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

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, Sonia Bartunkova, Katharina Haigh, Claire Schwab, Natalie Farla, Tim Pieters, Filip Matthijssens, Nadine Van Roy, J. Adam Best, Kim Deswarte, Pieter Bogaert, Catherine Carmichael, Adam Rickard, Santi Suryani, Lauryn S. Bracken, Raed Alserihi, Kirsten Canté-Barrett, Lieven Haenebalcke, Emmanuelle Clappier, Pieter Rondou, Karolina Slowicka, Danny Huylebroeck, Ananda W. Goldrath, Viktor Janzen, Matthew P. McCormack, Richard B. Lock, David J. Curtis, Christine Harrison, Geert Berx, Frank Speleman, Jules P. P. Meijerink, Jean Soulier, Pieter Van Vlierberghe and Jody J. Haigh ()
Additional contact information
Steven Goossens: Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
Enrico Radaelli: Mouse and Animal Pathology Laboratory, Università degli Studi di Milano
Odile Blanchet: Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis
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
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
Claire Schwab: Northern Institute for Cancer Research, Newcastle University
Natalie Farla: Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
Tim Pieters: Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
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
Emmanuelle Clappier: Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis
Pieter Rondou: Center for Medical Genetics, Ghent University Hospital
Karolina Slowicka: Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University
Danny Huylebroeck: KU Leuven
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
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
Pieter Van Vlierberghe: Center for Medical Genetics, Ghent University Hospital
Jody J. Haigh: Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms6794

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