2. Academic Validation
  3. The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability

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

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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