TitleEpigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers.
Publication TypeJournal Article
Year of Publication2017
AuthorsGlass, Jacob L., Hassane Duane, Wouters Bas J., Kunimoto Hiroyoshi, Avellino Roberto, Garrett-Bakelman Francine E., Guryanova Olga A., Bowman Robert, Redlich Shira, Intlekofer Andrew M., Meydan Cem, Qin Tingting, Fall Mame, Alonso Alicia, Guzman Monica L., Valk Peter J. M., Thompson Craig B., Levine Ross, Elemento Olivier, Delwel Ruud, Melnick Ari, and Figueroa Maria E.
JournalCancer Discov
Volume7
Issue8
Pagination868-883
Date Published2017 08
ISSN2159-8290
KeywordsAdult, Aged, Animals, Disease Models, Animal, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA Methyltransferase 3A, Enhancer Elements, Genetic, Epigenesis, Genetic, Female, Humans, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Promoter Regions, Genetic, ras Proteins, Regulatory Sequences, Nucleic Acid
Abstract

<p>We performed cytosine methylation sequencing on genetically diverse patients with acute myeloid leukemia (AML) and found leukemic DNA methylation patterning is primarily driven by nonpromoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominantly of hypomethylation. AMLs with dominant hypermethylation featured greater epigenetic disruption of promoters, whereas those with dominant hypomethylation displayed greater disruption of distal and intronic regions. Mutations in and had opposing and mutually exclusive effects on the epigenome. Notably, co-occurrence of both mutations resulted in epigenetic antagonism, with most CpGs affected by either mutation alone no longer affected in double-mutant AMLs. Importantly, this epigenetic antagonism precedes malignant transformation and can be observed in preleukemic LSK cells from or single-mutant and / double-mutant mice. Notably, double-mutant AMLs manifested upregulation of a RAS signaling signature and displayed unique sensitivity to MEK inhibition as compared with AMLs with either single mutation. AML is biologically heterogeneous with subtypes characterized by specific genetic and epigenetic abnormalities. Comprehensive DNA methylation profiling revealed that differential methylation of nonpromoter regulatory elements is a driver of epigenetic identity, that gene mutations can be context-dependent, and that co-occurrence of mutations in epigenetic modifiers can result in epigenetic antagonism. .</p>

DOI10.1158/2159-8290.CD-16-1032
Alternate JournalCancer Discov
PubMed ID28408400
PubMed Central IDPMC5540802
Grant ListR01 CA198089 / CA / NCI NIH HHS / United States
K08 CA169055 / CA / NCI NIH HHS / United States
T32 CA009207 / CA / NCI NIH HHS / United States
R00 CA178191 / CA / NCI NIH HHS / United States
R01 HL126947 / HL / NHLBI NIH HHS / United States
K99 CA178191 / CA / NCI NIH HHS / United States