DDX5 is a positive regulator of oncogenic NOTCH1 signaling in T cell acute lymphoblastic leukemia.
DDX5 is a positive regulator of oncogenic NOTCH1 signaling in T cell acute lymphoblastic leukemia.
复制标题
DDX5 是 T 细胞急性淋巴细胞白血病中致癌 NOTCH1 信号传导的正调节因子
作者：
Lin S;Tian L;Shen H;Gu Y;Li JL;Chen Z;Sun X;You MJ;Wu L
Notch信号转导是一种高度保守的细胞间通讯途径，调节正常发育和组织稳态。异常Notch信号传导代表了T细胞急性淋巴细胞白血病（T-ALL）的重要致癌机制，T-ALL是最常见的恶性儿童癌症ALL的侵袭性子集。因此，理解Notch信号传导的分子调控对于确定阻断异常Notch致癌活性的新方法至关重要。三个MAML转录共激活因子家族对于Notch信号传导激活至关重要。原型成员MAML 1是调节白血病细胞中Notch致癌活性的主要共激活剂。然而，MAML 1辅激活因子功能的分子基础，有助于Notch信号转导仍然不清楚。在这项研究中，我们进行了蛋白质组学研究，并确定DDX 5，ATP依赖的DEAD盒RNA解旋酶，作为MAML 1蛋白复合物的组成部分。DDX 5在体外和体内与MAML 1相互作用，并与人T-ALL白血病细胞中的内源性NOTCH 1转录激活复合物相关。慢病毒介导的DDX 5的shRNA敲低导致Notch靶基因的表达降低，细胞增殖减少，并在Notch信号传导的组成性激活的培养的人白血病细胞中增加凋亡。此外，DDX 5耗竭抑制裸鼠中人白血病异种移植物的生长。此外，基于Oncomine和GEO数据库和免疫组织化学染色的分析，DDX 5在原代人T-ALL白血病细胞中高度表达。我们的总体研究结果揭示了DDX 5在促进白血病细胞中Notch介导的有效转录中的关键作用，表明DDX 5可能对NOTCH 1介导的T-ALL发病机制至关重要，因此是调节白血病Notch信号传导的潜在新靶点。
Notch signaling is a highly conserved cell-cell communication pathway regulating normal development and tissue homeostasis. Aberrant Notch signaling represents an important oncogenic mechanism for T cell acute lymphoblastic leukemia (T-ALL), an aggressive subset of the most common malignant childhood cancer ALL. Therefore, understanding the molecular regulation of Notch signaling is critical to identifying new approaches to block aberrant Notch oncogenic activity. The family of three MAML transcriptional co-activators is crucial for Notch signaling activation. The prototypic member MAML1 is the major co-activator that regulates Notch oncogenic activities in leukemic cells. However, the molecular basis underlying MAML1 co-activator function that contributes to Notch signaling remains unclear. In this study, we performed proteomic studies and identified DDX5, an ATP-dependent DEAD-box RNA helicase, as a component of the MAML1 protein complex. DDX5 interacts with MAML1 in vitro and in vivo, and is associated with the endogenous NOTCH1 transcription activation complex in human T-ALL leukemic cells. Lentivirus-mediated shRNA knockdown of DDX5 resulted in decreased expression of Notch target genes, reduced cell proliferation, and increased apoptosis in cultured human leukemic cells with constitutive activation of Notch signaling. Also, DDX5 depletion inhibited the growth of human leukemia xenograft in nude mice. Moreover, DDX5 is highly expressed in primary human T-ALL leukemic cells based on the analyses of Oncomine and GEO databases and Immunohistochemical staining. Our overall findings revealed a critical role of DDX5 in promoting efficient Notch-mediated transcription in leukemic cells, suggesting that DDX5 might be critical for NOTCH1-mediated T-ALL pathogenesis and thus is a potential new target for modulating the Notch signaling in leukemia.