Goossens Steven, Radaelli Enrico, Blanchet Odile, Durinck Kaat, Van der Meulen Joni, Peirs Sofie, Taghon Tom, Tremblay Cedric S, Costa Magdaline, Farhang Ghahremani Morvarid, De Medts Jelle, Bartunkova Sonia, Haigh Katharina, Schwab Claire, Farla Natalie, Pieters Tim, Matthijssens Filip, Van Roy Nadine, Best J Adam, Deswarte Kim, Bogaert Pieter, Carmichael Catherine, Rickard Adam, Suryani Santi, Bracken Lauryn S, Alserihi Raed, Canté-Barrett Kirsten, Haenebalcke Lieven, Clappier Emmanuelle, Rondou Pieter, Slowicka Karolina, Huylebroeck Danny, Goldrath Ananda W, Janzen Viktor, McCormack Matthew P, Lock Richard B, Curtis David J, Harrison Christine, Berx Geert, Speleman Frank, Meijerink Jules P P, Soulier Jean, Van Vlierberghe Pieter, Haigh Jody J
1] Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [2] Department for Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium [3] Unit for Molecular and Cellular Oncology, VIB Inflammation Research Center, Ghent University, Ghent B-9052, Belgium [4] Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, 99 Commercial Road, Melbourne, Victoria 3004, Australia.
1] Mouse and Animal Pathology Laboratory, Department of Veterinary Medicine, Università degli Studi di Milano, Milan 20122, Italy [2] VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, KU Leuven, Leuven B-3000, Belgium.
Nat Commun. 2015 Jan 7;6:5794. doi: 10.1038/ncomms6794.
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.
早期T细胞前体白血病（ETP-ALL）是一种人类白血病的高危亚型，在分子水平上人们对其了解甚少。在此，我们报告锌指E盒结合转录因子ZEB2的易位是未成熟/ETP-ALL中反复出现的遗传病变。使用条件性功能获得小鼠模型，我们证明持续的Zeb2表达会引发T细胞白血病。此外，Zeb2驱动的小鼠白血病表现出人类未成熟/ETP-ALL基因表达特征的一些特点，以及增强的白血病起始潜能，并通过IL7R的转录激活激活了Janus激酶（JAK）/信号转导子和转录激活子（STAT）信号通路。本研究揭示ZEB2是未成熟/ETP-ALL生物学中的一种癌基因，并为使用我们的Zeb2驱动小鼠模型对治疗这种侵袭性人类T-ALL亚型的新型化合物进行临床前研究铺平了道路。
