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Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression.

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Narayan, Nisha 
Vohra, Shabana 
Giotopoulos, George  ORCID logo
Mupo, Annalisa 


Altered transcription is a cardinal feature of acute myeloid leukemia (AML); however, exactly how mutations synergize to remodel the epigenetic landscape and rewire three-dimensional DNA topology is unknown. Here, we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML: Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. Our studies demonstrate that Flt3-ITD signals to chromatin to alter the epigenetic environment and synergizes with mutations in Npm1c to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a previously unknown superenhancer of Hoxa locus, as well as larger and more detailed gene-regulatory networks, driven by transcription factors including PU.1 and IRF8, whose importance we demonstrate through perturbation of network members.



Animals, Base Sequence, Chromatin Assembly and Disassembly, DNA, Neoplasm, Disease Models, Animal, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, Gene Regulatory Networks, Genetic Loci, Histones, Humans, Leukemia, Myeloid, Acute, Mice, Inbred C57BL, Mutation, Nuclear Proteins, Nucleophosmin, Principal Component Analysis, Protein Processing, Post-Translational, RNA, Messenger, Transcription, Genetic, fms-Like Tyrosine Kinase 3, Mice

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Nat Genet

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Springer Science and Business Media LLC


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European Research Council (647685)
Cancer Research UK (25508)
Kay Kendall Leukaemia Fund (KKL1243)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (886474)
Medical Research Council (MR/R009708/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (A25117)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (109967/Z/15/Z)
Wellcome Trust (205254/Z/16/Z)
Cancer Research UK (23015)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_PC_17230)
Cancer Research UK, European Research Council, Wellcome Trust, Kay Kendall Leukaemia Fund, American Society of Haematology