Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders.
Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders.
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DOI：
10.1097/moh.0000000000000254
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发表时间：
2016-07
影响因子：
3.2
通讯作者：
Maillard I
中科院分区：
文献类型：
--
作者：
Chiang MY;Radojcic V;Maillard I
重点介绍有关 Notch 激活及其在淋巴恶性肿瘤中的致癌功能的最新发现，并讨论 Notch 抑制的治疗潜力。 NOTCH 突变出现在多种淋巴恶性肿瘤中，并且越来越多地被视为假定的治疗靶点。在 T 细胞急性淋巴细胞白血病 (T-ALL) 中，NOTCH1 突变影响细胞外负调控区并导致 Notch 组成型激活，尽管突变受体仍然对 Notch 配体敏感。 T-ALL 中的其他 NOTCH1 突变和多种 B 细胞恶性肿瘤中的 NOTCH1/2 突变会截断 C 端 PEST 结构域，导致配体介导的激活后 Notch 降解减少。因此，靶向Notch配体-受体相互作用可以提供治疗益处。此外，我们还讨论了最近关于 Notch 抑制剂在 T-ALL 中的临床测试的报告，这些报告影响了当代对针对癌症的 Notch 靶向挑战的思考。我们回顾了实验室在药物靶点、Notch 驱动的代谢组以及作为致癌 Notch 功能基础的依赖于 Notch 的超级增强子中复杂的蛋白质-蛋白质相互作用方面的进展，以解决这些挑战。 Notch 信号传导是多种 T 和 B 细胞淋巴增殖性疾病中的复发性致癌途径。了解 Notch 激活的复杂性和后果对于确定针对 Notch 通路的最佳治疗策略至关重要。
Highlight recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discuss the therapeutic potential of Notch inhibition. NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B cell malignancies truncate the C-terminal PEST domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent super-enhancers that underlie oncogenic Notch functions. Notch signaling is a recurrent oncogenic pathway in multiple T and B cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.