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; Jody J Haigh

doi:10.1038/ncomms6794

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

Nat Commun. 2015 Jan 7:6:5794. doi: 10.1038/ncomms6794.

Authors

Steven Goossens¹, Enrico Radaelli², Odile Blanchet³, Kaat Durinck⁴, Joni Van der Meulen⁴, Sofie Peirs⁴, Tom Taghon⁵, Cedric S Tremblay⁶, Magdaline Costa⁷, Morvarid Farhang Ghahremani⁸, Jelle De Medts⁵, Sonia Bartunkova⁹, Katharina Haigh¹⁰, Claire Schwab¹¹, Natalie Farla¹², Tim Pieters¹³, Filip Matthijssens⁴, Nadine Van Roy⁴, J Adam Best¹⁴, Kim Deswarte¹⁵, Pieter Bogaert¹⁶, Catherine Carmichael⁷, Adam Rickard⁷, Santi Suryani¹⁷, Lauryn S Bracken¹⁷, Raed Alserihi¹⁸, Kirsten Canté-Barrett¹⁹, Lieven Haenebalcke⁸, Emmanuelle Clappier³, Pieter Rondou⁴, Karolina Slowicka⁸, Danny Huylebroeck²⁰, Ananda W Goldrath¹⁴, Viktor Janzen²¹, Matthew P McCormack¹⁸, Richard B Lock¹⁷, David J Curtis⁶, Christine Harrison¹¹, Geert Berx²², Frank Speleman²³, Jules P P Meijerink¹⁹, Jean Soulier³, Pieter Van Vlierberghe⁴, Jody J Haigh¹⁰

Affiliations

¹ 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.
² 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.
³ 1] Institut Universitaire d'Hématologie and U944 INSERM, Hopital Saint-Louis, Paris 75010, France [2] Department of Hematology and Immunology, CHU, Angers 49100, France.
⁴ Center for Medical Genetics, Ghent University Hospital, Ghent B-9000, Belgium.
⁵ Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent B-9000, Belgium.
⁶ Stem Cell Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
⁷ 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.
⁸ 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.
⁹ Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium.
¹⁰ 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.
¹¹ Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne NE2 4AD, UK.
¹² 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.
¹³ 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.
¹⁴ Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA.
¹⁵ VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium.
¹⁶ Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
¹⁷ Children's Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
¹⁸ Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3052, Australia.
¹⁹ Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam 3015CE, The Netherlands.
²⁰ 1] Department of Development and Regeneration, KU Leuven, Leuven B-3000, Belgium [2] Department of Cell Biology, Erasmus MC, Rotterdam 3015CE, The Netherlands.
²¹ Department of Internal Medicine III, Hematology and Oncology, University of Bonn, D-53012 Bonn, Germany.
²² 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.
²³ Department of Hematology and Immunology, CHU, Angers 49100, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Chromatin Immunoprecipitation
Flow Cytometry
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / genetics
Gene Expression Regulation, Neoplastic / physiology*
Histological Techniques
Homeodomain Proteins / genetics*
Homeodomain Proteins / immunology
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Janus Kinases / metabolism
Kaplan-Meier Estimate
Karyotyping
Leukemia, T-Cell / physiopathology*
Luciferases
Mice
Real-Time Polymerase Chain Reaction
Receptors, Interleukin-7 / metabolism
Repressor Proteins / genetics*
Repressor Proteins / immunology
STAT Transcription Factors / metabolism
Signal Transduction / genetics
Signal Transduction / physiology*
Zinc Finger E-box Binding Homeobox 2

Substances

Homeodomain Proteins
Receptors, Interleukin-7
Repressor Proteins
STAT Transcription Factors
ZEB2 protein, mouse
Zinc Finger E-box Binding Homeobox 2
Luciferases
Janus Kinases

Grants and funding

R37 AI067545/AI/NIAID NIH HHS/United States