| Literature DB >> 31735627 |
Yun Huang1, Brice Mouttet1, Hans-Jörg Warnatz2, Thomas Risch2, Fabian Rietmann1, Fabian Frommelt3, Quy A Ngo1, Maria Pamela Dobay1, Blerim Marovca1, Silvia Jenni1, Yi-Chien Tsai1, Sören Matzk2, Vyacheslav Amstislavskiy2, Martin Schrappe4, Martin Stanulla5, Matthias Gstaiger3, Beat Bornhauser1, Marie-Laure Yaspo2, Jean-Pierre Bourquin6.
Abstract
The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia.Entities:
Keywords: BRD4; EP300; ERG; MYC; TCF3-HLF; chimeric transcription factor; drug resistance; enhancer; leukemia; topologically associating domain
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Year: 2019 PMID： 31735627 DOI： 10.1016/j.ccell.2019.10.004
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743