Gene expression profiling of P53/R26 +/+ (n=2) versus P53/R26-Zeb2tg/tg (n=3) thymic tumors. Mus musculus

Early T-cell precursor leukemia (ETP-ALL) is a high-risk subtype of human leukemia that is poorly understood at the molecular level. Here, we report translocations targeting the zinc finger E-box binding transcription factor ZEB2 as a new and recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression perturbs normal T-cell differentiation and initiates T-cell leukemia. Moreover, Zeb2 driven mouse leukemia exhibit some features of the human immature/ETPALL gene expression signature, as well as an enhanced leukemia-initiation potential and activated JAK/STAT signaling through transcriptional activation of IL7R. This study reveals ZEB2 as a novel 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. Overall design: Conditional Zeb2 knockin mouse model was developed and crossed into p53 null background. Murine T-cell leukemia/lymphoma tumors developed both in the p53 null control and the p53 null Zeb2 transgenic group. In this experiment, gene expression profiling was performed on these murine leukemias to determine the transcriptional program associated with sustained Zeb2 expression in the context of P53 null driven murine T cell leukemogenesis.

早期T细胞前体白血病（Early T-cell precursor leukemia, ETP-ALL）是一类高危型人类白血病，其分子层面的致病机制尚未得到充分解析。本研究首次报道，靶向锌指E盒结合转录因子ZEB2（zinc finger E-box binding transcription factor ZEB2）的染色体易位，是未成熟型/早期T细胞前体白血病中一种新的复发性遗传病变。借助条件性功能获得性小鼠模型（conditional gain-of-function mouse model），本研究证实持续表达Zeb2会扰乱正常T细胞分化进程，并诱发T细胞白血病。此外，由Zeb2驱动的小鼠白血病模型不仅展现出人类未成熟型/早期T细胞前体白血病的部分基因表达特征，还可通过转录激活白细胞介素7受体（IL7R）增强白血病起始潜能，并激活JAK/STAT信号通路（JAK/STAT signaling）。本研究揭示ZEB2是未成熟型/早期T细胞前体白血病发病机制中的新型致癌基因，并依托本研究构建的Zeb2驱动小鼠模型，为针对这类侵袭性人类T细胞急性淋巴细胞白血病的新型化合物临床前研究铺平了道路。实验整体设计：本研究构建了条件性Zeb2敲入小鼠模型（conditional Zeb2 knockin mouse model），并将其回交至p53基因敲除背景（p53 null background）中。p53敲除对照组与p53敲除且Zeb2转基因组均形成了小鼠T细胞白血病/淋巴瘤肿瘤。本实验通过对上述小鼠白血病样本开展基因表达谱分析（gene expression profiling），旨在明确在p53敲除驱动的小鼠T细胞白血病发生过程中，与持续Zeb2表达相关的转录调控程序。