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

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 Bourquin

doi:10.1016/j.ccell.2019.10.004

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

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 Bourquin

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	630-644.e9
Number of pages	15
Journal	Cancer Cell
Volume	36
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2019.10.004
Publication status	Published - 09 Dec 2019
Externally published	Yes

Fields of science

302011 Dermatology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2019.10.004

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Huang, Y., Mouttet, B., Warnatz, H.-J., Risch, T., Rietmann, F., Frommelt, F., Ngo, Q. A., Dobay, M. P., Marovca, B., Jenni, S., Tsai, Y.-C., Matzk, S., Amstislavskiy, V., Schrappe, M., Stanulla, M., Gstaiger, M., Bornhauser, B., Yaspo, M.-L., & Bourquin, J.-P. (2019). The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability. Cancer Cell, 36(6), 630-644.e9. https://doi.org/10.1016/j.ccell.2019.10.004

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

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 = "Basic-Leucine Zipper Transcription Factors/genetics, DNA-Binding Proteins/genetics, E1A-Associated p300 Protein/genetics, Humans, Oncogene Proteins, Fusion/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics, Translocation, Genetic",

author = "Yun Huang and Brice Mouttet and Hans-J{\"o}rg Warnatz and Thomas Risch and Fabian Rietmann and Fabian Frommelt and Ngo, \{Quy A\} and Dobay, \{Maria Pamela\} and Blerim Marovca and Silvia Jenni and Yi-Chien Tsai and S{\"o}ren Matzk and Vyacheslav Amstislavskiy and Martin Schrappe and Martin Stanulla and Matthias Gstaiger and Beat Bornhauser and Marie-Laure Yaspo and Jean-Pierre Bourquin",

year = "2019",

month = dec,

day = "9",

doi = "10.1016/j.ccell.2019.10.004",

language = "English",

volume = "36",

pages = "630--644.e9",

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Huang, Y, Mouttet, B, Warnatz, H-J, Risch, T, Rietmann, F, Frommelt, F, Ngo, QA, Dobay, MP, Marovca, B, Jenni, S, Tsai, Y-C, Matzk, S, Amstislavskiy, V, Schrappe, M, Stanulla, M, Gstaiger, M, Bornhauser, B, Yaspo, M-L & Bourquin, J-P 2019, 'The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability', Cancer Cell, vol. 36, no. 6, pp. 630-644.e9. https://doi.org/10.1016/j.ccell.2019.10.004

TY - JOUR

T1 - The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability

AU - Huang, Yun

AU - Mouttet, Brice

AU - Warnatz, Hans-Jörg

AU - Risch, Thomas

AU - Rietmann, Fabian

AU - Frommelt, Fabian

AU - Ngo, Quy A

AU - Dobay, Maria Pamela

AU - Marovca, Blerim

AU - Jenni, Silvia

AU - Tsai, Yi-Chien

AU - Matzk, Sören

AU - Amstislavskiy, Vyacheslav

AU - Schrappe, Martin

AU - Stanulla, Martin

AU - Gstaiger, Matthias

AU - Bornhauser, Beat

AU - Yaspo, Marie-Laure

AU - Bourquin, Jean-Pierre

PY - 2019/12/9

Y1 - 2019/12/9

N2 - 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.

AB - 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.

KW - Basic-Leucine Zipper Transcription Factors/genetics

KW - DNA-Binding Proteins/genetics

KW - E1A-Associated p300 Protein/genetics

KW - Humans

KW - Oncogene Proteins, Fusion/genetics

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics

KW - Translocation, Genetic

UR - https://www.scopus.com/pages/publications/85076387088

U2 - 10.1016/j.ccell.2019.10.004

DO - 10.1016/j.ccell.2019.10.004

M3 - Article

C2 - 31735627

SN - 1878-3686

VL - 36

SP - 630-644.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

Abstract

Fields of science

UN SDGs

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