A Consensus k-mean clustering of promoter methylation data at baseline revealed two distinct clusters. Methylation data are based on methylation beta value. Promoter CpG probes from top 1% most variably methylated CpG probes were selected for the analysis. Responders were defined as patients achieved best response of CR, CRp, MLFS, PR, and HI. Nonresponders were defined as patients achieved best response of PD and SD. B Top: Box plot comparing mean methylation beta value of top 1% most variably methylated CpGs among baseline samples for cluster 1 (N = 36) and cluster 2 (N = 15). IDH1/2 wild-type AML samples (N = 8) are used as control. Box plot shows the minimum, first quartile (Q1), median, third quartile (Q3), and maximum. Two-sided Student’s t test was performed. Bottom: Density distribution of top 1% most variably methylated CpG probes with methylation beta values comparing baseline samples of cluster 1 and cluster 2. Two-sided Kolmogorov–Smirnov test was performed. IDH1/2 wild-type AML samples (N = 8) are used as control. C Forrest plot showing enrichment of the mutations at baseline against cluster 2 by logarithmic odds ratio. Circles (center of the error bars) represent odds ratios. The error bars represent 95% confidence interval of odds ratio. Baseline mutation data with clustering information are available for 51 patients, out of which 15 is in cluster 2. D Bar plot comparing the overall response (OR) and CR rate between cluster 1 (N = 36) and cluster 2 (N = 14) patients. Two-sided Fisher’s exact test was performed. E Metascape analysis of hypermethylated promoter DMPs. F Starburst plot showing integrated analysis of gene expression and promoter methylation changes between cluster 1 and cluster 2. Of 215,521 promoter CpGs, 704 showed statistically significant differential methylation and differential expression between cluster 1 and cluster 2. A total of 558 of 704 double significant CpGs showed promoter hypermethylation and downregulation of the gene expression in cluster 2. G Gene set enrichment analysis (GSEA) comparing gene expression profiles between the two clusters revealed upregulation of genes associated with leukemia stem cells (LSCs) in cluster 2. Source data are provided as Source data files.