1. The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability.
- Author
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Huang Y, Mouttet B, Warnatz HJ, Risch T, Rietmann F, Frommelt F, Ngo QA, Dobay MP, Marovca B, Jenni S, Tsai YC, Matzk S, Amstislavskiy V, Schrappe M, Stanulla M, Gstaiger M, Bornhauser B, Yaspo ML, and Bourquin JP
- Subjects
- Basic-Leucine Zipper Transcription Factors genetics, DNA-Binding Proteins genetics, Humans, Translocation, Genetic, E1A-Associated p300 Protein genetics, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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