Journal
CANCER DISCOVERY
Volume 7, Issue 8, Pages 868-883Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-16-1032
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Funding
- LLSSCOR [7006-13, R01 CA198089]
- Dutch Cancer Society koningin Wilhelmina Fonds
- Lady Tata Foundation
- American Society of Hematology under the ASH-AMFDP [ASHAMFDP-20121]
- Robert Wood Johnson Foundation
- [T32CA009207]
- [K99CA178191]
- [1R01HL126947-01]
- [LLS QFC-3154-14]
- [NCIK08CA169055]
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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 IDH and DNMT3A 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 Idh2(R140Q) or Dnmt3a(R882H) single-mutant and Idh2(R140Q)/Dnmt3a(R882H) double-mutant mice. Notably, IDH/DNMT3A double-mutant AMLs manifested upregulation of a RAS signaling signature and displayed unique sensitivity to MEK inhibition ex vivo as compared with AMLs with either single mutation. SIGNIFICANCE: 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.
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