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Chromatin landscape and epigenetic heterogeneity of acute myeloid leukaemia

Ochi, Yotaro ; Liew-Littorin, Markus LU ; Nannya, Yasuhito ; Bengtzen, Sofia ; Piauger, Benedicte ; Deneberg, Stefan ; Jädersten, Martin ; Lazarevic, Vladimir LU orcid ; Cammenga, Jörg LU and Robelius, Anna , et al. (2026) In Nature
Abstract

Acute myeloid leukaemia (AML) is an aggressive blood cancer characterized by the unregulated proliferation of immature myeloblasts. Gene mutations have been shown to have a large effect on pathogenesis, inter-tumour heterogeneity and clinical outcomes in AML1, 2, 3, 4, 5, 6, 7–8; however, the role of epigenetic alterations in these respects has been investigated less extensively. Here we use ATAC-seq (assay for transposase-accessible chromatin with sequencing) in a cohort of 1,563 individuals with a recent diagnosis of AML (the ‘eCHROMA’ cohort) to show that AML can be classified into 16 subgroups on the basis of chromatin accessibility profiles. Multiomics analyses of gene mutations, the transcriptome, DNA methylation and... (More)

Acute myeloid leukaemia (AML) is an aggressive blood cancer characterized by the unregulated proliferation of immature myeloblasts. Gene mutations have been shown to have a large effect on pathogenesis, inter-tumour heterogeneity and clinical outcomes in AML1, 2, 3, 4, 5, 6, 7–8; however, the role of epigenetic alterations in these respects has been investigated less extensively. Here we use ATAC-seq (assay for transposase-accessible chromatin with sequencing) in a cohort of 1,563 individuals with a recent diagnosis of AML (the ‘eCHROMA’ cohort) to show that AML can be classified into 16 subgroups on the basis of chromatin accessibility profiles. Multiomics analyses of gene mutations, the transcriptome, DNA methylation and histone marks show that these ATAC subgroups exhibit distinct driver mutations, differentiation states, gene expression, DNA methylation and super-enhancer profiles, and are also associated with clinical outcomes. These findings were validated in independent cohorts. Single-cell ATAC sequencing reveals that all leukaemic cells in each subgroup share a common chromatin accessibility profile, which suggests that subgroup-specific epigenomic fingerprints underlie the ATAC-based classification. Mechanistically, the subgroups have distinct gene-regulatory networks that are driven by the activities of key transcription factors in haematopoiesis, and in which subgroup-specific super-enhancers have a pivotal role. Multiomics single-cell analysis further reveals deregulated trajectories of differentiation coupled with chromatin accessibility and gene expression. Notably, ATAC subgroups have an independent prognostic effect, compared with genomic classification, and are associated with particular drug sensitivities. In summary, ATAC-based chromatin profiling, combined with multiomics data, provides insights into AML pathogenesis beyond genomics and constitutes a valuable resource for AML research.

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organization
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Contribution to journal
publication status
in press
subject
in
Nature
publisher
Nature Publishing Group
external identifiers
  • pmid:42420449
  • scopus:105044343706
ISSN
0028-0836
DOI
10.1038/s41586-026-10703-4
language
English
LU publication?
yes
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Publisher Copyright: © The Author(s) 2026.
id
5001edc9-79a0-45fd-ae5a-ff1861933286
date added to LUP
2026-07-23 08:05:39
date last changed
2026-07-24 03:00:02
@article{5001edc9-79a0-45fd-ae5a-ff1861933286,
  abstract     = {{<p>Acute myeloid leukaemia (AML) is an aggressive blood cancer characterized by the unregulated proliferation of immature myeloblasts. Gene mutations have been shown to have a large effect on pathogenesis, inter-tumour heterogeneity and clinical outcomes in AML<sup>1, 2, 3, 4, 5, 6, 7–8</sup>; however, the role of epigenetic alterations in these respects has been investigated less extensively. Here we use ATAC-seq (assay for transposase-accessible chromatin with sequencing) in a cohort of 1,563 individuals with a recent diagnosis of AML (the ‘eCHROMA’ cohort) to show that AML can be classified into 16 subgroups on the basis of chromatin accessibility profiles. Multiomics analyses of gene mutations, the transcriptome, DNA methylation and histone marks show that these ATAC subgroups exhibit distinct driver mutations, differentiation states, gene expression, DNA methylation and super-enhancer profiles, and are also associated with clinical outcomes. These findings were validated in independent cohorts. Single-cell ATAC sequencing reveals that all leukaemic cells in each subgroup share a common chromatin accessibility profile, which suggests that subgroup-specific epigenomic fingerprints underlie the ATAC-based classification. Mechanistically, the subgroups have distinct gene-regulatory networks that are driven by the activities of key transcription factors in haematopoiesis, and in which subgroup-specific super-enhancers have a pivotal role. Multiomics single-cell analysis further reveals deregulated trajectories of differentiation coupled with chromatin accessibility and gene expression. Notably, ATAC subgroups have an independent prognostic effect, compared with genomic classification, and are associated with particular drug sensitivities. In summary, ATAC-based chromatin profiling, combined with multiomics data, provides insights into AML pathogenesis beyond genomics and constitutes a valuable resource for AML research.</p>}},
  author       = {{Ochi, Yotaro and Liew-Littorin, Markus and Nannya, Yasuhito and Bengtzen, Sofia and Piauger, Benedicte and Deneberg, Stefan and Jädersten, Martin and Lazarevic, Vladimir and Cammenga, Jörg and Robelius, Anna and Wennström, Lovisa and Ölander, Emma and Kasahara, Senji and Hiramoto, Nobuhiro and Kanemura, Nobuhiro and Sezaki, Nobuo and Sakurada, Maki and Iwasaki, Makoto and Kanda, Junya and Ueda, Yasunori and Yoshihara, Satoshi and Erkers, Tom and Struyf, Nona and Watanabe, Yu and Motomura, Masanori and Nakagawa, Masahiro M. and Saiki, Ryunosuke and Fukushima, Hidehito and Okazaki, Koji and Morimoto, Suguru and Yoda, Akinori and Okuda, Rurika and Komatsu, Shintaro and Xie, Guoxiang and Österroos, Albin and Kon, Ayana and Zhao, Lanying and Shiraishi, Yuichi and Ishikawa, Takayuki and Miyano, Satoru and Katayama, Kotoe and Imoto, Seiya and Matsuda, Shuichi and Takaori-Kondo, Akifumi and Aburatani, Hiroyuki and Suzuki, Hiroshi I. and Kallioniemi, Olli and Juliusson, Gunnar and Höglund, Martin and Lehmann, Sören and Ogawa, Seishi}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Chromatin landscape and epigenetic heterogeneity of acute myeloid leukaemia}},
  url          = {{http://dx.doi.org/10.1038/s41586-026-10703-4}},
  doi          = {{10.1038/s41586-026-10703-4}},
  year         = {{2026}},
}