ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling
Identifieur interne : 000C28 ( Pmc/Checkpoint ); précédent : 000C27; suivant : 000C29ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling
Auteurs : Steven Goossens [Belgique, Australie] ; Enrico Radaelli [Italie, Belgique] ; Odile Blanchet [France] ; Kaat Durinck [Belgique] ; Joni Van Der Meulen [Belgique] ; Sofie Peirs [Belgique] ; Tom Taghon [Belgique] ; Cedric S. Tremblay [Australie] ; Magdaline Costa [Australie] ; Morvarid Farhang Ghahremani [Belgique] ; Jelle De Medts [Belgique] ; Sonia Bartunkova [Belgique] ; Katharina Haigh [Belgique, Australie] ; Claire Schwab [Royaume-Uni] ; Natalie Farla [Belgique] ; Tim Pieters [Belgique] ; Filip Matthijssens [Belgique] ; Nadine Van Roy [Belgique] ; J. Adam Best [États-Unis] ; Kim Deswarte [Belgique] ; Pieter Bogaert [Belgique] ; Catherine Carmichael [Australie] ; Adam Rickard [Australie] ; Santi Suryani [Australie] ; Lauryn S. Bracken [Australie] ; Raed Alserihi [Australie] ; Kirsten Canté-Barrett [Pays-Bas] ; Lieven Haenebalcke [Belgique] ; Emmanuelle Clappier [France] ; Pieter Rondou [Belgique] ; Karolina Slowicka [Belgique] ; Danny Huylebroeck [Belgique, Pays-Bas] ; Ananda W. Goldrath [États-Unis] ; Viktor Janzen [Allemagne] ; Matthew P. Mccormack [Australie] ; Richard B. Lock [Australie] ; David J. Curtis [Australie] ; Christine Harrison [Royaume-Uni] ; Geert Berx [Belgique] ; Frank Speleman [France] ; Jules P. P. Meijerink [Pays-Bas] ; Jean Soulier [France] ; Pieter Van Vlierberghe [Belgique] ; Jody J. Haigh [Belgique, Australie]Source :
- Nature Communications [ 2041-1723 ] ; 2015.
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
Url:
DOI: 10.1038/ncomms6794
PubMed: 25565005
PubMed Central: 4354161
Affiliations:
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<author><name sortKey="Blanchet, Odile" sort="Blanchet, Odile" uniqKey="Blanchet O" first="Odile" last="Blanchet">Odile Blanchet</name>
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<author><name sortKey="Van Der Meulen, Joni" sort="Van Der Meulen, Joni" uniqKey="Van Der Meulen J" first="Joni" last="Van Der Meulen">Joni Van Der Meulen</name>
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<author><name sortKey="Peirs, Sofie" sort="Peirs, Sofie" uniqKey="Peirs S" first="Sofie" last="Peirs">Sofie Peirs</name>
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<author><name sortKey="Taghon, Tom" sort="Taghon, Tom" uniqKey="Taghon T" first="Tom" last="Taghon">Tom Taghon</name>
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<author><name sortKey="Tremblay, Cedric S" sort="Tremblay, Cedric S" uniqKey="Tremblay C" first="Cedric S." last="Tremblay">Cedric S. Tremblay</name>
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<author><name sortKey="Costa, Magdaline" sort="Costa, Magdaline" uniqKey="Costa M" first="Magdaline" last="Costa">Magdaline Costa</name>
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<author><name sortKey="Ghahremani, Morvarid Farhang" sort="Ghahremani, Morvarid Farhang" uniqKey="Ghahremani M" first="Morvarid Farhang" last="Ghahremani">Morvarid Farhang Ghahremani</name>
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, Ghent B-9052,<country>Belgium</country>
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<author><name sortKey="De Medts, Jelle" sort="De Medts, Jelle" uniqKey="De Medts J" first="Jelle" last="De Medts">Jelle De Medts</name>
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, Ghent B-9000,<country>Belgium</country>
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<country xml:lang="fr">Belgique</country>
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<author><name sortKey="Bartunkova, Sonia" sort="Bartunkova, Sonia" uniqKey="Bartunkova S" first="Sonia" last="Bartunkova">Sonia Bartunkova</name>
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, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
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<author><name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name>
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, Ghent B-9052,<country>Belgium</country>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
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<author><name sortKey="Schwab, Claire" sort="Schwab, Claire" uniqKey="Schwab C" first="Claire" last="Schwab">Claire Schwab</name>
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, Newcastle-upon-Tyne NE2 4AD,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
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<author><name sortKey="Farla, Natalie" sort="Farla, Natalie" uniqKey="Farla N" first="Natalie" last="Farla">Natalie Farla</name>
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<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Pieters, Tim" sort="Pieters, Tim" uniqKey="Pieters T" first="Tim" last="Pieters">Tim Pieters</name>
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</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</nlm:aff>
<country xml:lang="fr">Belgique</country>
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<author><name sortKey="Matthijssens, Filip" sort="Matthijssens, Filip" uniqKey="Matthijssens F" first="Filip" last="Matthijssens">Filip Matthijssens</name>
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, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Van Roy, Nadine" sort="Van Roy, Nadine" uniqKey="Van Roy N" first="Nadine" last="Van Roy">Nadine Van Roy</name>
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, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author><name sortKey="Best, J Adam" sort="Best, J Adam" uniqKey="Best J" first="J. Adam" last="Best">J. Adam Best</name>
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, La Jolla, California 92093,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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</affiliation>
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<author><name sortKey="Deswarte, Kim" sort="Deswarte, Kim" uniqKey="Deswarte K" first="Kim" last="Deswarte">Kim Deswarte</name>
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, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Bogaert, Pieter" sort="Bogaert, Pieter" uniqKey="Bogaert P" first="Pieter" last="Bogaert">Pieter Bogaert</name>
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, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author><name sortKey="Carmichael, Catherine" sort="Carmichael, Catherine" uniqKey="Carmichael C" first="Catherine" last="Carmichael">Catherine Carmichael</name>
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</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Rickard, Adam" sort="Rickard, Adam" uniqKey="Rickard A" first="Adam" last="Rickard">Adam Rickard</name>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
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<author><name sortKey="Suryani, Santi" sort="Suryani, Santi" uniqKey="Suryani S" first="Santi" last="Suryani">Santi Suryani</name>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
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<author><name sortKey="Bracken, Lauryn S" sort="Bracken, Lauryn S" uniqKey="Bracken L" first="Lauryn S." last="Bracken">Lauryn S. Bracken</name>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
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<author><name sortKey="Alserihi, Raed" sort="Alserihi, Raed" uniqKey="Alserihi R" first="Raed" last="Alserihi">Raed Alserihi</name>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
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<author><name sortKey="Cante Barrett, Kirsten" sort="Cante Barrett, Kirsten" uniqKey="Cante Barrett K" first="Kirsten" last="Canté-Barrett">Kirsten Canté-Barrett</name>
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</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
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</affiliation>
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<author><name sortKey="Haenebalcke, Lieven" sort="Haenebalcke, Lieven" uniqKey="Haenebalcke L" first="Lieven" last="Haenebalcke">Lieven Haenebalcke</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Clappier, Emmanuelle" sort="Clappier, Emmanuelle" uniqKey="Clappier E" first="Emmanuelle" last="Clappier">Emmanuelle Clappier</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis</institution>
, Paris 75010,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rondou, Pieter" sort="Rondou, Pieter" uniqKey="Rondou P" first="Pieter" last="Rondou">Pieter Rondou</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Slowicka, Karolina" sort="Slowicka, Karolina" uniqKey="Slowicka K" first="Karolina" last="Slowicka">Karolina Slowicka</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Huylebroeck, Danny" sort="Huylebroeck, Danny" uniqKey="Huylebroeck D" first="Danny" last="Huylebroeck">Danny Huylebroeck</name>
<affiliation wicri:level="1"><nlm:aff id="a18"><institution>Department of Development and Regeneration, KU Leuven</institution>
, Leuven B-3000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a19"><institution>Department of Cell Biology, Erasmus MC</institution>
, Rotterdam 3015CE,<country>The Netherlands</country>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goldrath, Ananda W" sort="Goldrath, Ananda W" uniqKey="Goldrath A" first="Ananda W." last="Goldrath">Ananda W. Goldrath</name>
<affiliation wicri:level="1"><nlm:aff id="a13"><institution>Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego</institution>
, La Jolla, California 92093,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Janzen, Viktor" sort="Janzen, Viktor" uniqKey="Janzen V" first="Viktor" last="Janzen">Viktor Janzen</name>
<affiliation wicri:level="1"><nlm:aff id="a20"><institution>Department of Internal Medicine III, Hematology and Oncology, University of Bonn</institution>
, D-53012 Bonn,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mccormack, Matthew P" sort="Mccormack, Matthew P" uniqKey="Mccormack M" first="Matthew P." last="Mccormack">Matthew P. Mccormack</name>
<affiliation wicri:level="1"><nlm:aff id="a16"><institution>Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne University</institution>
, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lock, Richard B" sort="Lock, Richard B" uniqKey="Lock R" first="Richard B." last="Lock">Richard B. Lock</name>
<affiliation wicri:level="1"><nlm:aff id="a15"><institution>Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales</institution>
, Sydney, New South Wales 2052,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Curtis, David J" sort="Curtis, David J" uniqKey="Curtis D" first="David J." last="Curtis">David J. Curtis</name>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>Stem Cell Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Harrison, Christine" sort="Harrison, Christine" uniqKey="Harrison C" first="Christine" last="Harrison">Christine Harrison</name>
<affiliation wicri:level="1"><nlm:aff id="a12"><institution>Northern Institute for Cancer Research, Newcastle University</institution>
, Newcastle-upon-Tyne NE2 4AD,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Berx, Geert" sort="Berx, Geert" uniqKey="Berx G" first="Geert" last="Berx">Geert Berx</name>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Speleman, Frank" sort="Speleman, Frank" uniqKey="Speleman F" first="Frank" last="Speleman">Frank Speleman</name>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Meijerink, Jules P P" sort="Meijerink, Jules P P" uniqKey="Meijerink J" first="Jules P. P." last="Meijerink">Jules P. P. Meijerink</name>
<affiliation wicri:level="1"><nlm:aff id="a17"><institution>Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam—Sophia Children’s Hospital</institution>
, Rotterdam 3015CE,<country>The Netherlands</country>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Soulier, Jean" sort="Soulier, Jean" uniqKey="Soulier J" first="Jean" last="Soulier">Jean Soulier</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis</institution>
, Paris 75010,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Vlierberghe, Pieter" sort="Van Vlierberghe, Pieter" uniqKey="Van Vlierberghe P" first="Pieter" last="Van Vlierberghe">Pieter Van Vlierberghe</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J." last="Haigh">Jody J. Haigh</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">25565005</idno>
<idno type="pmc">4354161</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354161</idno>
<idno type="RBID">PMC:4354161</idno>
<idno type="doi">10.1038/ncomms6794</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">000734</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000734</idno>
<idno type="wicri:Area/Pmc/Curation">000733</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000733</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000C28</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000C28</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling</title>
<author><name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Radaelli, Enrico" sort="Radaelli, Enrico" uniqKey="Radaelli E" first="Enrico" last="Radaelli">Enrico Radaelli</name>
<affiliation wicri:level="1"><nlm:aff id="a5"><institution>Mouse and Animal Pathology Laboratory, Department of Veterinary Medicine, Università degli Studi di Milano</institution>
, Milan 20122,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a6"><institution>VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics</institution>
, KU Leuven, Leuven B-3000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Blanchet, Odile" sort="Blanchet, Odile" uniqKey="Blanchet O" first="Odile" last="Blanchet">Odile Blanchet</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis</institution>
, Paris 75010,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Durinck, Kaat" sort="Durinck, Kaat" uniqKey="Durinck K" first="Kaat" last="Durinck">Kaat Durinck</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Der Meulen, Joni" sort="Van Der Meulen, Joni" uniqKey="Van Der Meulen J" first="Joni" last="Van Der Meulen">Joni Van Der Meulen</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Peirs, Sofie" sort="Peirs, Sofie" uniqKey="Peirs S" first="Sofie" last="Peirs">Sofie Peirs</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Taghon, Tom" sort="Taghon, Tom" uniqKey="Taghon T" first="Tom" last="Taghon">Tom Taghon</name>
<affiliation wicri:level="1"><nlm:aff id="a10"><institution>Department of Clinical Chemistry, Microbiology and Immunology, Ghent University</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tremblay, Cedric S" sort="Tremblay, Cedric S" uniqKey="Tremblay C" first="Cedric S." last="Tremblay">Cedric S. Tremblay</name>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>Stem Cell Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Costa, Magdaline" sort="Costa, Magdaline" uniqKey="Costa M" first="Magdaline" last="Costa">Magdaline Costa</name>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ghahremani, Morvarid Farhang" sort="Ghahremani, Morvarid Farhang" uniqKey="Ghahremani M" first="Morvarid Farhang" last="Ghahremani">Morvarid Farhang Ghahremani</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="De Medts, Jelle" sort="De Medts, Jelle" uniqKey="De Medts J" first="Jelle" last="De Medts">Jelle De Medts</name>
<affiliation wicri:level="1"><nlm:aff id="a10"><institution>Department of Clinical Chemistry, Microbiology and Immunology, Ghent University</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bartunkova, Sonia" sort="Bartunkova, Sonia" uniqKey="Bartunkova S" first="Sonia" last="Bartunkova">Sonia Bartunkova</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Schwab, Claire" sort="Schwab, Claire" uniqKey="Schwab C" first="Claire" last="Schwab">Claire Schwab</name>
<affiliation wicri:level="1"><nlm:aff id="a12"><institution>Northern Institute for Cancer Research, Newcastle University</institution>
, Newcastle-upon-Tyne NE2 4AD,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Farla, Natalie" sort="Farla, Natalie" uniqKey="Farla N" first="Natalie" last="Farla">Natalie Farla</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pieters, Tim" sort="Pieters, Tim" uniqKey="Pieters T" first="Tim" last="Pieters">Tim Pieters</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Matthijssens, Filip" sort="Matthijssens, Filip" uniqKey="Matthijssens F" first="Filip" last="Matthijssens">Filip Matthijssens</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Roy, Nadine" sort="Van Roy, Nadine" uniqKey="Van Roy N" first="Nadine" last="Van Roy">Nadine Van Roy</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Best, J Adam" sort="Best, J Adam" uniqKey="Best J" first="J. Adam" last="Best">J. Adam Best</name>
<affiliation wicri:level="1"><nlm:aff id="a13"><institution>Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego</institution>
, La Jolla, California 92093,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Deswarte, Kim" sort="Deswarte, Kim" uniqKey="Deswarte K" first="Kim" last="Deswarte">Kim Deswarte</name>
<affiliation wicri:level="1"><nlm:aff id="a14"><institution>VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bogaert, Pieter" sort="Bogaert, Pieter" uniqKey="Bogaert P" first="Pieter" last="Bogaert">Pieter Bogaert</name>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Carmichael, Catherine" sort="Carmichael, Catherine" uniqKey="Carmichael C" first="Catherine" last="Carmichael">Catherine Carmichael</name>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rickard, Adam" sort="Rickard, Adam" uniqKey="Rickard A" first="Adam" last="Rickard">Adam Rickard</name>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Suryani, Santi" sort="Suryani, Santi" uniqKey="Suryani S" first="Santi" last="Suryani">Santi Suryani</name>
<affiliation wicri:level="1"><nlm:aff id="a15"><institution>Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales</institution>
, Sydney, New South Wales 2052,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bracken, Lauryn S" sort="Bracken, Lauryn S" uniqKey="Bracken L" first="Lauryn S." last="Bracken">Lauryn S. Bracken</name>
<affiliation wicri:level="1"><nlm:aff id="a15"><institution>Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales</institution>
, Sydney, New South Wales 2052,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Alserihi, Raed" sort="Alserihi, Raed" uniqKey="Alserihi R" first="Raed" last="Alserihi">Raed Alserihi</name>
<affiliation wicri:level="1"><nlm:aff id="a16"><institution>Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne University</institution>
, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cante Barrett, Kirsten" sort="Cante Barrett, Kirsten" uniqKey="Cante Barrett K" first="Kirsten" last="Canté-Barrett">Kirsten Canté-Barrett</name>
<affiliation wicri:level="1"><nlm:aff id="a17"><institution>Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam—Sophia Children’s Hospital</institution>
, Rotterdam 3015CE,<country>The Netherlands</country>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Haenebalcke, Lieven" sort="Haenebalcke, Lieven" uniqKey="Haenebalcke L" first="Lieven" last="Haenebalcke">Lieven Haenebalcke</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Clappier, Emmanuelle" sort="Clappier, Emmanuelle" uniqKey="Clappier E" first="Emmanuelle" last="Clappier">Emmanuelle Clappier</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis</institution>
, Paris 75010,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rondou, Pieter" sort="Rondou, Pieter" uniqKey="Rondou P" first="Pieter" last="Rondou">Pieter Rondou</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Slowicka, Karolina" sort="Slowicka, Karolina" uniqKey="Slowicka K" first="Karolina" last="Slowicka">Karolina Slowicka</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Huylebroeck, Danny" sort="Huylebroeck, Danny" uniqKey="Huylebroeck D" first="Danny" last="Huylebroeck">Danny Huylebroeck</name>
<affiliation wicri:level="1"><nlm:aff id="a18"><institution>Department of Development and Regeneration, KU Leuven</institution>
, Leuven B-3000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a19"><institution>Department of Cell Biology, Erasmus MC</institution>
, Rotterdam 3015CE,<country>The Netherlands</country>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Goldrath, Ananda W" sort="Goldrath, Ananda W" uniqKey="Goldrath A" first="Ananda W." last="Goldrath">Ananda W. Goldrath</name>
<affiliation wicri:level="1"><nlm:aff id="a13"><institution>Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego</institution>
, La Jolla, California 92093,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Janzen, Viktor" sort="Janzen, Viktor" uniqKey="Janzen V" first="Viktor" last="Janzen">Viktor Janzen</name>
<affiliation wicri:level="1"><nlm:aff id="a20"><institution>Department of Internal Medicine III, Hematology and Oncology, University of Bonn</institution>
, D-53012 Bonn,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mccormack, Matthew P" sort="Mccormack, Matthew P" uniqKey="Mccormack M" first="Matthew P." last="Mccormack">Matthew P. Mccormack</name>
<affiliation wicri:level="1"><nlm:aff id="a16"><institution>Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne University</institution>
, Parkville, Victoria 3052,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lock, Richard B" sort="Lock, Richard B" uniqKey="Lock R" first="Richard B." last="Lock">Richard B. Lock</name>
<affiliation wicri:level="1"><nlm:aff id="a15"><institution>Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales</institution>
, Sydney, New South Wales 2052,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Curtis, David J" sort="Curtis, David J" uniqKey="Curtis D" first="David J." last="Curtis">David J. Curtis</name>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>Stem Cell Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Harrison, Christine" sort="Harrison, Christine" uniqKey="Harrison C" first="Christine" last="Harrison">Christine Harrison</name>
<affiliation wicri:level="1"><nlm:aff id="a12"><institution>Northern Institute for Cancer Research, Newcastle University</institution>
, Newcastle-upon-Tyne NE2 4AD,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Berx, Geert" sort="Berx, Geert" uniqKey="Berx G" first="Geert" last="Berx">Geert Berx</name>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Speleman, Frank" sort="Speleman, Frank" uniqKey="Speleman F" first="Frank" last="Speleman">Frank Speleman</name>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Meijerink, Jules P P" sort="Meijerink, Jules P P" uniqKey="Meijerink J" first="Jules P. P." last="Meijerink">Jules P. P. Meijerink</name>
<affiliation wicri:level="1"><nlm:aff id="a17"><institution>Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam—Sophia Children’s Hospital</institution>
, Rotterdam 3015CE,<country>The Netherlands</country>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Soulier, Jean" sort="Soulier, Jean" uniqKey="Soulier J" first="Jean" last="Soulier">Jean Soulier</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis</institution>
, Paris 75010,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Vlierberghe, Pieter" sort="Van Vlierberghe, Pieter" uniqKey="Van Vlierberghe P" first="Pieter" last="Van Vlierberghe">Pieter Van Vlierberghe</name>
<affiliation wicri:level="1"><nlm:aff id="a9"><institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J." last="Haigh">Jody J. Haigh</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a4"><institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature Communications</title>
<idno type="eISSN">2041-1723</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>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 <italic>ZEB2</italic>
as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained <italic>Zeb2</italic>
expression initiates T-cell leukaemia. Moreover, <italic>Zeb2</italic>
-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 <italic>IL7R</italic>
. 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 <italic>Zeb2</italic>
-driven mouse model.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id>
<journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id>
<journal-title-group><journal-title>Nature Communications</journal-title>
</journal-title-group>
<issn pub-type="epub">2041-1723</issn>
<publisher><publisher-name>Nature Pub. Group</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25565005</article-id>
<article-id pub-id-type="pmc">4354161</article-id>
<article-id pub-id-type="pii">ncomms6794</article-id>
<article-id pub-id-type="doi">10.1038/ncomms6794</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Goossens</surname>
<given-names>Steven</given-names>
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</contrib>
<contrib contrib-type="author"><name><surname>Radaelli</surname>
<given-names>Enrico</given-names>
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</contrib>
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<given-names>Odile</given-names>
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<given-names>Morvarid Farhang</given-names>
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<given-names>Jelle</given-names>
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<given-names>Sonia</given-names>
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</contrib>
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<given-names>Katharina</given-names>
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<given-names>Claire</given-names>
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<given-names>Natalie</given-names>
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<given-names>Tim</given-names>
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<given-names>Filip</given-names>
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<given-names>Adam</given-names>
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<given-names>Kirsten</given-names>
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<given-names>Lieven</given-names>
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<given-names>Emmanuelle</given-names>
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<given-names>Pieter</given-names>
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</contrib>
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<given-names>Karolina</given-names>
</name>
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</contrib>
<contrib contrib-type="author"><name><surname>Huylebroeck</surname>
<given-names>Danny</given-names>
</name>
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</contrib>
<contrib contrib-type="author"><name><surname>Goldrath</surname>
<given-names>Ananda W.</given-names>
</name>
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</contrib>
<contrib contrib-type="author"><name><surname>Janzen</surname>
<given-names>Viktor</given-names>
</name>
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</contrib>
<contrib contrib-type="author"><name><surname>McCormack</surname>
<given-names>Matthew P.</given-names>
</name>
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</contrib>
<contrib contrib-type="author"><name><surname>Lock</surname>
<given-names>Richard B.</given-names>
</name>
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</contrib>
<contrib contrib-type="author"><name><surname>Curtis</surname>
<given-names>David J.</given-names>
</name>
<xref ref-type="aff" rid="a11">11</xref>
</contrib>
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<given-names>Christine</given-names>
</name>
<xref ref-type="aff" rid="a12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Berx</surname>
<given-names>Geert</given-names>
</name>
<xref ref-type="aff" rid="a2">2</xref>
<xref ref-type="aff" rid="a3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Speleman</surname>
<given-names>Frank</given-names>
</name>
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</contrib>
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<given-names>Jules P. P.</given-names>
</name>
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<given-names>Jean</given-names>
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<given-names>Pieter</given-names>
</name>
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<given-names>Jody J.</given-names>
</name>
<xref ref-type="corresp" rid="c1">a</xref>
<xref ref-type="aff" rid="a1">1</xref>
<xref ref-type="aff" rid="a2">2</xref>
<xref ref-type="aff" rid="a4">4</xref>
</contrib>
<aff id="a1"><label>1</label>
<institution>Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</aff>
<aff id="a2"><label>2</label>
<institution>Department for Biomedical Molecular Biology, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</aff>
<aff id="a3"><label>3</label>
<institution>Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</aff>
<aff id="a4"><label>4</label>
<institution>Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre</institution>
, 99 Commercial Road, Melbourne, Victoria 3004,<country>Australia</country>
</aff>
<aff id="a5"><label>5</label>
<institution>Mouse and Animal Pathology Laboratory, Department of Veterinary Medicine, Università degli Studi di Milano</institution>
, Milan 20122,<country>Italy</country>
</aff>
<aff id="a6"><label>6</label>
<institution>VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics</institution>
, KU Leuven, Leuven B-3000,<country>Belgium</country>
</aff>
<aff id="a7"><label>7</label>
<institution>Institut Universitaire d’Hématologie and U944 INSERM, Hopital Saint-Louis</institution>
, Paris 75010,<country>France</country>
</aff>
<aff id="a8"><label>8</label>
<institution>Department of Hematology and Immunology, CHU</institution>
, Angers 49100,<country>France</country>
</aff>
<aff id="a9"><label>9</label>
<institution>Center for Medical Genetics, Ghent University Hospital</institution>
, Ghent B-9000,<country>Belgium</country>
</aff>
<aff id="a10"><label>10</label>
<institution>Department of Clinical Chemistry, Microbiology and Immunology, Ghent University</institution>
, Ghent B-9000,<country>Belgium</country>
</aff>
<aff id="a11"><label>11</label>
<institution>Stem Cell Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University</institution>
, Melbourne, Victoria 3004,<country>Australia</country>
</aff>
<aff id="a12"><label>12</label>
<institution>Northern Institute for Cancer Research, Newcastle University</institution>
, Newcastle-upon-Tyne NE2 4AD,<country>UK</country>
</aff>
<aff id="a13"><label>13</label>
<institution>Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego</institution>
, La Jolla, California 92093,<country>USA</country>
</aff>
<aff id="a14"><label>14</label>
<institution>VIB Inflammation Research Center, Ghent University</institution>
, Ghent B-9052,<country>Belgium</country>
</aff>
<aff id="a15"><label>15</label>
<institution>Children’s Cancer Institute, Leukaemia Biology Program, Lowy Cancer Research Centre, University of New South Wales</institution>
, Sydney, New South Wales 2052,<country>Australia</country>
</aff>
<aff id="a16"><label>16</label>
<institution>Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne University</institution>
, Parkville, Victoria 3052,<country>Australia</country>
</aff>
<aff id="a17"><label>17</label>
<institution>Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam—Sophia Children’s Hospital</institution>
, Rotterdam 3015CE,<country>The Netherlands</country>
</aff>
<aff id="a18"><label>18</label>
<institution>Department of Development and Regeneration, KU Leuven</institution>
, Leuven B-3000,<country>Belgium</country>
</aff>
<aff id="a19"><label>19</label>
<institution>Department of Cell Biology, Erasmus MC</institution>
, Rotterdam 3015CE,<country>The Netherlands</country>
</aff>
<aff id="a20"><label>20</label>
<institution>Department of Internal Medicine III, Hematology and Oncology, University of Bonn</institution>
, D-53012 Bonn,<country>Germany</country>
</aff>
</contrib-group>
<author-notes><corresp id="c1"><label>a</label>
<email>jody.haigh@monash.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>07</day>
<month>01</month>
<year>2015</year>
</pub-date>
<volume>6</volume>
<elocation-id>5794</elocation-id>
<history><date date-type="received"><day>16</day>
<month>09</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>07</day>
<month>11</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
</license-p>
</license>
</permissions>
<abstract><p>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 <italic>ZEB2</italic>
as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained <italic>Zeb2</italic>
expression initiates T-cell leukaemia. Moreover, <italic>Zeb2</italic>
-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 <italic>IL7R</italic>
. 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 <italic>Zeb2</italic>
-driven mouse model.</p>
</abstract>
<abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms6794-i1.jpg"></inline-graphic>
Driver mutations in early T-cell precursor leukaemia (ETP-ALL) are poorly characterized. Here the authors show that <italic>Zeb2</italic>
overexpression is often found in ETP-ALL, can recapitulate the disease in transgenic mice and confers survival advantage by upregulating IL-7 signalling.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="f1"><label>Figure 1</label>
<caption><title>Identification of ETP-ALL cases with translocations involving the <italic>ZEB2</italic>
locus and enhanced <italic>ZEB2</italic>
expression in the immature subtype of human T-ALL patients.</title>
<p>(<bold>a</bold>
) Partial karyotype (RHG banding) in case TL88 showing a t(2;14)(q22;q32) translocation. (<bold>b</bold>
) Dual-colour FISH analysis using combination of BCL11B and ZEB2 probes on metaphase spreads from leukaemic cells in case TL88. FISH probe RP11-68I8 is shown in green, RP11-889B13 in red. Scale bar, 10 μm. (<bold>c</bold>
) <italic>ZEB2</italic>
expression levels in a previously published<xref ref-type="bibr" rid="b4">4</xref>
cohort of 64 human paediatric T-ALL cases. Unsupervised hierarchical classification of T-ALL subtypes was based on gene expression and genomic annotations. Mean expression is indicated and Mann–Whitney <italic>U</italic>
-Test used for statistical analysis. (<bold>d</bold>
) <italic>ZEB2</italic>
expression levels in an independent published cohort of 57 human adult T-ALL cases. Unsupervised hierarchical classification of immature and mature subclasses was based on gene expression and genomic annotations as reported<xref ref-type="bibr" rid="b17">17</xref>
. Mean expression is indicated and Mann–Whitney <italic>U</italic>
-Test used for statistical analysis. (<bold>e</bold>
) Heatmap showing expression levels of the miRNA-141/200c cluster in a published cohort of human T-ALL patients<xref ref-type="bibr" rid="b48">48</xref>
. (<bold>f</bold>
) qRT–PCR analysis; relative mRNA expression for <italic>ZEB2</italic>
and the immature marker genes <italic>LYL1</italic>
, <italic>HHEX</italic>
, <italic>MEF2C</italic>
, <italic>PSCD4</italic>
, <italic>FAM46A</italic>
in six human T-ALL cell lines. Data were presented as average±s.d.</p>
</caption>
<graphic xlink:href="ncomms6794-f1"></graphic>
</fig>
<fig id="f2"><label>Figure 2</label>
<caption><title>Tie2-Cre-mediated expression of <italic>Zeb2</italic>
on its own or in synergy with <italic>p53</italic>
loss leads to T-cell lymophoblastic leukaemia.</title>
<p>(<bold>a</bold>
) Schematic representation of the conditional <italic>ROSA26</italic>
-based <italic>Zeb2</italic>
overexpression mouse model. The mouse <italic>Zeb2</italic>
open reading frame was targeted to the <italic>ROSA26</italic>
locus preceded by a floxed (fl) transcriptional stop (PGK-Neo-3XpA) cassette and followed by IRES-EGFP reporter sequence. (<bold>b</bold>
) Quantification of relative Zeb2 and EGFP mRNA levels in thymus of <italic>Tie2cre, R26-Zeb2</italic>
<sup><italic>tg/+</italic>
</sup>
(<italic>R26-Zeb2</italic>
<sup><italic>tg/+</italic>
</sup>
) and <italic>Tie2cre, R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
(<italic>R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
) mice compared with Tie2-Cre-negative control littermates (Control). qRT–PCR data were presented as average±s.d. (<bold>c</bold>
) Kaplan–Meier survival curve of <italic>R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
mice (<italic>n</italic>
=21) compared with control littermates (<italic>n</italic>
=9). Mantel–Cox test was used for statistical analysis. (<bold>d</bold>
) From 5 months of age, <italic>R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
spontaneously develop thymus tumours (asterisk). (<bold>e</bold>
) Histopathological analysis of thymic mass displaying dense monomorphic sheets of neoplastic lymphoid cells; haematoxylin and eosin (H&E) staining, scale bar, 100 μm. Neoplastic lymphoid cells are diffusely positive for the T-cell marker CD3; CD3 immunohistochemistry, scale bar, 80 μm. Neoplastic T cells also exhibit moderate degree of cKit expression; cKit immunohistochemistry, scale bar, 100 μm. IBA-1-positive histiocytes/macrophages are scattered among the neoplastic lymphoid sheets; IBA-1 immunohistochemistry, scale bar, 100 μm. (<bold>f</bold>
) Precursor T-cell lymphoblastic leukaemia (Pre-T LBL) invading the adjacent pulmonary parenchyma with dense infiltrates of CD3-positive cells expanding the peribronchial/perivascular interstitium; CD3 immunohistochemistry, scale bar, 400 μm. PTLL exhibits systemic dissemination with dense infiltrates of CD3-positive cells expanding the centrilobular and portal areas and dissecting along the surrounding hepatic cords; CD3 immunohistochemistry, scale bar, 200 μm. (<bold>g</bold>
) Bone marrow of <italic>R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
with Pre-T LBL. H&E stain, scale bar, 50 μm. (<bold>h</bold>
) Microscopic analysis of blood smears from <italic>R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
with Pre-T LBL, with a high number of large and atypical leukaemic lymphoid cells in the circulation. May Grunwald Giemsa stain, scale bar, 50 μm. (<bold>i</bold>
) Kaplan–Meier survival curve after intercrossing <italic>Zeb2</italic>
-overexpressing mice on to a <italic>Tie2cre, p53</italic>
<sup><italic>f/f</italic>
</sup>
thymic tumour-prone background: a significant decrease in tumour latency and survival could be observed (<bold>j</bold>
) with a shift in tumour spectrum. Mantel–Cox test was used to determine significance for Kaplan–Meier curve. **<italic>P</italic>
<0.01, ***<italic>P</italic>
<0.001.</p>
</caption>
<graphic xlink:href="ncomms6794-f2"></graphic>
</fig>
<fig id="f3"><label>Figure 3</label>
<caption><title><italic>Zeb2</italic>
overexpression leads to increased expression of immature/stem cell marker genes, and ETP-ALL-like expression profile.</title>
<p>(<bold>a</bold>
) Differential gene expression profiling of <italic>P53/R26</italic>
<sup><italic>+/+</italic>
</sup>
(<italic>n</italic>
=2) vs <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
(<italic>n</italic>
=3) thymic tumours (log<sub>2</sub>
(FC)>3, <italic>P</italic>
<0.05). A heatmap of the top differentially expressed genes is shown. Genes in the heat map are shown in rows and each individual tumour sample is shown in one column. (<bold>b</bold>
) Gene set enrichment analysis of a top-500 probe sets enriched in immature/ETP-ALL patients in the gene expression signature of control vs <italic>Zeb2</italic>
-overexpressing mouse tumours. The top 25 leading edge genes are also shown. (<bold>c</bold>
) Flow cytometric analysis of thymic tumours upon Zeb2 overexpression showing a decrease in more mature markers sCD3 and CD8 and increase of the stem/progenitor marker cKit. Dotplots of representative control P53/R26<sup>+/+</sup>
and <italic>Zeb2</italic>
-overexpressing tumours <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
are depicted. (<bold>d</bold>
) Immunohistochemistry for cKit of representative tumours for each genotype (<bold>e</bold>
) qRT–PCR analysis of control <italic>P53/R26</italic>
<sup><italic>+/+</italic>
</sup>
and <italic>Zeb2</italic>
-overexpressing <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/+</italic>
</sup>
and <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
thymic tumours for the immature/ETP-ALL marker gene <italic>Lyl1</italic>
. Mean expression is indicated±s.d. *<italic>P</italic>
<0.05 (vs control).</p>
</caption>
<graphic xlink:href="ncomms6794-f3"></graphic>
</fig>
<fig id="f4"><label>Figure 4</label>
<caption><title><italic>Zeb2</italic>
overexpression leads to increased leukaemia-initiating potential.</title>
<p>(<bold>a</bold>
) Quantification of leukaemic stem cell (LSC) frequency in control <italic>P53/R26</italic>
<sup><italic>+/+</italic>
</sup>
(<italic>n</italic>
=4) and <italic>Zeb2</italic>
-overexpressing <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/+</italic>
</sup>
(<italic>n</italic>
=3) and <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
(<italic>n</italic>
=3) thymic tumours via serial dilution transplantation of primary tumours cells into immunodeficient NOD/SCID recipient mice. One-way analysis of variance (ANOVA) statistical analysis was used. (<bold>b</bold>
) Secondary leukaemia-initiating capacity was tested for <italic>P53/R26-Zeb2</italic>
<sup><italic>+/+</italic>
</sup>
tumours (<italic>n</italic>
=2) vs <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/+</italic>
</sup>
(<italic>n</italic>
=1) and <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
(<italic>n</italic>
=4) tumours via serial dilution transplantation of primary tumour cells into NOD/SCID mice. The cell lines were derived from individual mouse thymic tumours and kept in culture for at least six passages. One-way ANOVA statistical analysis was used. (<bold>c</bold>
) Transplantation of Luciferase-positive LOUCY cells in NSG mice after ZEB2 knockdown (+pLV-TH shZEB2, <italic>n</italic>
=3) resulted in decreased leukaemia development compared with the control cell line (+pLV-TH empty vector, <italic>n</italic>
=3). Student’s <italic>t</italic>
-test was used for statistical analysis. All leukaemia cell transplantation experiments were conducted once.</p>
</caption>
<graphic xlink:href="ncomms6794-f4"></graphic>
</fig>
<fig id="f5"><label>Figure 5</label>
<caption><title>Strong positive correlation between <italic>Zeb2</italic>
and <italic>Il7r</italic>
mRNA levels associates with increased JAK/STAT signalling.</title>
<p>(<bold>a</bold>
) Quantitative Real-time (qRT)-PCR for <italic>Il7r</italic>
in control <italic>P53/R26</italic>
<sup><italic>+/+</italic>
</sup>
(<italic>n</italic>
=5) and <italic>Zeb2</italic>
-overexpressing <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/+</italic>
</sup>
(<italic>n</italic>
=6) and <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
(<italic>n</italic>
=6) thymic tumours. Mean±s.d. are indicated. (<bold>b</bold>
) A correlation curve between <italic>Zeb2</italic>
and <italic>Il7r</italic>
mRNA levels. Pearson Correlation coefficient (<italic>r</italic>
) was calculated. (<bold>c</bold>
) qRT–PCR for <italic>IL7R</italic>
and <italic>ZEB2</italic>
in a cohort of human paediatric T-ALL patients; immature/ETP-ALL (<italic>n</italic>
=9) and mature (<italic>n</italic>
=8). A correlation curve between <italic>ZEB2</italic>
and <italic>IL7R</italic>
mRNA is shown. Pearson Correlation coefficient (<italic>r</italic>
) was calculated. (<bold>d</bold>
) qRT–PCR for <italic>ZEB2</italic>
and <italic>IL7R</italic>
after knockdown of <italic>ZEB2</italic>
using two independent siRNAs in the immature human T-ALL cell line LOUCY. Results are presented as averages±s.d. of three electroporations/siRNA. Student’s <italic>t</italic>
-test was used for statistical analysis. (<bold>e</bold>
) Genomic alignment with multiple species showing that a highly conserved region in the <italic>Il7r</italic>
promoter is located 2.5–3.0 kbp upstream of the transcription initiation start site (red arrow). Localization of the amplicon used for ChIP is depicted. Figure was made using UCSC genome bioinformatics software (<ext-link ext-link-type="uri" xlink:href="http://genome.ucsc.edu/">http://genome.ucsc.edu/</ext-link>
). ChIP was performed using a specific anti-ZEB2 monoclonal antibody in a <italic>Zeb2</italic>
-overexpressing T-ALL cell line. PCR amplification was analysed via agarose gel electrophoresis. Each lane is an independent immunoprecipitation. (<bold>f</bold>
) Western blot analysis for total STAT5 and P-STAT5 levels in control <italic>P53/R26</italic>
<sup><italic>+/+</italic>
</sup>
and <italic>Zeb2</italic>
-overexpressing <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/+</italic>
</sup>
and <italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
T-ALL cell lines with and without recombinant murine IL-7 administration. (<bold>g</bold>
) Western blot analysis for total STAT5 and P-STAT5 levels in control and <italic>Zeb2</italic>
-overexpressing mouse thymic tumours. (<bold>h</bold>
) The pro-survival effects of IL-7 administration on cell survival of control and <italic>Zeb2</italic>
-overexpressing mouse T-ALL cell lines cultured under stressed conditions. Every line represents the average of two-cell lines/genotype. Student’s <italic>t</italic>
-test was used for statistical analysis. Knockdown experiments in <bold>d</bold>
were repeated three times using triplicate biological samples. Western blots (<bold>f</bold>
,<bold>g</bold>
) were performed twice and representative blots and graphs are shown. Images have been cropped for presentation. Full size images are presented in <xref ref-type="supplementary-material" rid="S1">Supplementary Fig. 12</xref>
. Survival experiments (<bold>h</bold>
) were performed twice. *<italic>P</italic>
<0.05, **<italic>P</italic>
<0.01, ***<italic>P</italic>
<0.001 (vs control).</p>
</caption>
<graphic xlink:href="ncomms6794-f5"></graphic>
</fig>
<fig id="f6"><label>Figure 6</label>
<caption><title>ZEB2 overexpression promotes T-ALL cell survival and can be prevented by blocking IL7R or JAK1/2 inhibition <italic>in vitro</italic>
and <italic>in vivo</italic>
.</title>
<p>(<bold>a</bold>
) The IL-7-dependent pro-survival effect of <italic>Zeb2</italic>
-overexpressing cell lines can be prevented by co-administration of an IL7R-blocking antibody (A7R34), but not by the isotype control IgG. No effects are seen on the survival of the control cell lines. Student’s <italic>t</italic>
-test was used for statistical analysis. (<bold>b</bold>
) The IL-7-dependent pro-survival effect of <italic>Zeb2</italic>
-overexpressing cell lines can be prevented by co-administration of 1 μg per ml Ruxolitinib phosphate (RUX), a JAK1/2 inhibitor. No effects are seen on the survival of the control cell lines. Student’s <italic>t</italic>
-test was used for statistical analysis. (<bold>c</bold>
) RUX effects were accompanied by the loss of the increased levels of phosphorylated P-STAT5 as well as phosphorylated AKT and GSK3β as determined by western blot analysis. Indicated quantifications represent the relative increase of signal compared with the signal observed without IL-7 and RUX administration. Student’s <italic>t</italic>
-test was used for statistical analysis. (<bold>d</bold>
) <italic>In vivo</italic>
administration of the IL7R-blocking A7R34 antibody extended the lifespan of NOD/SCID mice transplanted with 2 × 10<sup>6</sup>
<italic>P53/R26-Zeb2</italic>
<sup><italic>tg/tg</italic>
</sup>
cells. The experiments depicted in <bold>a</bold>
–<bold>c</bold>
were performed twice and representative graphs of western blots are shown. Images have been cropped for presentation. Full size images are presented in <xref ref-type="supplementary-material" rid="S1">Supplementary Fig. 12</xref>
. The experiment in <bold>d</bold>
was performed once, using four mice per group. *<italic>P</italic>
<0.05, **<italic>P</italic>
<0.01 (vs control).</p>
</caption>
<graphic xlink:href="ncomms6794-f6"></graphic>
</fig>
</floats-group>
</pmc>
<affiliations><list><country><li>Allemagne</li>
<li>Australie</li>
<li>Belgique</li>
<li>France</li>
<li>Italie</li>
<li>Pays-Bas</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="Belgique"><noRegion><name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name>
</noRegion>
<name sortKey="Bartunkova, Sonia" sort="Bartunkova, Sonia" uniqKey="Bartunkova S" first="Sonia" last="Bartunkova">Sonia Bartunkova</name>
<name sortKey="Berx, Geert" sort="Berx, Geert" uniqKey="Berx G" first="Geert" last="Berx">Geert Berx</name>
<name sortKey="Berx, Geert" sort="Berx, Geert" uniqKey="Berx G" first="Geert" last="Berx">Geert Berx</name>
<name sortKey="Bogaert, Pieter" sort="Bogaert, Pieter" uniqKey="Bogaert P" first="Pieter" last="Bogaert">Pieter Bogaert</name>
<name sortKey="De Medts, Jelle" sort="De Medts, Jelle" uniqKey="De Medts J" first="Jelle" last="De Medts">Jelle De Medts</name>
<name sortKey="Deswarte, Kim" sort="Deswarte, Kim" uniqKey="Deswarte K" first="Kim" last="Deswarte">Kim Deswarte</name>
<name sortKey="Durinck, Kaat" sort="Durinck, Kaat" uniqKey="Durinck K" first="Kaat" last="Durinck">Kaat Durinck</name>
<name sortKey="Farla, Natalie" sort="Farla, Natalie" uniqKey="Farla N" first="Natalie" last="Farla">Natalie Farla</name>
<name sortKey="Farla, Natalie" sort="Farla, Natalie" uniqKey="Farla N" first="Natalie" last="Farla">Natalie Farla</name>
<name sortKey="Farla, Natalie" sort="Farla, Natalie" uniqKey="Farla N" first="Natalie" last="Farla">Natalie Farla</name>
<name sortKey="Ghahremani, Morvarid Farhang" sort="Ghahremani, Morvarid Farhang" uniqKey="Ghahremani M" first="Morvarid Farhang" last="Ghahremani">Morvarid Farhang Ghahremani</name>
<name sortKey="Ghahremani, Morvarid Farhang" sort="Ghahremani, Morvarid Farhang" uniqKey="Ghahremani M" first="Morvarid Farhang" last="Ghahremani">Morvarid Farhang Ghahremani</name>
<name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name>
<name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name>
<name sortKey="Haenebalcke, Lieven" sort="Haenebalcke, Lieven" uniqKey="Haenebalcke L" first="Lieven" last="Haenebalcke">Lieven Haenebalcke</name>
<name sortKey="Haenebalcke, Lieven" sort="Haenebalcke, Lieven" uniqKey="Haenebalcke L" first="Lieven" last="Haenebalcke">Lieven Haenebalcke</name>
<name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J." last="Haigh">Jody J. Haigh</name>
<name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J." last="Haigh">Jody J. Haigh</name>
<name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name>
<name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name>
<name sortKey="Huylebroeck, Danny" sort="Huylebroeck, Danny" uniqKey="Huylebroeck D" first="Danny" last="Huylebroeck">Danny Huylebroeck</name>
<name sortKey="Matthijssens, Filip" sort="Matthijssens, Filip" uniqKey="Matthijssens F" first="Filip" last="Matthijssens">Filip Matthijssens</name>
<name sortKey="Peirs, Sofie" sort="Peirs, Sofie" uniqKey="Peirs S" first="Sofie" last="Peirs">Sofie Peirs</name>
<name sortKey="Pieters, Tim" sort="Pieters, Tim" uniqKey="Pieters T" first="Tim" last="Pieters">Tim Pieters</name>
<name sortKey="Pieters, Tim" sort="Pieters, Tim" uniqKey="Pieters T" first="Tim" last="Pieters">Tim Pieters</name>
<name sortKey="Pieters, Tim" sort="Pieters, Tim" uniqKey="Pieters T" first="Tim" last="Pieters">Tim Pieters</name>
<name sortKey="Pieters, Tim" sort="Pieters, Tim" uniqKey="Pieters T" first="Tim" last="Pieters">Tim Pieters</name>
<name sortKey="Radaelli, Enrico" sort="Radaelli, Enrico" uniqKey="Radaelli E" first="Enrico" last="Radaelli">Enrico Radaelli</name>
<name sortKey="Rondou, Pieter" sort="Rondou, Pieter" uniqKey="Rondou P" first="Pieter" last="Rondou">Pieter Rondou</name>
<name sortKey="Slowicka, Karolina" sort="Slowicka, Karolina" uniqKey="Slowicka K" first="Karolina" last="Slowicka">Karolina Slowicka</name>
<name sortKey="Slowicka, Karolina" sort="Slowicka, Karolina" uniqKey="Slowicka K" first="Karolina" last="Slowicka">Karolina Slowicka</name>
<name sortKey="Taghon, Tom" sort="Taghon, Tom" uniqKey="Taghon T" first="Tom" last="Taghon">Tom Taghon</name>
<name sortKey="Van Der Meulen, Joni" sort="Van Der Meulen, Joni" uniqKey="Van Der Meulen J" first="Joni" last="Van Der Meulen">Joni Van Der Meulen</name>
<name sortKey="Van Roy, Nadine" sort="Van Roy, Nadine" uniqKey="Van Roy N" first="Nadine" last="Van Roy">Nadine Van Roy</name>
<name sortKey="Van Vlierberghe, Pieter" sort="Van Vlierberghe, Pieter" uniqKey="Van Vlierberghe P" first="Pieter" last="Van Vlierberghe">Pieter Van Vlierberghe</name>
</country>
<country name="Australie"><noRegion><name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name>
</noRegion>
<name sortKey="Alserihi, Raed" sort="Alserihi, Raed" uniqKey="Alserihi R" first="Raed" last="Alserihi">Raed Alserihi</name>
<name sortKey="Bracken, Lauryn S" sort="Bracken, Lauryn S" uniqKey="Bracken L" first="Lauryn S." last="Bracken">Lauryn S. Bracken</name>
<name sortKey="Carmichael, Catherine" sort="Carmichael, Catherine" uniqKey="Carmichael C" first="Catherine" last="Carmichael">Catherine Carmichael</name>
<name sortKey="Costa, Magdaline" sort="Costa, Magdaline" uniqKey="Costa M" first="Magdaline" last="Costa">Magdaline Costa</name>
<name sortKey="Curtis, David J" sort="Curtis, David J" uniqKey="Curtis D" first="David J." last="Curtis">David J. Curtis</name>
<name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J." last="Haigh">Jody J. Haigh</name>
<name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name>
<name sortKey="Lock, Richard B" sort="Lock, Richard B" uniqKey="Lock R" first="Richard B." last="Lock">Richard B. Lock</name>
<name sortKey="Mccormack, Matthew P" sort="Mccormack, Matthew P" uniqKey="Mccormack M" first="Matthew P." last="Mccormack">Matthew P. Mccormack</name>
<name sortKey="Rickard, Adam" sort="Rickard, Adam" uniqKey="Rickard A" first="Adam" last="Rickard">Adam Rickard</name>
<name sortKey="Suryani, Santi" sort="Suryani, Santi" uniqKey="Suryani S" first="Santi" last="Suryani">Santi Suryani</name>
<name sortKey="Tremblay, Cedric S" sort="Tremblay, Cedric S" uniqKey="Tremblay C" first="Cedric S." last="Tremblay">Cedric S. Tremblay</name>
</country>
<country name="Italie"><noRegion><name sortKey="Radaelli, Enrico" sort="Radaelli, Enrico" uniqKey="Radaelli E" first="Enrico" last="Radaelli">Enrico Radaelli</name>
</noRegion>
</country>
<country name="France"><noRegion><name sortKey="Blanchet, Odile" sort="Blanchet, Odile" uniqKey="Blanchet O" first="Odile" last="Blanchet">Odile Blanchet</name>
</noRegion>
<name sortKey="Blanchet, Odile" sort="Blanchet, Odile" uniqKey="Blanchet O" first="Odile" last="Blanchet">Odile Blanchet</name>
<name sortKey="Clappier, Emmanuelle" sort="Clappier, Emmanuelle" uniqKey="Clappier E" first="Emmanuelle" last="Clappier">Emmanuelle Clappier</name>
<name sortKey="Clappier, Emmanuelle" sort="Clappier, Emmanuelle" uniqKey="Clappier E" first="Emmanuelle" last="Clappier">Emmanuelle Clappier</name>
<name sortKey="Soulier, Jean" sort="Soulier, Jean" uniqKey="Soulier J" first="Jean" last="Soulier">Jean Soulier</name>
<name sortKey="Soulier, Jean" sort="Soulier, Jean" uniqKey="Soulier J" first="Jean" last="Soulier">Jean Soulier</name>
<name sortKey="Speleman, Frank" sort="Speleman, Frank" uniqKey="Speleman F" first="Frank" last="Speleman">Frank Speleman</name>
</country>
<country name="Royaume-Uni"><noRegion><name sortKey="Schwab, Claire" sort="Schwab, Claire" uniqKey="Schwab C" first="Claire" last="Schwab">Claire Schwab</name>
</noRegion>
<name sortKey="Harrison, Christine" sort="Harrison, Christine" uniqKey="Harrison C" first="Christine" last="Harrison">Christine Harrison</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Best, J Adam" sort="Best, J Adam" uniqKey="Best J" first="J. Adam" last="Best">J. Adam Best</name>
</noRegion>
<name sortKey="Goldrath, Ananda W" sort="Goldrath, Ananda W" uniqKey="Goldrath A" first="Ananda W." last="Goldrath">Ananda W. Goldrath</name>
</country>
<country name="Pays-Bas"><noRegion><name sortKey="Cante Barrett, Kirsten" sort="Cante Barrett, Kirsten" uniqKey="Cante Barrett K" first="Kirsten" last="Canté-Barrett">Kirsten Canté-Barrett</name>
</noRegion>
<name sortKey="Huylebroeck, Danny" sort="Huylebroeck, Danny" uniqKey="Huylebroeck D" first="Danny" last="Huylebroeck">Danny Huylebroeck</name>
<name sortKey="Meijerink, Jules P P" sort="Meijerink, Jules P P" uniqKey="Meijerink J" first="Jules P. P." last="Meijerink">Jules P. P. Meijerink</name>
</country>
<country name="Allemagne"><noRegion><name sortKey="Janzen, Viktor" sort="Janzen, Viktor" uniqKey="Janzen V" first="Viktor" last="Janzen">Viktor Janzen</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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