Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance

项目摘要/摘要 急性髓系白血病(AML)是一种侵袭性的血癌，包括多种遗传因素。 不同的子类型。总的来说，急性髓细胞白血病患者的5年生存率是所有患者中最低的(25%)。 癌症被诊断出来，目前被列为最致命的白血病。这些不令人满意的结果是 在很大程度上是现有化疗无效和毒性的结果，并突出了迫切需要 用于更有效的治疗，以取代或提高这些化疗的有效性。 更有效的治疗方法的开发始于确定 急性髓系白血病的发病机制和化疗无效。我们最近发现，这两个 转录因子(TF)转录因子、ATF4和XBP1s，它们是信号转导网络的组成部分， 未折叠蛋白反应(UPR)是AML细胞存活和疾病进展的关键调节因子。 具体地说，我们发现抑制ATF4或XBP1s可以对抗AML细胞的存活和疾病 多种AML体外和体内模型的研究进展。我们还发现，小分子抑制物 PERK和IRE1分别是ATF4和XBP1s的上游激活剂，对急性髓系白血病细胞有拮抗作用 生存，并提高一线化疗的有效性。 这项提议的集体目标旨在解决两个关键的悬而未决的问题：1.什么是 支持AML生物学的ATF4和XBP1的下游转录靶点和2。 UPR的分子节点可以通过化学策略进行靶向吗？关于第一个问题， 我们已经确定了两个候选基因DDIT4和SREBF1，它们是已知的自噬和 胆固醇生物学。我们将使用已建立的基因工程小鼠的组合 评估DDIT4和SREBF1在AML中的功能作用的AML模型和患者来源的AML样本 以及它们与普遍定期审议的关系。此外，我们将评估DDIT4和SREBF1的贡献- 以及下游调控的过程有助于ATF4和XBP1s的促白血病功能。 其次，我们将评估针对UPR、自噬和胆固醇生物学的治疗策略 在急性髓系白血病的实验模型中单独或同时进行。这些研究的结果将提供新的 支持急性髓系白血病发病机制和化疗反应的分子机制 建立一个开发新的治疗策略的平台。此外，普遍定期审议的组成部分支持 许多其他肿瘤环境的病理生理学，因此我们提议的研究结果可能会有 对其他形式的人类癌症的影响。

Project Summary/Abstract Acute myeloid leukemia (AML) is an aggressive blood cancer that encompasses a variety of genetically distinct sub-types. AML patients overall, display one of the lowest overall 5-year survival rates (<25%) of all cancer diagnoses and currently ranks as the deadliest form of leukemia. These unsatisfactory outcomes are largely the result of the ineffectiveness and toxicities of existing chemotherapies and highlight the urgent need for more-effective therapies that either replace or improve the effectiveness these chemotherapies. The development of more-effective therapies begins by identifying the molecular mechanisms that underpin AML pathogenesis and chemotherapy ineffectiveness. We recently discovered that the two transcription factors (TFs) TFs, ATF4 and XBP1s, which are components of the signal transduction network, the unfolded protein response (UPR), are key mediators of AML cell survival and disease progression. Specifically, we have found that inhibition of ATF4 or XBP1s antagonizes AML cell survival and disease progression in multiple in vitro and in vivo models of AML. We also found that small-molecule inhibitors of PERK and IRE1, which are upstream activators of ATF4 and XBP1s, respectively, antagonizes AML cell survival and enhances the effectiveness of first-line chemotherapies. The collective goals of this proposal aim to address two key unanswered questions: 1. What are the downstream transcriptional targets of ATF4 and XBP1s that support AML biology and 2. What are the molecular nodes of the UPR that can be targeted with chemical strategies? With respect to the first question, we have identified two candidates, DDIT4 and SREBF1, which are known regulators of autophagy and cholesterol biology, respectively. We will use a combination of established genetically engineered mouse models of AML and patient-derived AML samples to assess the functional roles of DDIT4 and SREBF1 in AML as well as their relationship to the UPR. Additionally, we will assess the contribution of DDIT4 and SREBF1 – as well as the downstream-regulated processes contribute to the pro-leukemia functions of ATF4 and XBP1s. Second, we will assess therapeutic strategies for targeting the UPR, autophagy and cholesterol biology either alone or simultaneously in experimental models of AML. The results of these studies will provide new insight on the molecular mechanisms that support the pathogenesis and chemotherapy responses of AML and establish a platform for developing novel therapeutic strategies. Moreover, components of the UPR support the pathophysiology of many other tumor settings and thus results from our proposed studies will likely have implications for other forms of human cancers.