American Association for Cancer Research
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Supplementary Methods, Figure Legends, Table Legends, Figures S1 - S5 from Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers

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posted on 2023-04-03, 21:46 authored by Jacob L. Glass, Duane Hassane, Bas J. Wouters, Hiroyoshi Kunimoto, Roberto Avellino, Francine E. Garrett-Bakelman, Olga A. Guryanova, Robert Bowman, Shira Redlich, Andrew M. Intlekofer, Cem Meydan, Tingting Qin, Mame Fall, Alicia Alonso, Monica L. Guzman, Peter J.M. Valk, Craig B. Thompson, Ross Levine, Olivier Elemento, Ruud Delwel, Ari Melnick, Maria E. Figueroa

The supplementary methods contain a more detailed description of the analytic and experimental approach beyond the scope of the main methods section. Supplementary Figure S1. Ability of specific genomic lesions to predict epigenetic clustering. Supplementary Figure S2. ERRBS coverage. Supplementary Figure S3. Differential methylation at promoters and active enhancers. Supplementary Figure S4. DMC distribution. Supplementary Figure S5. Transcription factor binding site analysis at differentially methylated active enhancers in IDH2, DNMT3A, and IDH1/DNMT3A AMLs.

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LLS

Dutch Cancer Society

NCI

American Society of Hematology

Robert Wood Johnson Foundation

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ARTICLE ABSTRACT

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 Idh2R140Q or Dnmt3aR882H single-mutant and Idh2R140Q/Dnmt3aR882H 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. Cancer Discov; 7(8); 868–83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783

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