A Novel Modulator of Notch in Acute Lymphoblastic Leukemia

描述(由申请人提供：急性淋巴细胞性白血病(ALL)是儿童最常见的恶性肿瘤，由血液(造血)干细胞和祖细胞转化而引起。骨髓中产生的受损细胞会排挤正常细胞，也会转移到其他器官。尽管近年来所有患者的预后都有所改善，但仍有相当数量的患者死于复发疾病。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是非常重要的。最近的研究表明，大约60%的儿童T细胞急性淋巴细胞白血病(T-ALL)患者存在Notch1受体的异常激活。然而，在T-ALL中阻断致癌Notch1信号的小分子β-分泌酶抑制剂(GSI)不能表现出客观的临床反应，并造成严重的毒性。因此，在T-ALL中成功靶向Notch1需要我们对Notch1在T细胞白血病中的调控有相当大的了解。通过以果蝇为遗传模型，我们最近的研究表明，UVRAG(紫外线辐射抵抗相关基因)是一个高度保守的肿瘤抑制基因，它介导了Notch1的内吞降解，并阻止了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的Notch1活性增加，这是由于Notch1的内吞降解受损所致。这些观察表明Notch1代表了UVRAG的一个关键靶分子。鉴于T-ALL对Notch1的致癌成瘾，我们假设UVRAG介导的Notch1下调在T-ALL的发展和GSI耐药中起关键作用。为了验证这一假设，目标1将研究UVRAG调节Notch1激活和信号的分子机制。目的研究UVRAG介导的Notch1基因下调在T细胞白血病发生中的生物学意义。在良好的体外和体内实验条件下，这项拟议的研究不仅将确定UVRAG是Notch1诱导的T-ALL中的一个新的和关键的参与者，而且还将阐明关于Notch1调节的新观点，以设计更有效的白血病/淋巴瘤患者的治疗方案。 公共卫生相关性：T细胞急性淋巴细胞白血病(T-ALL)的主要原因是Notch1的异常激活，T-ALL是一种由血液干细胞和祖细胞转化引起的侵袭性恶性肿瘤。本研究的目的是探讨UVRAG介导的Notch1下调在T-ALL发病机制和耐药中的分子机制。这项研究的结果将确定UVRAG是Notch1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.