|
| Status |
Public on Dec 18, 2019 |
| Title |
HBO1 is required for the maintenance of leukaemia stem cells [shRNA screen] |
| Organism |
Mus musculus |
| Experiment type |
Other
|
| Summary |
Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by transcriptional dysregulation resulting in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, with most showing modest efficacy due to an inability to effectively eradicate leukaemia stem cells (LSC). To specifically identify novel dependencies in LSC we screened a bespoke library of small hairpin RNAs (shRNAs) targeting chromatin regulators in a unique ex vivo model of LSC. We identified the MYST acetyltransferases HBO1 (KAT7) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance ex vivo and conditional ablation of HBO1 confirmed its requirement for LSC maintenance in vivo. CRISPR domain screening identified the histone acetyltransferases (HAT) domain of HBO1 as being essential to acetylate histone H3K14, which is required for the expression of the key genes including HOXA9 and HOXA10 that maintain the immature phenotype and self-renewal properties of LSC. To leverage this dependency therapeutically we developed highly potent small molecule inhibitors of HBO1 and provide structural data to demonstrate their mode of activity as competitive analogues of acetyl-CoA. These inhibitors phenocopy our genetic data and show efficacy in a broad range of human cell lines and primary patient samples encompassing the most common genetic subtypes of AML.
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| |
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| Overall design |
shRNA screen of pooled BET inhibitor resistant and sensitive leukaemic cells.
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| |
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| Contributor(s) |
Dawson MA, MacPherson L, Lam EY |
| Citation(s) |
31827282 |
| |
| Submission date |
Oct 18, 2019 |
| Last update date |
Dec 18, 2019 |
| Contact name |
Mark Dawson |
| E-mail(s) |
[email protected]
|
| Organization name |
Peter MacCallum Cancer Centre
|
| Street address |
305 Grattan St
|
| City |
Melbourne |
| State/province |
VIC |
| ZIP/Postal code |
3000 |
| Country |
Australia |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (20)
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| This SubSeries is part of SuperSeries: |
| GSE120813 |
HBO1 is required for the maintenance of leukaemia stem cells |
|
| Relations |
| BioProject |
PRJNA578410 |
| SRA |
SRP226237 |
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