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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 04, 2011 |
| Title |
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Epigenetic pathways regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. While chromatin alterations are, in principle, reversible and often amendable to drug intervention, the promise of targeting such pathways therapeutically has been hampered by our limited understanding of cancer-specific epigenetic dependencies. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukemia (AML) – an aggressive hematopoietic malignancy often associated with aberrant chromatin states. By screening a custom shRNA library targeting known chromatin regulators in a genetically defined AML mouse model, we identify the bromodomain-containing protein Brd4 as a critical requirement for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust anti-leukemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation. Extensive evaluation of JQ1-sensitivity in primary human leukemia samples and in established cell lines revealed a broad activity of this compound against diverse AML subtypes. These effects are, at least in part, due to a requirement for Brd4 in maintaining Myc expression and promoting aberrant self-renewal. Together, our results indicate that Brd4 is a promising therapeutic target in AML and identify a small molecule that efficiently targets Myc. These findings also highlight the utility of RNAi screening as a discovery platform for revealing epigenetic vulnerabilities for direct pharmacologic intervention in cancer.
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| Overall design |
In order to understand downstream targets of Brd4, we performed array in murine or human MLL-AF9/NrasG12D cell line under the condition that Brd4 was suppressed by using shRNAs or the small molecule inhibitor JQ1. To test the hypothesis that Myc might be an important target of Brd4, we performed arrary on murine ectopic Myc overexpression MLL-AF9/NrasG12D cell under JQ1 treatment.
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| Contributor(s) |
Zuber J, Shi J, Wang E, Rappaport AR, Qi J, Taylor MJ, Johns C, Bradner JE, Lowe SW, Vakoc CR |
| Citation(s) |
21814200 |
| Submission date |
Jun 07, 2011 |
| Last update date |
Mar 04, 2019 |
| Contact name |
Junwei Shi |
| Organization name |
cold spring harbor lab
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| Street address |
1 Bungtown Rd
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| City |
Cold Spring Harbor |
| State/province |
NY |
| ZIP/Postal code |
11724 |
| Country |
USA |
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| Platforms (2) |
| GPL6244 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] |
| GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (30)
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| GSM738394 |
MLL-AF9/Nras 100nM JQ1 48h sample1 |
| GSM738395 |
MLL-AF9/Nras 100nM JQ1 48h sample2 |
| GSM738396 |
MLL-AF9/Nras 100nM JQ1 48h sample3 |
| GSM738397 |
MLL-AF9/Nras TtTMPV Rluc dox 72h sample1 |
| GSM738398 |
MLL-AF9/Nras TtTMPV Rluc dox 72h sample2 |
| GSM738399 |
MLL-AF9/Nras TtTMPV Rluc dox 72h sample3 |
| GSM738400 |
MLL-AF9/Nras TtTMPV Brd4sh-552 dox 72h |
| GSM738401 |
MLL-AF9/Nras TtTMPV Brd4sh-1448 dox 72h |
| GSM738402 |
MLL-AF9/Nras TtTMPV Brd4sh-2097 dox 72h |
| GSM738403 |
MLL-AF9/Nras MSCV empty DMSO 48h sample1 |
| GSM738404 |
MLL-AF9/Nras MSCV empty DMSO 48h sample2 |
| GSM738405 |
MLL-AF9/Nras MSCV empty DMSO 48h sample3 |
| GSM738406 |
MLL-AF9/Nras MSCV empty 100nM JQ1 48h sample1 |
| GSM738407 |
MLL-AF9/Nras MSCV empty 100nM JQ1 48h sample2 |
| GSM738408 |
MLL-AF9/Nras MSCV empty 100nM JQ1 48h sample3 |
| GSM738409 |
MLL-AF9/Nras MSCV Myc DMSO 48h sample1 |
| GSM738410 |
MLL-AF9/Nras MSCV Myc DMSO 48h sample2 |
| GSM738411 |
MLL-AF9/Nras MSCV Myc DMSO 48h sample3 |
| GSM738412 |
MLL-AF9/Nras MSCV Myc 100nM JQ1 48h sample1 |
| GSM738413 |
MLL-AF9/Nras MSCV Myc 100nM JQ1 48h sample2 |
| GSM738414 |
MLL-AF9/Nras MSCV Myc 100nM JQ1 48h sample3 |
| GSM738415 |
THP-1 DMSO 48h sample1 |
| GSM738416 |
THP-1 DMSO 48h sample2 |
| GSM738417 |
THP-1 DMSO 48h sample3 |
| GSM738418 |
THP-1 250nM JQ1 48h sample1 |
| GSM738419 |
THP-1 250nM JQ1 48h sample2 |
| GSM738420 |
THP-1 250nM JQ1 48h sample3 |
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| Relations |
| BioProject |
PRJNA141017 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE29799_RAW.tar |
128.3 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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