New control of oncogene activation in T-cell leukemia

项目摘要/摘要 NOTCH1信号是干细胞自我更新和治疗耐药的重要介质，而且大多数 侵袭性T细胞肿瘤T细胞急性淋巴细胞白血病(T-ALL)中常见癌基因(~60%) 对儿童和成人都有影响的祖先。虽然目前的强化化疗可以抑制 疾病，它们以严重的副作用为代价，不足以消除Notch1驱动的白血病 细胞。五分之一的儿童和二分之一的成人T-ALL由于反应迟钝或 复发的疾病。用小分子抑制剂靶向致癌Notch1的努力受到以下因素的阻碍 它们固有的细胞毒性。克服这些困难将需要更好地理解致癌因素 Notch1控制的机制和对调控Notch1的基因和途径的更好理解- 促使白血病发生作为T-ALL治疗的潜在靶点。通过对果蝇的研究和世代 在T-ALL小鼠模型中，我们发现，与T-ALL相关的Notch可以被一种 通过与自噬肿瘤抑制因子的物理相互作用实现非传统的内切溶酶体模块 UVRAG，它重塑Notch的活性和由此产生的Notch依赖的细胞反应。因此，中央 这一提议的假设是，UVRAG对Notch活性的内切酶体内滴定代表着一种独特的 在蛋白质降解处理之前调控Notch1机制，以及该调控模块的破坏 影响T细胞的动态平衡并导致T-ALL。具体地说，我们建议进行实验，以 全面剖析UVRAG介导的Notch1内切酶抑制的分子机制 全部都是。此外，我们还将阐明这一机制对自我更新和 人类T-ALL原发样本中白血病启动细胞功能的干性。最后，我们将使用鼠标 模型测试这一概念，即增强这一机制可以恢复Notch稳态并实现 T-ALL持续缓解。将使用多学科创新方法来实现这些目标 集成最先进的遗传、生物化学、高分辨率成像和细胞和生理分析 转基因小鼠模型。我们现在将T-All的全球领导者的合作纳入到这个提案中 病理学和分子生物学以及临床医生和病理学家。我们使用患者来源的T-ALL 样本将最大限度地提高我们的研究结果的相关性，最终翻译给临床上的T-ALL患者。 总体而言，该项目将导致对Notch1驱动的白血病发生的深入理解，并提供 针对这种侵袭性淋巴组织开发最佳抗白血病策略的关键轨迹 恶毒。

Project Summary/Abstract Notch1 signaling is an important mediator of stem cell self-renewal and therapeutic resistance, and the most prevalent oncogene (~60%) in T-cell acute lymphoblastic leukemia (T-ALL) - an aggressive neoplasm of T cell progenitors that affects both children and adults. Although current intensive chemotherapies can suppress the disease, they come at the cost of serious side effects and are insufficient to eliminate Notch1-driven leukemic cells. One in five children and one in two adults with T-ALL do not survive due to either unresponsive or relapsed disease. Efforts to target oncogenic Notch1 with small-molecule inhibitors have been hampered by their inherent cytotoxicity. Overcoming these difficulties will require improved understanding of the oncogenic mechanisms controlled by Notch1 and a better appreciation of the genes and pathways that regulate Notch1- driven leukemogenesis as potential targets of T-ALL therapy. Through Drosophila studies and the generation of mouse models for T-ALL, we have discovered that, T-ALL-associated Notch could be degraded by an unconventional endo-lysosomal module through a physical interaction with the autophagic tumor suppressor UVRAG, which reshapes Notch activity and resultant Notch-dependent cellular response. Thus, the central hypothesis of this proposal is that the endo-lysosomal titration of Notch activity by UVRAG represents a unique mechanism governing Notch1 before proteolytic processing, and that disruption of this regulatory module impacts T-cell homeostasis and contributes to T-ALL. Specifically, we propose experiments to comprehensively dissect the molecular mechanism of UVRAG-mediated endo-lysosomal inhibition of Notch1 in T-ALL. Furthermore, we will elucidate the unequivocal impact of this mechanism on the self-renewal and stemness of leukemia-initiating cell function in human T-ALL primary samples. Finally, we will use the mouse models to test the concept that boosting this mechanism could restore Notch homeostasis and achieve sustained T-ALL remission. These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, high-resolution imaging, and physiological assays in cells and transgenic mouse models. We now bring within this proposal a collaboration of world-wide leaders in T-ALL pathology and molecular biology along with clinicians and pathologists. Our use of patient-derived T-ALL samples will maximize the relevance of our findings for eventual translation to T-ALL patients in the clinic. Overall, this project will lead to an in-depth understanding of Notch1-driven leukemogenesis, and provides a critical trajectory for the development of optimal anti-leukemia strategies against this aggressive lymphoid malignancy.