Mechanisms of T-cell leukemogenesis induced by NOTCH1

NOTCH1诱导T细胞白血病发生的机制

• 批准号: 7816499
• 负责人: Adolfo A. Ferrando
• 金额: $ 53.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7816499
• 关键词: Accounting; Acute Lymphocytic Leukemia; Address; Adult Acute Lymphocytic Leukemia; Alzheimer' s Disease; Anabolism; Apoptosis; Automobile Driving; Cell Cycle Arrest; Cell Differentiation process; Cell Proliferation; Cells; Childhood; Choices and Control; Clinical; Clinical Trials; Development; Disease; Dose-Limiting; Effectiveness; Epithelial Cells; FBXW7 gene; Gene Expression Profiling; Gene Targeting; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Goblet Cells; Group Identifications; Hematologic Neoplasms; Human; Interleukin 7 Receptor; Intestines; Knock-out; Ligands; Lymphoblastic Leukemia; Malignant Neoplasms; Mediating; Microarray Analysis; Modeling; Molecular; Mutation; NF-kappa B; NOTCH1 gene; Notch Signaling Pathway; Oncogenes; Oncogenic; PTEN gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Production; Receptor Activation; Receptor Gene; Recurrent disease; Research; Research Project Grants; Resistance; Role; Signal Transduction; Solid Neoplasm; Structure; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Toxic effect; base; cell growth; extracellular; gamma secretase; gastrointestinal; inhibitor/antagonist; intestinal crypt; leukemia; leukemogenesis; lymphoblast; notch protein; novel; outcome forecast; peptide A; presenilin; progenitor; programs; public health relevance; receptor; receptor expression; research study; resistance mechanism; secretase; small molecule; stem

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.

描述（由申请人提供）：阻断Presenilin-gamma泌尿酶配合酶复合物的γ-分泌酶抑制剂（GSIS），抑制了参与阿尔茨海默氏病发病机理的淀粉样生成A肽的产生和Notch受体的激活。在超过50％的T细胞淋巴细胞白血病（T-ALL）病例中，Notch1受体基因中激活突变的最新鉴定促使临床试验开始了一项临床试验，以测试用这种疾病中的小分子GSI阻断Notch1信号传导的有效性。然而，由于这些药物在人类T-All中诱导凋亡的能力有限，以及由于抑制肠道中缺口信号的抑制作用而导致严重的胃肠道毒性的发展，这些药物的临床发展受到了诱导人类T-All凋亡的有限能力的阻碍。在过去的两年中，我们的小组使用了片上芯片分析和微阵列基因表达分析的组合，以阐明由T-ALL中的Oncenogenic Notch1信号控制的转录调节网络的结构。这项研究揭示了Notch1激活的致癌计划的基本方面。在此竞争性修订应用中，我们将将项目的范围扩展到肠上皮细胞中Notch信号控制的基因和途径的范围。这些研究将提供有关介导胃肠道毒性发展的机制，随着GSIS的全身性抑制信号传导而导致胃肠道毒性的发展。 公共卫生相关性：阻断Presenilin-gamma泌尿酶络合物络合物的γ-分泌酶抑制剂（GSIS）是治疗人类癌症的有前途的药物。然而，由于肠道中缺口信号的抑制，基于GSI的疗法的临床发育阻碍了严重的胃肠道毒性的发展。这种竞争性的修订应用程序解决了在全身抑制GSIS的Notch信号传导下介导胃肠道毒性发展的机制。