Chromatin landscape and epigenetic heterogeneity of acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by proliferation of immature myeloblasts. It shows profound molecular heterogeneity, which has been primarily studied through genetic abnormalities, providing the basis for disease classification, prognostication, and therapeutic choice. However, genetic factors alone may not fully explain AML pathogenesis and diversity, while leaving the role of abnormal epigenome, particularly chromatin state, largely unexplored in a large cohort of patients. Here we show that AML is classified into 16 subgroups with distinct chromatin accessibility profiles based on ATAC-seq in 1,563 AML cases, including novel AML subgroups not previously recognized in conventional genomic classifications. By integrating multi-omics analyses of genome, transcriptome, and major histone marks, we show that these epigenetic subgroups exhibit unique features in clinical presentation, gene mutations, differentiation states, gene expression, and super-enhancer profiles, which are validated across independent cohorts. Single-cell sequencing demonstrates the presence of subgroup-specific ATAC signatures that are shared by all leukemic cells, confirming the definitive role of the epigenome in the ATAC-based classification. Mechanistically, each subgroup is associated with a distinct gene regulatory network centered on key transcription factors, where subgroup-specific super-enhancers play a pivotal role. These ATAC subgroups also have prognostic significance independent of genomic classification, and help reveal unexpected drug sensitivities. In summary, ATAC-based chromatin profiling in this large sample set, combined with multi-omics data, provides new insights into AML pathogenesis beyond genomic profiling and also serves as an invaluable resource for AML research. Competing Interest Statement Y.O. has received research funding from Nippon Shinyaku. Y.N. has held leadership positions or advisory roles for Otsuka Pharmaceutical and Bristol Myers Squibb, and has received honoraria from Bristol Myers Squibb, Takeda Pharmaceuticals, Daiichi Sankyo, Kyowa Kirin, Novartis, Pfizer, Nippon Shinyaku, Otsuka Pharmaceutical, AstraZeneca, Astellas Pharma, and AbbVie. S.K. has received honoraria from Daiichi Sankyo and AbbVie and funding for clinical trials from Astellas, Novartis, and Incyte biosciences japan. J.K. has received honoraria from Daiichi Sankyo and Asahi Kasei Pharma. S.Y. has received honoraria from Bristol Myers Squibb, Janssen Pharmaceutical, and Novartis. A.Y. was employed in an endowed department funded by Chordia Therapeutics. H.A. has served in an advisory role for and has received research funding from Konica Minolta, and has an endowed chair funded by Chugai Pharmaceutical. H.I.S. has received research funding from FUJIFILM. S.O. has received research funding from Chordia Therapeutics, Eisai, and Otsuka Pharmaceutical, consulting fees from Chordia Therapeutics, Eisai, and Montage Bio, and owns stock in Asahi Genomics. The aforementioned companies were not involved in any aspect of this study. The remaining authors declare no competing interests. Footnotes This version corresponds to the originally submitted manuscript version.