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ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

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Listed:
  • Steven Goossens

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University
    Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University
    Mammalian Functional Genetics Laboratory, Australian Centre for Blood Diseases, Monash University and Alfred Health Alfred Centre)

  • Enrico Radaelli

    (Mouse and Animal Pathology Laboratory, Università degli Studi di Milano
    VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics)

  • Odile Blanchet

    (Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis
    CHU)

  • Kaat Durinck

    (Center for Medical Genetics, Ghent University Hospital)

  • Joni Van der Meulen

    (Center for Medical Genetics, Ghent University Hospital)

  • Sofie Peirs

    (Center for Medical Genetics, Ghent University Hospital)

  • Tom Taghon

    (Microbiology and Immunology, Ghent University)

  • Cedric S. Tremblay

    (Stem Cell Research Group, Australian Centre for Blood Diseases, Monash University)

  • Magdaline Costa

    (Mammalian Functional Genetics Laboratory, Australian Centre for Blood Diseases, Monash University and Alfred Health Alfred Centre)

  • Morvarid Farhang Ghahremani

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University)

  • Jelle De Medts

    (Microbiology and Immunology, Ghent University)

  • Sonia Bartunkova

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University)

  • Katharina Haigh

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University
    Mammalian Functional Genetics Laboratory, Australian Centre for Blood Diseases, Monash University and Alfred Health Alfred Centre)

  • Claire Schwab

    (Northern Institute for Cancer Research, Newcastle University)

  • Natalie Farla

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University
    Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University)

  • Tim Pieters

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University
    Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University
    Center for Medical Genetics, Ghent University Hospital)

  • Filip Matthijssens

    (Center for Medical Genetics, Ghent University Hospital)

  • Nadine Van Roy

    (Center for Medical Genetics, Ghent University Hospital)

  • J. Adam Best

    (Section of Molecular Biology, University of California at San Diego)

  • Kim Deswarte

    (VIB Inflammation Research Center, Ghent University)

  • Pieter Bogaert

    (Ghent University)

  • Catherine Carmichael

    (Mammalian Functional Genetics Laboratory, Australian Centre for Blood Diseases, Monash University and Alfred Health Alfred Centre)

  • Adam Rickard

    (Mammalian Functional Genetics Laboratory, Australian Centre for Blood Diseases, Monash University and Alfred Health Alfred Centre)

  • Santi Suryani

    (Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales)

  • Lauryn S. Bracken

    (Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales)

  • Raed Alserihi

    (Walter and Eliza Hall Institute of Medical Research, Melbourne University)

  • Kirsten Canté-Barrett

    (Erasmus MC Rotterdam—Sophia Children’s Hospital)

  • Lieven Haenebalcke

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University)

  • Emmanuelle Clappier

    (Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis
    CHU)

  • Pieter Rondou

    (Center for Medical Genetics, Ghent University Hospital)

  • Karolina Slowicka

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University)

  • Danny Huylebroeck

    (KU Leuven
    Erasmus MC)

  • Ananda W. Goldrath

    (Section of Molecular Biology, University of California at San Diego)

  • Viktor Janzen

    (Hematology and Oncology, University of Bonn)

  • Matthew P. McCormack

    (Walter and Eliza Hall Institute of Medical Research, Melbourne University)

  • Richard B. Lock

    (Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales)

  • David J. Curtis

    (Stem Cell Research Group, Australian Centre for Blood Diseases, Monash University)

  • Christine Harrison

    (Northern Institute for Cancer Research, Newcastle University)

  • Geert Berx

    (Ghent University
    Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University)

  • Frank Speleman

    (CHU)

  • Jules P. P. Meijerink

    (Erasmus MC Rotterdam—Sophia Children’s Hospital)

  • Jean Soulier

    (Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis
    CHU)

  • Pieter Van Vlierberghe

    (Center for Medical Genetics, Ghent University Hospital)

  • Jody J. Haigh

    (Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
    Ghent University
    Mammalian Functional Genetics Laboratory, Australian Centre for Blood Diseases, Monash University and Alfred Health Alfred Centre)

Abstract

Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model.

Suggested Citation

  • Steven Goossens & Enrico Radaelli & Odile Blanchet & Kaat Durinck & Joni Van der Meulen & Sofie Peirs & Tom Taghon & Cedric S. Tremblay & Magdaline Costa & Morvarid Farhang Ghahremani & Jelle De Medts, 2015. "ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms6794
    DOI: 10.1038/ncomms6794
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