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

S Goossens, E Radaelli, O Blanchet, K Durinck, J van der Meulen, S Peirs, T Taghon, CS Tremblay, M (Marco) Costa, MF Ghahremani, J De Medts, S Bartunkova, K Haigh, C Schwab, N Farla, T Pieters, F Matthijssens, N van Roy, JA Best, K DeswarteP Bogaert, C Carmichael, A Rickard, S Suryani, LS Bracken, R Alserihi, Kirsten Canté, L Haenebalcke, E Clappier, P Rondou, K Slowicka, Danny Huylebroeck, AW Goldrath, V Janzen, MP McCormack, RB Lock, DJ Curtis, C Harrison, G Berx, F Speleman, Jules Meijerink, J Soulier, P van Vlierberghe, JJ Haigh

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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.
Original languageUndefined/Unknown
Number of pages12
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

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