The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability

Publication date: Available online 14 November 2019Source: Cancer CellAuthor(s): Yun Huang, Brice Mouttet, Hans-Jörg Warnatz, Thomas Risch, Fabian Rietmann, Fabian Frommelt, Quy A. Ngo, Maria Pamela Dobay, Blerim Marovca, Silvia Jenni, Yi-Chien Tsai, Sören Matzk, Vyacheslav Amstislavskiy, Martin Schrappe, Martin Stanulla, Matthias Gstaiger, Beat Bornhauser, Marie-Laure Yaspo, Jean-Pierre BourquinSummaryThe 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research