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. 2021 Dec 6;36(4):935–945. doi: 10.1038/s41375-021-01476-y

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — A Summary of the mutations in 51 primary AML patients analyzed using whole-genome bisulfite sequencing. B Principal component analysis of genome-wide methylation in AML samples and CD34+ cells. Points show the values of the first and second principal components by variance explained from an analysis of genome-wide methylation summarized in mean methylation in 1 kb bins, with colors representing the defining mutation for each sample. Stratification of IDH^mut samples from CD34+ cells and AML samples with DNMT3A^R882 mutations are highlighted by colored ellipses. C Two-way hierarchical clustering of relative (difference from CD34+ cells) mean methylation levels in genomic regions defined by 15 chromatin states [36] in CD34+ cells, where rows are AML samples and columns are chromatin states. Blue is less methylated than CD34+ cells and red is more methylated. IDH1 and IDH2 mutation status are indicated in the colored bar on the left, and selected chromatin states are shown underneath the panel. D Mean methylation levels in the enhancer chromHMM state (derived from publicly available CD34+ epigenetic data) from WGBS for CD34+ cells (N = 6) and AML subtypes (IDH1^mut or IDH2^mut, n = 15; TET2^mut, n = 5; DNMT3A^R882, n = 6; DNMT3A^R882/IDH^mut, n = 7; normal karyotype with NPM1c and wild-type IDH1, IDH2, TET2, and DNMT3A, n = 4; Normal karyotype with wild-type NPM1, IDH1, IDH2, TET2, and DNMT3A, n = 4; CBFB-MYH11, n = 3; MLL-ELL, n = 3; RUNX1-RUNX1T1, n = 3). E Mean methylation levels for ~28 million genome-wide CpGs in CD34+ cells and AML subtypes. F Mean methylation at CpG islands in CD34+ cells and AML subtypes. G Number of differentially methylated regions (DMRs) identified for each AML subtype compared with normal CD34+ cells. Teal and orange bars represent hypomethylated and hypermethylated DMRs with respect to normal CD34+ cells, respectively. Mean number of CpGs per DMR (top panel) and DMR length (bottom panel) are shown for each AML subtype. H Mean methylation in IDH^mut DMRs in IDH^mut samples versus CD34+ cells. The red line indicates the percent of all DMRs with mean methylation in CD34+ cells <0.3.