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.
Acknowledgments
We thank the Stanford Hematology Division Tissue Bank and the patients for donating their samples. This work was supported by US National Institutes of Health grants CA65438 to A.P.F, R01CA188055 to R.M., US National Science Foundation Grant CCF-1656201 to J.G, and the Damon Runyon-Sohn Pediatric Cancer Fellowship and St. Baldrick’s Foundation Fellowship to M.A.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Data Availability
WGBS/informME data have been deposited in the Gene Expression Omnibus under accession GSE135869.
Disclosure Statement
R.M. is co-founder, consultant, equity holder, and serves on the Board of Directors of Forty Seven Inc. The are no other potential competing interests.
Supplementary material
Supplemental data for this article can be accessed here.