Decreased DNA methylation in acute myeloid leukemia patients with DNMT3A mutations and prognostic implications of DNA methylation

Hájková, H; Marková, Jana; Haškovec, C; Sarova, Iveta; Fuchs, Ota; Kostecka, Arnost; Cetkovský, Petr; Michalová, K; Schwarz, Jiřı́

doi:10.1016/j.leukres.2012.05.012

Cited by 43 publications

(37 citation statements)

References 29 publications

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“…A remarkable 60% of patients with DNMT3A mutations also carry an NPM1 mutation, whereas only 13% of patients with DNMT3A WT harbour an NPM1 mutation 76,78,89,91,92,96,123,124 . Similarly, FLT3 ITD mutations are specifically enriched in patients with DNMT3A mutations 76,78,89,91,94,96,123,125 (FIG. 4).…”

Section: Dnmt3a-related Disease Featuresmentioning

confidence: 99%

“…Given that DNMT3A mutations seem to have no clear impact on ability to achieve complete remission, the poor survival rate associated with such mutations is probably attributable to a high relapse rate 91,93,125,144 . Because DNMT3A mutations show remarkable stability during disease evolution, it is likely that the high relapse rate is due to the presence of DNMT3A mutations in ostensibly normal-appearing patient HSCs that persist even after chemotherapy and during relapse 82,83 .…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

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DNMT3A in haematological malignancies

2015

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DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, pointing to DNMT3A as a critically important new tumour suppressor. Here, we review the clinical findings related to DNMT3A, tie these data to insights from basic science studies conducted over the past 20 years and present a roadmap for future research that should advance the agenda for new therapeutic strategies.

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Section: Dnmt3a-related Disease Featuresmentioning

confidence: 99%

Section: Therapeutic Implicationsmentioning

confidence: 99%

DNMT3A in haematological malignancies

2015

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“…2 On the other hand, we found that mutations in DNMT3A were linked to the largest number of HI-LO implications (3469) compared with far fewer HI-HI relationships (325), consistent with its known loss of DNA methyltransferase activity and its hypomethylating effect. 21,22 These IDH2 and DNMT3A results validate this implication-based approach to the identification of mutational drivers of aberrant methylation in AML.…”

Section: Association Of Individual Aml Mutations With Dna Methylationmentioning

confidence: 54%

Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition

Sinha

Thomas

et al. 2015

Blood

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• Boolean implications are a useful computational algorithm to mine mutationspecific methylation relationships in large cancer data sets.• Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML, and inhibition of EZH2 induces myeloid differentiation.Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many cases do not bear mutations in known regulators of cytosine guanine dinucleotide (CpG) methylation. We found that mutations in WT1, IDH2, and CEBPA were strongly linked to DNA hypermethylation in AML using a novel integrative analysis of The Cancer Genome Atlas data based on Boolean implications, if-then rules that identify all individual CpG sites that are hypermethylated in the presence of a mutation. Introduction of mutant WT1 (WT1mut) into wild-type AML cells induced DNA hypermethylation, confirming mutant WT1 to be causally associated with DNA hypermethylation. Methylated genes in WT1mut primary patient samples were highly enriched for polycomb repressor complex 2 (PRC2) targets, implicating PRC2 dysregulation in WT1mut leukemogenesis. We found that PRC2 target genes were aberrantly repressed in WT1mut AML, and that expression of mutant WT1 in CD34 1 cord blood cells induced myeloid differentiation block. Treatment of WT1mut AML cells with short hairpin RNA or pharmacologic PRC2/ enhancer of zeste homolog 2 (EZH2) inhibitors promoted myeloid differentiation, suggesting EZH2 inhibitors may be active in this AML subtype. Our results highlight a strong association between mutant WT1 and DNA hypermethylation in AML and demonstrate that Boolean implications can be used to decipher mutation-specific methylation patterns that may lead to therapeutic insights. (Blood. 2015;125(2):316-326)

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“…Although DNMT3A mutations have not been found to dramatically alter 5-methylcytosine content and global DNA methylation levels in AML genomes [31,32], a more recent study has disclosed that DNMT3A-R882 mutation severely reduces de novo methyltransferase activity in AML cells, which induces focal hypomethylation at specific CpGs throughout genomic DNA [33]. A link of decreased methylation of specific genes with DNMT3A mutations has also been shown in AML patients [34]. The difference in methodology seems to contribute to the controversy above mentioned.…”

Section: Discussionmentioning

confidence: 99%

Let-7a-3 hypomethylation is associated with favorable/intermediate karyotypes but not with survival in acute myeloid leukemia

Zhu

Yao

et al. 2015

Tumor Biol.

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Aberrant methylation of let-7a-3 promoter has been observed in various malignancies. However, the clinical relevance of let-7a-3 methylation remains poorly known in acute myeloid leukemia (AML). This study was to investigate the let-7a-3 methylation status and to explore its clinical significance in AML. let-7a-3 promoter was significantly hypomethylated in AML patients compared to controls (median 4.51 vs 0.49) (P = 0.0003). Receiver operating characteristic curve (ROC) analysis discriminated all patients or cytogenetically normal patients from controls with an areas under the ROC curve (AUC) of 0.737 or 0.783, respectively (P < 0.001). Patients with favorable/intermediate karyotypes had significantly higher let-7a-3 unmethylation than controls. Patients with DNMT3A mutations had a trend of high level of let-7a-3 unmethylation than did those with wild-type DNMT3A (median 6.76 vs 3.66, P = 0.096). There was no significant difference in overall survival between patients with and without hypomethylated let-7a-3 (median 12 vs 5 months, P = 0.103). No correlation was observed between the level of let-7a-3 expression and let-7a-3 unmethylation in AML samples (R = 0.197, P = 0.150). However, the level of let-7a-3 expression was increased in a dose-dependent manner in THP-1 line treated with 5-aza-dC, while the methylation density of let-7a-3 promoter decreased with 5-aza-dC dose. Our findings suggest that let-7a-3 hypomethylation is associated with favorable and intermediate karyotypes but not a prognostic predictor for AML patients. Let-7a-3 expression may be partially regulated by promoter methylation.

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Decreased DNA methylation in acute myeloid leukemia patients with DNMT3A mutations and prognostic implications of DNA methylation

Cited by 43 publications

References 29 publications

DNMT3A in haematological malignancies

DNMT3A in haematological malignancies

Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition

Let-7a-3 hypomethylation is associated with favorable/intermediate karyotypes but not with survival in acute myeloid leukemia

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