Goossens Steven, Peirs Sofie, Van Loocke Wouter, Wang Jueqiong, Takawy Mina, Matthijssens Filip, Sonderegger Stefan E, Haigh Katharina, Nguyen Thao, Vandamme Niels, Costa Magdaline, Carmichael Catherine, Van Nieuwerburgh Filip, Deforce Dieter, Kleifeld Oded, Curtis David J, Berx Geert, Van Vlierberghe Pieter, Haigh Jody J
Mammalian Functional Genetics Group, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
Molecular and Cellular Oncology Laboratory, VIB Inflammation Research Center, Ghent, Belgium.
Blood. 2017 Feb 23;129(8):981-990. doi: 10.1182/blood-2016-06-721191. Epub 2017 Jan 9.
Elevated expression of the Zinc finger E-box binding homeobox transcription factor-2 (ZEB2) is correlated with poor prognosis and patient outcome in a variety of human cancer subtypes. Using a conditional gain-of-function mouse model, we recently demonstrated that ZEB2 is an oncogenic driver of immature T-cell acute lymphoblastic leukemia (T-ALL), a heterogenic subgroup of human leukemia characterized by a high incidence of remission failure or hematological relapse after conventional chemotherapy. Here, we identified the lysine-specific demethylase KDM1A as a novel interaction partner of ZEB2 and demonstrated that mouse and human T-ALLs with increased ZEB2 levels critically depend on KDM1A activity for survival. Therefore, targeting the ZEB2 protein complex through direct disruption of the ZEB2-KDM1A interaction or pharmacological inhibition of the KDM1A demethylase activity itself could serve as a novel therapeutic strategy for this aggressive subtype of human leukemia and possibly other ZEB2-driven malignancies.
锌指E盒结合同源框转录因子2（ZEB2）的高表达与多种人类癌症亚型的不良预后和患者结局相关。利用条件性功能获得小鼠模型，我们最近证明ZEB2是未成熟T细胞急性淋巴细胞白血病（T-ALL）的致癌驱动因子，T-ALL是人类白血病的一个异质性亚组，其特征是传统化疗后缓解失败或血液学复发的发生率很高。在此，我们确定赖氨酸特异性去甲基化酶KDM1A是ZEB2的一种新型相互作用伙伴，并证明ZEB2水平升高的小鼠和人类T-ALL严重依赖KDM1A活性来维持生存。因此，通过直接破坏ZEB2-KDM1A相互作用或对KDM1A去甲基化酶活性本身进行药理抑制来靶向ZEB2蛋白复合物，可能成为这种侵袭性人类白血病亚型以及其他可能由ZEB2驱动的恶性肿瘤的一种新型治疗策略。
