Nature Communications 2015-01-01

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

Index: Nat. Commun. 6 , 5794, (2015)

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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.