Characterization of Two Distinct Lymphoproliferative Diseases Caused by Ectopic Expression of the Notch Ligand DLL4 on T Cells

Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass β-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity.Notch信号通路（Notch signaling）通过细胞表面的NOTCH1受体（NOTCH1 receptor）与胸腺上皮细胞（thymic epithelial cells）表达的配体Delta样蛋白4（Delta-like 4, DLL4）相互作用，对T细胞祖细胞的发育至关重要。当细胞完成β选择（β-selection）后，Notch信号通路会迅速关闭，且CD4/CD8双阳性（CD4/CD8 double positive, DP）细胞对Notch信号无响应。过去二十年间，多项研究报道Notch信号通路过度激活可引发T细胞急性淋巴细胞白血病（T cell acute lymphoblastic leukemia, T-ALL）——这是一类在多种小鼠模型中以循环单克隆CD4/CD8双阳性T细胞为核心特征的恶性肿瘤。然而，目前尚不清楚T细胞发育不同阶段的Notch过度激活会产生何种结局，且引发T-ALL的Notch信号精准调控时机也尚未明确。本研究通过构建在发育中的T细胞内异位表达DLL4的小鼠模型，证实T-ALL的发生高度依赖于DP阶段持续的Notch活性，该活性可诱导额外突变以进一步增强信号通路。与之形成对比的是，在DP阶段终止的短时长Notch激活会引发一种多克隆、不可传播的淋巴增殖性疾病，且该疾病同样具有致死性。上述发现解决了此前关于小鼠体内DLL4驱动的血液系统疾病相关研究的分歧，并凸显了Notch活性的时机与持续时间的关键重要性。