TY - JOUR
T1 - A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML
AU - Koldobskiy, Michael A.
AU - Abante, Jordi
AU - Jenkinson, Garrett
AU - Pujadas, Elisabet
AU - Tetens, Ashley
AU - Zhao, Feifei
AU - Tryggvadottir, Rakel
AU - Idrizi, Adrian
AU - Reinisch, Andreas
AU - Majeti, Ravindra
AU - Goutsias, John
AU - Feinberg, Andrew P.
N1 - Funding Information:
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.
Funding Information:
This work was supported by the Damon Runyon Cancer Research Foundation [Damon Runyon-Sohn Pediatric Cancer Fellowship DRSG-15P-16]; National Cancer Institute [CA188055]; National Cancer Institute [CA65438]; National Science Foundation [CCF-1656201]; St. Baldrick?s Foundation [St. Baldrick?s Fellowship]. 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.
Publisher Copyright:
© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/8/2
Y1 - 2020/8/2
N2 - 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.
AB - 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.
KW - DNA methylation
KW - DNA methylation stochasticity
KW - Leukaemia
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U2 - 10.1080/15592294.2020.1734149
DO - 10.1080/15592294.2020.1734149
M3 - Article
C2 - 32114880
AN - SCOPUS:85081030068
VL - 15
SP - 841
EP - 858
JO - Epigenetics
JF - Epigenetics
SN - 1559-2294
IS - 8
ER -