A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML.
Epigenetics
; 15(8): 841-858, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-32114880
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Leucemia Bifenotípica Aguda
/
Leucemia Mieloide Aguda
/
Regulación Neoplásica de la Expresión Génica
/
Metilación de ADN
Límite:
Humans
Idioma:
En
Revista:
Epigenetics
Asunto de la revista:
GENETICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos