Journal
CELL REPORTS
Volume 18, Issue 2, Pages 482-495Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.12.054
Keywords
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Funding
- Medical Research Council (MRC, UK) Molecular Haematology Unit Grant [MC_UU_12009/6]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) Programme
- UCSF Academic Senate
- European Research Council [681440]
- Wellcome Trust [098024/Z/11/Z, 090532/Z/09/Z]
- Bloodwise Clinician Scientist Fellowship [14041]
- EHA-ASH Translational Research Training in Hematology Fellowship
- University of Oxford
- Bloodwise Programme [13001]
- NIHR Oxford BRC
- Cancer Research UK programme [C27943/A12788]
- Computational Biology Research Group (CBRG)
- Radcliffe Department of Medicine, at the University of Oxford
- MRC Strategic Award
- MRC/Wellcome Trust [099175/Z/12/Z]
- Wellcome Trust [098024/Z/11/Z] Funding Source: Wellcome Trust
- MRC [G0700089, MC_UU_12009/14, MC_UU_00016/6, MC_PC_15004, MC_UU_12009/6] Funding Source: UKRI
- Cancer Research UK [12788] Funding Source: researchfish
- Medical Research Council [1145012, G0700089, MC_PC_15004, MC_UU_12009/6, MC_UU_00016/6, 1378531, 1148235, MC_UU_12009/14, MC_UU_00016/13, 1477617] Funding Source: researchfish
- National Institute for Health Research [CL-2010-21-011] Funding Source: researchfish
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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.
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