Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance

项目总结/摘要 急性髓性白血病（AML）是一种侵袭性血液癌症，包括多种遗传学上的异常。 不同的子类型总体而言，AML患者是所有患者中总体5年生存率最低的患者之一（<25%） 癌症诊断，目前被列为最致命的白血病。这些不令人满意的结果是 主要是由于现有化疗的无效性和毒性，并强调迫切需要 寻找更有效的疗法来替代或提高这些化疗的效果。 开发更有效的治疗方法首先要确定 支持AML发病机制和化疗无效。我们最近发现， 转录因子（TF）TF、ATF 4和XBP 1，它们是信号转导网络的组分， 未折叠蛋白反应（UPR）是AML细胞存活和疾病进展的关键介质。 具体地说，我们已经发现抑制ATF 4或XBP 1拮抗AML细胞存活和疾病， 在AML的多种体外和体内模型中的进展。我们还发现，小分子抑制剂， PERK和IRE 1 β分别是ATF 4和XBP 1的上游激活剂， 提高一线化疗的有效性。 该提案的集体目标旨在解决两个关键的未回答的问题：1。有哪些 支持AML生物学的ATF 4和XBP 1的下游转录靶点，以及2.有哪些 可以用化学战略瞄准的普遍定期审议的分子节点？关于第一个问题， 我们已经确定了两个候选者，DDIT 4和SREBF 1，它们是已知的自噬调节因子， 胆固醇生物学。我们将使用基因工程小鼠 AML和患者来源的AML样本模型，以评估DDIT 4和SREBF 1在AML中的功能作用 以及它们与普遍定期审议的关系。此外，我们将评估DDIT 4和SREBF 1的贡献- 以及下游调节过程有助于ATF 4和XBP 1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 单独或同时在AML的实验模型中。这些研究结果将提供新的 深入了解支持AML发病机制和化疗反应的分子机制， 为开发新的治疗策略建立平台。此外，普遍定期审议的各个组成部分支持 许多其他肿瘤环境的病理生理学，因此我们提出的研究结果可能具有 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.