NOTCH1 信号通路在 T 细胞急性淋巴细胞白血病中的作用。
The role of NOTCH1 signaling in T-ALL.
机构信息
Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
出版信息
Hematology Am Soc Hematol Educ Program. 2009:353-61. doi: 10.1182/asheducation-2009.1.353.
The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule gamma-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.
NOTCH1 激活突变在超过 50%的 T 细胞急性淋巴细胞白血病（T-ALL）中被发现，这激发了人们对阐明致癌 NOTCH 下游转化机制以及针对该疾病 NOTCH 信号通路的靶向治疗的极大兴趣。小分子 γ-分泌酶抑制剂（GSIs）可阻断 T-ALL 淋巴母细胞中的 NOTCH1 信号，但由于胃肠道毒性的发展和对人 T-ALL 的弱抗白血病作用，GSIs 的临床开发受到了阻碍。然而，新的治疗策略旨在优化针对 T-ALL 的抗 NOTCH1 治疗，包括与分子靶向药物和糖皮质激素的联合治疗，由于对介导 GSI 在白血病细胞和肠道上皮细胞中作用的分子机制的深入了解，这些策略已经开始出现。本文重点介绍了 NOTCH1 诱导转化的分子基础、致癌 NOTCH1 的作用机制以及 NOTCH1 突变在 T-ALL 中的临床意义。
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