β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation
β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation
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DOI：
10.1182/blood-2006-11-059071
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发表时间：
2007-06-15
期刊：
影响因子：
20.3
通讯作者：
Gounari, Fotini
中科院分区：
文献类型：
--
作者：
Guo, Zhuyan;Dose, Marei;Gounari, Fotini
-连环蛋白的激活与结肠癌的病因学有因果关系。这个分子在前t细胞中的条件稳定促进胸腺细胞的发育，而不需要前tcr信号传导。我们在这里表明，激活的β -连环蛋白延缓了从双阳性（DP）到单阳性（SP）胸腺细胞阶段的发育转变，并使DP胸腺细胞更易转化。-连环蛋白诱导的胸腺淋巴瘤在早期DP阶段有白血病停搏。淋巴瘤的发生需要Rag活性，它在这个发育阶段达到顶峰，还需要其他的继发性遗传事件。一致的次要事件是c-Myc的转录上调，其活性是转化所必需的，因为它的条件消融消除了淋巴瘤发生。相反，Notch受体和靶点的表达在β -连环蛋白稳定的DIP胸腺细胞中降低，在淋巴瘤中保持低水平，表明Notch激活在β -连环蛋白诱导的淋巴瘤中不是必需的或选择的。因此，β -连环蛋白激活可能为t细胞急性淋巴细胞白血病（T-ALL）的诱导提供了一种不依赖于Notch激活的机制。
Activation of beta-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated beta-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. beta-Catenin-induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DIP thymocytes with stabilized beta-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in beta-catenininduced lymphomas. Thus, beta-catenin activation may provide a mechanism forthe induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.