation or silencing in leukemic cells and has been shown to be a universal feature occurring in all acute myeloid leukemia (AML) patients [1,2]. DNA methyltransferase 3 (DNMT3A, DNMT3B) are thought to act as de novo DNMTs mostly implicated in somatic alterations [5]. The mechanism(s) by which cancer cells acquire alteration in DNA methylation is unknown but aberrant transcription of the DNMT3B gene is frequent [13]. DNMT3B7, a truncated non catalytic DNMT3B isoform expressed in human tumors, has been shown to accelerate lymphomagenesis, increase chromosomal rearrangements and shows more locus specific perturbations in DNA methylation patterns in mice when Dnmt3b7 transgenic mice are bred with Em-Myc transgenic mice [14]. EVI1 functions as a transcription repressor complex recruiting diverse proteins involved in chromatin remodelling
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