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| Status |
Public on Jan 12, 2017 |
| Title |
MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia. |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
|
| Summary |
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 MLL-AF4 occupies a subset of unmethylated CG-enriched genes in combination with its cofactors Menin/LEDGF and ENL. MLL-AF4 mainly displays a punctate binding pattern near gene promoters, but we also observe a second less common pattern where MLL-AF4 spreads into the gene body and is associated with increased transcription and increased histone H3 lysine 79 methylation (H3K79me2/3). Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading genes are more sensitive to 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 new Achilles heel for guiding combination therapies in humans.
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| |
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| Overall design |
Examination of gene expression, histone marks and multiple chromatin proteins in MLL leukemia cell lines and patient samples
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| |
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| Contributor(s) |
Milne TA, Kerry J |
| Citation(s) |
28076791 |
| |
| Submission date |
Jun 23, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Thomas Milne |
| E-mail(s) |
[email protected]
|
| Organization name |
Weatherall Institute of Molecular Medicine
|
| Department |
Molecular Haematology Unit
|
| Street address |
John Radcliffe Hospital
|
| City |
Oxford |
| ZIP/Postal code |
OX3 9DS |
| Country |
United Kingdom |
| |
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| Platforms (3) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (59)
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| Relations |
| BioProject |
PRJNA326673 |
| SRA |
SRP077016 |
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