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

Area of Science:

• * Molecular Biology
• * Genomics
• * Cancer Epigenetics

Background:

• * KMT2A (MLL) gene translocations characterize an aggressive acute myeloid leukaemia (AML) subtype.
• * This AML subtype exhibits a distinct gene expression profile and low mutation frequency.
• * Comprehensive epigenetic analysis, particularly using whole genome bisulphite sequencing (WGBS), has been lacking for MLL-rearranged (MLL-r) AML.

Purpose of the Study:

• * To investigate epigenetic dysregulation in MLL-r AML using WGBS.
• * To compare the epigenome of MLL-r AML samples with normal myeloid controls.
• * To analyze DNA methylation patterns, including mean methylation and methylation stochasticity.

Main Methods:

• * Whole genome bisulphite sequencing (WGBS) was performed on nine MLL-r AML samples and six normal myeloid controls.
• * A computational method was employed to analyze mean DNA methylation and methylation stochasticity.
• * Epigenetic alterations were mapped to key genes and regulatory elements.

Main Results:

• * MLL-r AML exhibits a dramatically altered epigenetic profile characterized by genome-wide hypomethylation.
• * A markedly increased DNA methylation entropy was observed, indicating a disordered epigenome.
• * Methylation discordance was identified at bivalent promoters and active enhancers, correlating with known MLL-r AML expression signatures.

Conclusions:

• * The study establishes a link between epigenetic dysregulation and the transcriptional program in MLL-r AML.
• * Significant associations were found between methylation stochasticity discordances and gene expression.
• * These findings highlight the role of the altered epigenetic landscape in the MLL-r AML phenotype.