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

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

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  • Journal Nature communications

  • Published 07 Jan 2015

  • Volume 6

  • Pagination 5794

  • DOI 10.1038/ncomms6794

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.