A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML

Michael A. Koldobskiy, Jordi Abante, Garrett Jenkinson, Elisabet Pujadas, Ashley Tetens, Feifei Zhao, Rakel Tryggvadottir, Adrian Idrizi, Andreas Reinisch, Ravindra Majeti, John Goutsias, Andrew P. Feinberg

Research output: Contribution to journalArticle

Abstract

Translocations of the KMT2A (MLL) gene define a biologically distinct and clinically aggressive subtype of acute myeloid leukaemia (AML), marked by a characteristic gene expression profile and few cooperating mutations. Although dysregulation of the epigenetic landscape in this leukaemia is particularly interesting given the low mutation frequency, its comprehensive analysis using whole genome bisulphite sequencing (WGBS) has not been previously performed. Here we investigated epigenetic dysregulation in nine MLL-rearranged (MLL-r) AML samples by comparing them to six normal myeloid controls, using a computational method that encapsulates mean DNA methylation measurements along with analyses of methylation stochasticity. We discovered a dramatically altered epigenetic profile in MLL-r AML, associated with genome-wide hypomethylation and a markedly increased DNA methylation entropy reflecting an increasingly disordered epigenome. Methylation discordance mapped to key genes and regulatory elements that included bivalent promoters and active enhancers. Genes associated with significant changes in methylation stochasticity recapitulated known MLL-r AML expression signatures, suggesting a role for the altered epigenetic landscape in the transcriptional programme initiated by MLL translocations. Accordingly, we established statistically significant associations between discordances in methylation stochasticity and gene expression in MLL-r AML, thus providing a link between the altered epigenetic landscape and the phenotype.

Original languageEnglish (US)
JournalEpigenetics
DOIs
StateAccepted/In press - Jan 1 2020

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Keywords

  • DNA methylation
  • DNA methylation stochasticity
  • Leukaemia

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Koldobskiy, M. A., Abante, J., Jenkinson, G., Pujadas, E., Tetens, A., Zhao, F., Tryggvadottir, R., Idrizi, A., Reinisch, A., Majeti, R., Goutsias, J., & Feinberg, A. P. (Accepted/In press). A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML. Epigenetics. https://doi.org/10.1080/15592294.2020.1734149