Mechanisms of T-cell leukemogenesis induced by NOTCH1

性状（由申请人提供）：γ-分泌酶抑制剂（GSI），阻断早老素-γ分泌酶复合物，抑制参与阿尔茨海默病发病机制的淀粉样蛋白A肽的产生和NOTCH受体的激活。最近在超过50%的T细胞淋巴细胞白血病（T-ALL）病例中发现了NOTCH 1受体基因的激活突变，这促使启动了一项临床试验，以测试在这种疾病中用小分子GSI阻断NOTCH 1信号传导的有效性。然而，基于GSI的疗法的临床开发受到这些药物在人T-ALL中诱导细胞凋亡的有限能力以及由于抑制肠道中的NOTCH信号传导而产生的严重胃肠道毒性的阻碍。在过去的两年中，我们的小组已经使用了ChIP芯片分析和微阵列基因表达谱的组合来阐明T-ALL中由致癌NOTCH 1信号控制的转录调控网络的结构。这项研究揭示了由NOTCH 1激活的致癌程序的基本方面。在这个竞争性修订申请中，我们将扩大我们的项目范围，阐明肠道上皮细胞中由NOTCH信号控制的基因和途径。这些研究将提供有关GSI全身抑制NOTCH信号传导后介导胃肠道毒性发展的机制的有价值的信息。 公共卫生相关性：γ-分泌酶抑制剂（GSIs）阻断早老素-γ-分泌酶复合物，是治疗人类癌症的有希望的药物。然而，基于GSI的疗法的临床开发由于抑制肠道中的NOTCH信号传导而阻碍了严重胃肠道毒性的发展。本竞争性修订申请阐述了GSI全身抑制NOTCH信号传导后介导胃肠道毒性发展的机制。

DESCRIPTION (provided by applicant): Gamma-secretase inhibitors (GSIs), which block the presenilin-gamma secretase complex, inhibit the production of amyloidogenic A peptides involved in the pathogenesis of Alzheimer's disease and the activation of NOTCH receptors. Recent identification of activating mutations in the NOTCH1 receptor gene in over 50% of cases of T-cell lymphoblastic leukemia (T-ALL) prompted the initiation of a clinical trial to test the effectiveness of blocking NOTCH1 signaling with a small molecule GSI in this disease. However, the clinical development of GSI-based therapies has been hampered by the limited ability of these drugs to induce apoptosis in human T-ALL and by the development of severe gastrointestinal toxicity due to inhibition of NOTCH signaling in the gut. Over the last two years our group has used a combination of ChIP-on-chip analysis and microarray gene expression profiling to elucidate the structure of the transcriptional regulatory network controlled by oncogenic NOTCH1 signaling in T-ALL. This research has revealed fundamental aspects of the oncogenic program activated by NOTCH1. In this Competitive Revision Application we will expand the scope of our project to the elucidation of genes and pathways controlled by NOTCH signaling in intestinal epithelial cells. These studies will provide valuable information regarding the mechanisms mediating the development of gastrointestinal toxicity upon systemic inhibition of NOTCH signaling with GSIs. PUBLIC HEALTH RELEVANCE: Gamma-secretase inhibitors (GSIs), which block the presenilin-gamma secretase complex, are promising drugs for the treatment of human cancer. However, the clinical development of GSI-based therapies has been hampered the development of severe gastrointestinal toxicity due to inhibition of NOTCH signaling in the gut. This Competitive Revision Application address the mechanisms mediating the development of gastrointestinal toxicity upon systemic inhibition of NOTCH signaling with GSIs.