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

Lookup NU author(s): Claire Schwab, Professor Christine Harrison FRCPath FMedSci

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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.

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Author(s): Goossens S, Radaelli E, Blanchet O, Durinck K, Van der Meulen J, Peirs S, Taghon T, Tremblay CS, Costa M, Ghahremani MF, 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, Cante-Barret 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 JPP, Soulier J, Van Vlierberghe P, Haigh JJ

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2015

Volume: 6

Online publication date: 07/01/2015

Acceptance date: 07/11/2014

Date deposited: 09/06/2015

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ncomms6794

DOI: 10.1038/ncomms6794

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