Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Blood. 2010 Dec 16;116(25):5443-54. doi: 10.1182/blood-2010-05-286658. Epub 2010 Sep 9.
The Notch pathway is frequently activated in T-cell acute lymphoblastic leukemias (T-ALLs). Of the Notch receptors, Notch1 is a recurrent target of gain-of-function mutations and Notch3 is expressed in all T-ALLs, but it is currently unclear how these receptors contribute to T-cell transformation in vivo. We investigated the role of Notch1 and Notch3 in T-ALL progression by a genetic approach, in mice bearing a knockdown mutation in the Ikaros gene that spontaneously develop Notch-dependent T-ALL. While deletion of Notch3 has little effect, T cell-specific deletion of floxed Notch1 promoter/exon 1 sequences significantly accelerates leukemogenesis. Notch1-deleted tumors lack surface Notch1 but express γ-secretase-cleaved intracellular Notch1 proteins. In addition, these tumors accumulate high levels of truncated Notch1 transcripts that are caused by aberrant transcription from cryptic initiation sites in the 3' part of the gene. Deletion of the floxed sequences directly reprograms the Notch1 locus to begin transcription from these 3' promoters and is accompanied by an epigenetic reorganization of the Notch1 locus that is consistent with transcriptional activation. Further, spontaneous deletion of 5' Notch1 sequences occurs in approximately 75% of Ikaros-deficient T-ALLs. These results reveal a novel mechanism for the oncogenic activation of the Notch1 gene after deletion of its main promoter.
Notch 通路在 T 细胞急性淋巴细胞白血病（T-ALL）中经常被激活。在 Notch 受体中，Notch1 是功能获得性突变的反复靶标，Notch3 在所有 T-ALL 中表达，但目前尚不清楚这些受体如何在体内促进 T 细胞转化。我们通过遗传方法研究了 Notch1 和 Notch3 在 T-ALL 进展中的作用，该方法在携带 Ikaros 基因敲低突变的小鼠中进行，这些小鼠会自发发生依赖 Notch 的 T-ALL。虽然 Notch3 的缺失几乎没有影响，但 floxed Notch1 启动子/外显子 1 序列的 T 细胞特异性缺失显着加速了白血病的发生。 Notch1 缺失的肿瘤缺乏表面 Notch1，但表达 γ-分泌酶切割的细胞内 Notch1 蛋白。此外，这些肿瘤积累了高水平的截断 Notch1 转录本，这些转录本是由基因 3' 部分的隐匿起始位点异常转录引起的。 floxed 序列的缺失直接将 Notch1 基因座重新编程为从这些 3' 启动子开始转录，并伴随着与转录激活一致的 Notch1 基因座的表观遗传重排。此外，在大约 75%的 Ikaros 缺陷型 T-ALL 中会自发缺失 5' Notch1 序列。这些结果揭示了 Notch1 基因在其主要启动子缺失后致癌激活的新机制。
