New control of oncogene activation in T-cell leukemia

项目总结/摘要 Notch 1信号传导是干细胞自我更新和治疗抗性的重要介质， T细胞急性淋巴细胞白血病（T-ALL）中的一种流行癌基因（约60%）-一种侵袭性T细胞肿瘤 影响儿童和成人的祖细胞。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Notch 1驱动的白血病。 细胞五分之一的T-ALL儿童和二分之一的T-ALL成人由于反应迟钝或 复发性疾病用小分子抑制剂靶向致癌Notch 1的努力受到了阻碍， 其固有的细胞毒性。克服这些困难将需要提高对致癌基因的理解。 Notch 1控制的机制，以及更好地了解调控Notch 1的基因和途径， 作为T-ALL治疗的潜在靶点。通过对果蝇的研究， 在T-ALL小鼠模型中，我们发现，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的非常规内-溶酶体模块 UVRAG，其重塑Notch活性和所得的Notch依赖性细胞应答。因此，中央 该建议的假设是，通过UVRAG进行的Notch活性的内溶酶体滴定代表了一种独特的 在蛋白水解加工之前控制Notch 1的机制，以及该调节模块的破坏 影响T细胞稳态并导致T-ALL。具体来说，我们提出实验， 全面剖析UVRAG介导的Notch 1内溶酶体抑制的分子机制， T-ALL。此外，我们将阐明这种机制对自我更新的明确影响， 人类T-ALL原始样本中白血病起始细胞功能的干性。最后，我们将使用鼠标 模型来测试增强这种机制可以恢复Notch稳态并实现 T-ALL持续缓解。这些目标将通过多学科的创新方法来实现， 集成了最先进遗传学、生物化学、高分辨率成像和细胞生理学分析， 转基因小鼠模型。我们现在在这个提议中加入了全球T-ALL领导者的合作 病理学和分子生物学沿着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，以最终转化为临床上的T-ALL患者。 总的来说，该项目将导致对Notch 1驱动的白血病发生的深入了解，并提供了一个新的研究方向。 针对这种侵袭性淋巴细胞的最佳抗白血病策略的发展的关键轨迹 恶性肿瘤

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.