Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia.
Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia.
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Notch信号通路因其高发生率的激活突变而被认为是T细胞急性淋巴细胞白血病（T-ALL）发病的关键因素。Notch抑制可作为T-ALL的新治疗策略;然而，迄今为止，干扰Notch信号通路的尝试尚未成功。在这项研究中，我们发现蛋白酶体抑制剂对Notch 1组成性激活的T-ALL细胞产生细胞毒性作用，其程度与骨髓瘤细胞相似。蛋白酶体抑制剂硼替佐米抑制Notch 1及其下游效应子Hes 1、GATA 3、RUNX 3和核因子-κB（NF-κB）（p65和p50）的转录，与主要的反式激活因子Sp1的下调及其与Notch 1启动子的解离一致。Notch 1胞内结构域（NICD）的过表达显著改善了硼替佐米诱导的对T-ALL细胞的细胞毒性。药物联合研究显示硼替佐米与治疗T-ALL的关键药物如地塞米松（DEX）、多柔比星和环磷酰胺显示出协同或累加效应，这些效应很容易被NICD过表达所消除。硼替佐米和DEX的协同作用使用鼠异种移植模型在体内证实。我们的研究结果为蛋白酶体抑制剂纳入T-ALL的治疗策略提供了分子基础和理论依据。
The Notch signaling pathway has been recognized as a key factor for the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), because of the high incidence of activating mutations of Notch1. Notch inhibition could serve as a new treatment strategy for T-ALL; however, the attempts to perturb Notch signaling pathways have been unsuccessful so far. In this study, we found that proteasome inhibitors exert cytotoxic effects on T-ALL cells with constitutive activation of Notch1 to a similar extent as myeloma cells. The proteasome inhibitor bortezomib repressed the transcription of Notch1 and downstream effectors including Hes1, GATA3, RUNX3 and nuclear factor-κB (NF-κB) (p65 and p50), coincided with downregulation of the major transactivator Sp1 and its dissociation from Notch1 promoter. Overexpression of the Notch1 intracellular domain (NICD) significantly ameliorated bortezomib-induced cytotoxicity against T-ALL cells. Drug combination studies revealed that bortezomib showed synergistic or additive effects with key drugs for the treatment of T-ALL such as dexamethasone (DEX), doxorubicin and cyclophosphamide, which were readily abolished by NICD overexpression. The synergy of bortezomib and DEX was confirmed in vivo using a murine xenograft model. Our findings provide a molecular basis and rationale for the inclusion of proteasome inhibitors in treatment strategies for T-ALL.
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