A Novel Modulator of Notch in Acute Lymphoblastic Leukemia

急性淋巴细胞白血病中Notch的新型调节剂

• 批准号: 8309060
• 负责人: Chengyu Liang
• 金额: $ 17.62万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309060
• 关键词: Accounting; Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Acute leukemia; Address; Alleles; Autophagocytosis; Biochemical; Biological; Biological Assay; Blood; Bone Marrow; Cell Line; Cells; Child; Childhood Precursor T Lymphoblastic Leukemia; Clinical; Complex; Crowding; Defect; Degradation Pathway; Development; Disease; Down-Regulation; Drosophila genus; Drug resistance; Endocytosis; Endosomes; Exhibits; Gene Mutation; Gene Targeting; Genes; Genetic Models; Goals; Hematologic Neoplasms; Hematopoietic stem cells; Human; In Vitro; Indium; Lead; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Molecular; Mus; Neoplasm Metastasis; Normal Cell; Oncogenic; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Post-Translational Regulation; Process; Proteins; Receptor Activation; Receptor Signaling; Recurrent disease; Regulation; Resistance; Role; Signal Transduction; Sorting - Cell Movement; Stem cells; T-Cell Leukemia; T-Lymphocyte; Testing; Toxic effect; Tumor Suppressor Proteins; Vacuole; Vesicle; Work; Xenograft Model; Xenograft procedure; addiction; attenuation; base; cancer cell; cell injury; design; effective therapy; gene interaction; improved; in vivo; inhibitor/antagonist; leukemia/lymphoma; leukemogenesis; loss of function; lymphoblast; mouse model; notch protein; novel; novel therapeutics; outcome forecast; prevent; progenitor; receptor; response; secretase; small molecule; therapeutic target; trafficking; tumor; ultraviolet irradiation; young adult

DESCRIPTION (provided by applicant: Acute lymphoblastic leukemia (ALL), the most common form of malignancies in children, is induced by the transformation of blood (hematopoietic) stem cells and progenitors. The damaged cells produced in the bone marrow crowd out normal cells and also metastasize to other organs. Although the outcome of ALL patients has improved in recent years, significant numbers of patients die from recurrent disease. Better understanding of the molecular basis of this disease and the search for fresh ideas, and new-targeted therapies are thus in high gear. Recent studies have demonstrated that approximately 60% of cases of pediatric T-cell ALL (T- ALL) are marked with aberrant activation of the Notch1 receptor. However, small molecule ?-secretase inhibitors (GSIs), which abrogate oncogenic Notch1 signaling in T-ALL, fail to show objective clinical responses and cause severe toxicity. Therefore, successful targeting of Notch1 in T-ALL demands a considerable refinement of our understanding of Notch1 regulation in T cell leukemia. By using Drosophila as a genetic model, our recent study showed that UVRAG (UV irradiation resistance-associated gene), a highly conserved tumor suppressor, mediates the endocytic degradation of Notch1 and prevents its aberrant activation and cell overgrowth. Additionally, lymphocytes from UVRAG-deficient patient exhibit strongly increased Notch1 activity resulting from an impaired endocytic degradation of Notch1. These observations suggest that Notch1 represents a key target molecule of UVRAG. Given the oncogenic addiction of T-ALL to Notch1, we hypothesize that UVRAG-mediated downregulation of Notch1 plays a critical role in the development and GSIs-resistance of T-ALL. To test this hypothesis, Aim 1 will investigate the molecular mechanism by which UVRAG modulates Notch1 activation and signaling. Aim 2 will investigate the biological significance of UVRAG-mediated downregulation of Notch1 in T cell leukemogenesis by using both cell-based assays and T-ALL xenograft mouse model. With well-established in vitro and in vivo experimental conditions, the proposed study will not only identify UVRAG as a novel and critical player in Notch1-induced T-ALL, but will also illuminate new views on Notch1 regulation for the design of more effective treatment options for patients with leukemia/lymphoma.

描述（由申请人提供）：急性淋巴细胞白血病（ALL）是儿童最常见的恶性肿瘤，由血液（造血）干细胞和祖细胞的转化诱导。骨髓中产生的受损细胞排挤正常细胞，并转移到其他器官。尽管近年来ALL患者的预后有所改善，但仍有大量患者死于复发性疾病。因此，更好地了解这种疾病的分子基础，寻找新的想法和新的靶向治疗方法正在快速进行。最近的研究表明，大约60%的儿童T细胞ALL （T- ALL）病例以Notch1受体的异常激活为特征。然而，小分子呢？-分泌酶抑制剂（GSIs）可以消除T-ALL中致癌的Notch1信号，但不能表现出客观的临床反应，并导致严重的毒性。因此，Notch1在T- all中的成功靶向需要我们对Notch1在T细胞白血病中的调控的理解有相当大的改进。我们最近的研究以果蝇为遗传模型，发现高度保守的肿瘤抑制因子UVRAG （UV - radiation resistance-associated gene）可介导Notch1的内吞降解，并阻止Notch1的异常激活和细胞过度生长。此外，uvrag缺陷患者的淋巴细胞由于Notch1的内吞降解受损而表现出强烈的Notch1活性增加。这些观察结果表明，Notch1是UVRAG的一个关键靶分子。鉴于T-ALL对Notch1的致癌依赖，我们假设uvrag介导的Notch1下调在T-ALL的发展和gsis抗性中起关键作用。为了验证这一假设，Aim 1将研究UVRAG调节Notch1激活和信号传导的分子机制。目的2将通过基于细胞的实验和T- all异种移植小鼠模型研究uvrag介导的Notch1下调在T细胞白血病发生中的生物学意义。随着体外和体内实验条件的完善，该研究不仅将确定UVRAG在Notch1诱导的T-ALL中是一个新的关键角色，而且将阐明Notch1调控的新观点，为白血病/淋巴瘤患者设计更有效的治疗方案。