A Novel Modulator of Notch in Acute Lymphoblastic Leukemia

描述（由申请人提供）：急性淋巴细胞白血病（ALL）是儿童中最常见的恶性肿瘤，由血液（造血）干细胞和祖细胞转化诱导。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患者的结局有所改善，但仍有大量患者死于复发性疾病。更好地了解这种疾病的分子基础和寻找新的想法，以及新的靶向治疗因此处于高速发展状态。最近的研究表明，大约60%的儿童T细胞ALL（T-ALL）病例以Notch 1受体的异常激活为标志。然而，小分子？分泌酶抑制剂（GSI），消除致癌Notch 1信号在T-ALL，不能显示客观的临床反应，并导致严重的毒性。因此，在T-ALL中成功靶向Notch 1需要我们对T细胞白血病中Notch 1调控的理解进行相当大的改进。 以果蝇为遗传模型，我们最近的研究表明，UVRAG（紫外线辐射抗性相关基因），一个高度保守的肿瘤抑制因子，介导Notch 1的内吞降解，并防止其异常激活和细胞过度生长。此外，来自UVRAG缺陷患者的淋巴细胞表现出强烈增加的Notch 1活性，这是由于Notch 1的内吞降解受损。这些观察结果表明Notch 1是UVRAG的关键靶分子。考虑到T-ALL对Notch 1的致癌成瘾性，我们假设UVRAG介导的Notch 1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Notch 1激活和信号传导的分子机制。目的2通过细胞实验和T-ALL小鼠移植模型研究UVRAG介导的Notch 1下调在T细胞白血病发生中的生物学意义。通过完善的体外和体内实验条件，拟议的研究不仅将确定UVRAG作为Notch 1诱导的T-ALL中的一种新的关键参与者，而且还将阐明Notch 1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。 公共卫生相关性：Notch 1的异常激活是T细胞急性淋巴细胞白血病（T-ALL）的主要原因，T-ALL是一种由造血干细胞和祖细胞转化诱导的侵袭性恶性肿瘤。本研究的目的是探讨UVRAG介导Notch 1下调在T-ALL发病和耐药中的分子机制。从这项研究中获得的结果将确定UVRAG作为Notch 1诱导的T-ALL的关键因素，并有助于为T-ALL患者提供新的治疗策略。

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. PUBLIC HEALTH RELEVANCE: Aberrant Notch1 activation accounts for the majority of T-cell acute lymphoblastic leukemia (T- ALL), an aggressive malignancy induced by the transformation of blood stem cells and progenitors. The goal of this study is to investigate the molecular mechanism of the UVRAG-mediated downregulation of Notch1 in the pathogenesis and drug resistance of T-ALL. Results obtained from this study will identify UVRAG as a key element in Notch1-induced T-ALL and aid in providing novel therapeutic strategies for T-ALL patients.