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Cell Rep. 2017 Jan 10;18(2):482-495. doi: 10.1016/j.celrep.2016.12.054.

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia.

Author information

1
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
2
Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
3
Laboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
4
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Paediatrics, University of Oxford, Children's Hospital, John Radcliffe, Oxford OX3 9DU, UK.
6
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK.
7
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Department of Paediatrics, University of Oxford, Children's Hospital, John Radcliffe, Oxford OX3 9DU, UK.
8
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
9
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK. Electronic address: thomas.milne@imm.ox.ac.uk.

Abstract

Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans.

KEYWORDS:

DOT1L; H3K79me2; MLL; MLL-AF4; drug combination therapy; epigenetic spreading; epigenetic therapy; leukemia

PMID:
28076791
PMCID:
PMC5263239
DOI:
10.1016/j.celrep.2016.12.054
[Indexed for MEDLINE]
Free PMC Article

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