Chromatin landscape and epigenetic heterogeneity of acute myeloid leukemia

Authors:
Preprint
Publisher website
Google Scholar
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.

This publication has 79 references indexed in Scilit: