Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
Immunity. 2010 Nov 24;33(5):685-98. doi: 10.1016/j.immuni.2010.11.008.
Loss of the transcription factor Ikaros is correlated with Notch receptor activation in T cell acute lymphoblastic leukemia (T-ALL). However, the mechanism remains unknown. We identified promoters in Notch1 that drove the expression of Notch1 proteins in the absence of a ligand. Ikaros bound to both canonical and alternative Notch1 promoters and its loss increased permissive chromatin, facilitating recruitment of transcription regulators. At early stages of leukemogenesis, increased basal expression from the canonical and 5'-alternative promoters initiated a feedback loop, augmenting Notch1 signaling. Ikaros also repressed intragenic promoters for ligand-independent Notch1 proteins that are cryptic in wild-type cells, poised in preleukemic cells, and active in leukemic cells. Only ligand-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed during T cell development and T-ALL progression. Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis.
转录因子 Ikaros 的缺失与 T 细胞急性淋巴细胞白血病（T-ALL）中的 Notch 受体激活相关。然而，其机制尚不清楚。我们鉴定了 Notch1 中的启动子，这些启动子在没有配体的情况下驱动 Notch1 蛋白的表达。Ikaros 结合到经典和替代的 Notch1 启动子上，其缺失增加了允许性染色质，促进了转录调节剂的募集。在白血病发生的早期，来自经典和 5'-替代启动子的基础表达增加启动了一个反馈回路，增强了 Notch1 信号。Ikaros 还抑制了内源性启动子，这些启动子对于野生型细胞中的配体非依赖性 Notch1 蛋白是隐匿的，在白血病前细胞中处于预备状态，在白血病细胞中是活跃的。只有配体非依赖性 Notch1 异构体是 Ikaros 介导的白血病发生所必需的。在 T 细胞发育和 T-ALL 进展过程中观察到 Notch1 替代启动子的使用。因此，一组表观遗传和转录调节因子在正常发育和白血病发生过程中控制着传统和非常规的 Notch 信号。
