title: ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling.
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.
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3] Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [4] Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.affiliation: 1] Mouse and Animal Pathology Laboratory, Department of Veterinary Medicine, Università degli Studi di Milano, Milan 20122, Italy [2] VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, KU Leuven, Leuven B-3000, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: 1] Institut Universitaire d'Hématologie and U944 INSERM, Hopital Saint-Louis, Paris 75010, France [2] Department of Hematology and Immunology, CHU, Angers 49100, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Blanchet
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Kaat
authors.initials: K
authors.lastname: Durinck
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Joni
authors.initials: J
authors.lastname: Van der Meulen
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Peirs
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent B-9000, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Stem Cell Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Tremblay
authors.affiliation: Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Magdaline
authors.initials: M
authors.lastname: Costa
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Morvarid
authors.initials: M
authors.lastname: Farhang Ghahremani
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent B-9000, Belgium.
authors.forename: Jelle
authors.initials: J
authors.lastname: De Medts
authors.affiliation: Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bartunkova
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3] Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Katharina
authors.initials: K
authors.lastname: Haigh
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne NE2 4AD, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3] Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: Farla
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3] Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [4] Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Pieters
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Matthijssens
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: J Adam
authors.initials: JA
authors.lastname: Best
authors.affiliation: VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Deswarte
authors.affiliation: Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Bogaert
authors.affiliation: Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Carmichael
authors.affiliation: Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Rickard
authors.affiliation: Children's Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Santi
authors.initials: S
authors.lastname: Suryani
authors.affiliation: Children's Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Lauryn S
authors.initials: LS
authors.lastname: Bracken
authors.affiliation: Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3052, Australia.
authors.forename: Raed
authors.initials: R
authors.lastname: Alserihi
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam 3015CE, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Canté-Barrett
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Haenebalcke
authors.affiliation: 1] Institut Universitaire d'Hématologie and U944 INSERM, Hopital Saint-Louis, Paris 75010, France [2] Department of Hematology and Immunology, CHU, Angers 49100, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: Karolina
authors.initials: K
authors.lastname: Slowicka
authors.affiliation: 1] Department of Development and Regeneration, KU Leuven, Leuven B-3000, Belgium [2] Department of Cell Biology, Erasmus MC, Rotterdam 3015CE, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.affiliation: Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Ananda W
authors.initials: AW
authors.lastname: Goldrath
authors.affiliation: Department of Internal Medicine III, Hematology and Oncology, University of Bonn, D-53012 Bonn, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Janzen
authors.affiliation: Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3052, Australia.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: McCormack
authors.affiliation: Children's Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Stem Cell Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Curtis
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne NE2 4AD, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Harrison
authors.affiliation: 1] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [2] Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
authors.affiliation: Department of Hematology and Immunology, CHU, Angers 49100, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam 3015CE, The Netherlands.
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
authors.affiliation: 1] Institut Universitaire d'Hématologie and U944 INSERM, Hopital Saint-Louis, Paris 75010, France [2] Department of Hematology and Immunology, CHU, Angers 49100, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: 1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3] Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006652:Histological Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053612:Janus Kinases / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015458:Leukemia, T-Cell / Q000503:physiopathology*; D008156:Luciferases; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000276:immunology; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; D020395:Receptors, Interleukin-7; D012097:Repressor Proteins; D050791:STAT Transcription Factors; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D008156:Luciferases; D053612:Janus Kinases