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

  • Cancer Cell. 2019 Dec 9;36(6):630-644.e9. doi: 10.1016/j.ccell.2019.10.004.
Yun Huang  1 ,  Brice Mouttet  1 ,  Hans-Jörg Warnatz  2 ,  Thomas Risch  2 ,  Fabian Rietmann  1 ,  Fabian Frommelt  3 ,  Quy A Ngo  1 ,  Maria Pamela Dobay  1 ,  Blerim Marovca  1 ,  Silvia Jenni  1 ,  Yi-Chien Tsai  1 ,  Sören Matzk  2 ,  Vyacheslav Amstislavskiy  2 ,  Martin Schrappe  4 ,  Martin Stanulla  5 ,  Matthias Gstaiger  3 ,  Beat Bornhauser  1 ,  Marie-Laure Yaspo  2 ,  Jean-Pierre Bourquin  6
Affiliations
  • 1. Division of Oncology and Children's Research Centre, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
  • 2. Otto Warburg Laboratory Gene Regulation and Systems Biology of Cancer, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 3. Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.
  • 4. Department of Pediatrics, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.
  • 5. Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
  • 6. Division of Oncology and Children's Research Centre, University Children's Hospital Zurich, 8032 Zurich, Switzerland. Electronic address: [email protected].
PMID: 31735627 DOI: 10.1016/j.ccell.2019.10.004
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.

Keywords
BRD4; EP300; ERG; MYC; TCF3-HLF; chimeric transcription factor; drug resistance; enhancer; leukemia; topologically associating domain.
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