Kogoshi Hanae, Sato Taku, Koyama Takatoshi, Nara Nobuo, Tohda Shuji
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Oncol Rep. 2007 Jul;18(1):77-80.
gamma-Secretase inhibitors (GSI) suppress the growth of acute T-lymphoblastic leukemia (T-ALL) cells with NOTCH1 mutations. Recently, clinical trials of GSI for refractory T-ALL have commenced. In the present study, we examined the effects of three types of GSI; GSI-I, GSI-IX, and GSI-XII on the growth of four B-cell malignant lymphoma (B-ML) and four acute myeloid leukemia (AML) cell lines as well as four T-ALL cell lines. We found that GSI also suppressed the in vitro growth of some B-ML and AML cell lines in a dose-dependent manner. Growth suppression occurred through induction of apoptosis. Expression of the HES1 gene, one of the targets of Notch signaling, was high in T-ALL cells with NOTCH1 mutations, but was low in GSI-sensitive B-ML and AML cells. GSI treatment decreased HES1 mRNA expression in T-ALL cells, while GSI increased HES1 mRNA in two GSI-sensitive B-ML and AML cell lines. In immunoblot analysis, the band for the intracellular fragment of Notch1, an active form of Notch1, was dense in T-ALL cells but was faint in GSI-sensitive B-ML and AML cells; attenuation of the band by GSI was not evident. These findings suggest that GSI may act on Notch 2, 3 or 4 protein, or some pathways other than Notch signaling in GSI-sensitive B-ML and AML cells. Namely, growth suppression by GSI may involve cell growth-related proteins, which are gamma-secretase substrates. Taken together, we have shown that GSI may be useful for the treatment of hematological malignancies other than T-ALL. The mechanism behind the effects remains to be clarified. Our investigations lead to a novel molecular target therapy for chemotherapy-resistant leukemia and lymphomas.
γ-分泌酶抑制剂（GSI）可抑制具有NOTCH1突变的急性T淋巴细胞白血病（T-ALL）细胞的生长。最近，GSI用于难治性T-ALL的临床试验已经开始。在本研究中，我们检测了三种类型的GSI（GSI-I、GSI-IX和GSI-XII）对四种B细胞恶性淋巴瘤（B-ML）、四种急性髓系白血病（AML）细胞系以及四种T-ALL细胞系生长的影响。我们发现GSI也以剂量依赖性方式抑制了一些B-ML和AML细胞系的体外生长。生长抑制是通过诱导细胞凋亡发生的。Notch信号通路的靶点之一HES1基因在具有NOTCH1突变的T-ALL细胞中表达较高，但在对GSI敏感的B-ML和AML细胞中表达较低。GSI处理可降低T-ALL细胞中HES1 mRNA的表达，而GSI可增加两种对GSI敏感的B-ML和AML细胞系中HES1 mRNA的表达。在免疫印迹分析中，Notch1的活性形式Notch1细胞内片段的条带在T-ALL细胞中较浓，但在对GSI敏感的B-ML和AML细胞中较淡；GSI对该条带的减弱作用不明显。这些发现表明，GSI可能作用于GSI敏感的B-ML和AML细胞中的Notch 2、3或4蛋白，或Notch信号通路以外的某些途径。也就是说，GSI的生长抑制作用可能涉及γ-分泌酶底物等细胞生长相关蛋白。综上所述，我们表明GSI可能对治疗除T-ALL以外的血液系统恶性肿瘤有用。其作用背后的机制仍有待阐明。我们的研究为化疗耐药的白血病和淋巴瘤带来了一种新的分子靶向治疗方法。
