Targeting PML for leukemia therapy.

描述（由申请方提供）：已证明白血病的维持依赖于大量白血病群体中具有自我更新特性的一小部分细胞亚群，称为“白血病起始细胞”（LIC）。LIC与常规干细胞共享机械特性，包括更静止的性质，这被认为是介导它们对标准化疗治疗的抗性。未能有效靶向LIC可能导致疾病复发。慢性粒细胞白血病（CML）是一种被广泛研究的干细胞疾病，其中LIC池并不总是被当前的靶向治疗根除，导致停药后疾病复发。我们已经证明，早幼粒细胞白血病（PML）肿瘤抑制因子的表达在常规造血干细胞（HSC）和CML母细胞中都惊人地高，并且PML表达的缺失预示着CML中更有利的结果。我们随后证明，PML在维持HSC/LIC的静止和自我更新特性方面起着关键作用，尽管所涉及的确切分子机制尚不清楚。还已知用砷处理细胞可抑制PML，砷可特异性降低蛋白质的稳定性。利用这一点，我们在CML小鼠模型中使用砷介导的PML消融成功靶向LIC。然而，需要评估PML靶向治疗在临床中的有效性。因此，为了了解LIC维持所需的PML下游关键通路，并将PML消融LIC靶向转化为临床，我们提出以下具体目标：（1）研究PML在静止LIC中的分子功能及其在LIC和骨髓生态位之间的相互作用中的作用;（2）评估砷治疗在临床相关的CML小鼠模型中的有效性;（3）开展砷剂联合达沙替尼治疗慢性期CML的临床试验。这些目标的实现可以大大改善CML患者的治疗，可能允许在LIC根除后停止治疗。此外，了解PML功能可以为LIC和癌症干细胞消融提供其他治疗靶点。 公共卫生相关性：我们已经确定了PML在维持CML起始细胞中的重要作用，并提出了一种新的治疗方法，通过使用砷抑制PML的功能来靶向静止的白血病起始细胞（LICs）。我们的研究结果支持了这样一种观点，即砷消融PML可能是一种有效的工具，使CML起始细胞对抗肿瘤治疗更敏感。这项工作有可能对CML的治疗产生重大影响。酪氨酸激酶抑制剂在抑制大多数CML患者的恶性克隆方面是成功的。然而，在停止治疗后，疾病复发，并且一部分患者发生对TKI治疗耐药的疾病。在本提案中，我们将评估砷与TKI治疗相结合的效果，目标是靶向LIC，以便对这种疾病进行治愈性而不是抑制性治疗。对PML调节LIC池维持的机制的阐明可能反过来导致治疗白血病的新治疗方法。

DESCRIPTION (provided by applicant): Maintenance of leukemia has been demonstrated to be dependent upon a small sub-population of cells within the bulk leukemic population that have self-renewal properties and are termed "leukemia-initiating cells" (LICs). LICs share mechanistic properties with regular stem cells including a more quiescent nature, which is thought to mediate their resistance to standard chemotherapy-based treatment. Failure to effectively target LICs can result in disease relapse. Chronic Myelogenous Leukemia (CML) is an extensively studied stem cell disorder in which the LIC pool is not always eradicated by current targeted therapy, leading to disease relapse upon drug discontinuation. We have demonstrated that expression of the Promyelocytic Leukemia (PML) tumor suppressor is surprisingly high in both regular hematopoietic stem cells (HSCs) and in CML blasts and that loss of PML expression predicts a more favorable outcome in CML. We subsequently demonstrated that PML plays a key role in maintaining the quiescence and self-renewal properties of HSCs/LICs although the exact molecular mechanisms involved are poorly understood. PML is also known to be pharmacologically inhibited by treatment of cells with arsenic, which specifically decreases the stability of the protein. Taking advantage of this, we have used arsenic-mediated ablation of Pml in a mouse model of CML to successfully target LICs. However, the effectiveness of PML targeting in the clinic needs to be assessed. Therefore, in order to understand the key pathways downstream PML required for LIC maintenance and to translate PML-ablative LIC targeting to the clinic we propose the following Specific Aims: (1) to study the molecular function of PML in quiescent LICs and its role in the cross-talk between LICs and the bone marrow niche; (2) to assess effectiveness of arsenic treatment in more clinically relevant mouse models of CML; (3) to develop a clinical trial of combination arsenic+dasatinib treatment for chronic phase CML. Accomplishment of these aims could greatly improve treatment of patients with CML, possibly allowing discontinuation of therapy after LIC eradication. Further, understanding PML function could provide other therapeutic targets for LIC and cancer stem cell ablation. PUBLIC HEALTH RELEVANCE: We have defined the essential role of PML in the maintenance of CML-initiating-cells, and present a new therapeutic approach for targeting quiescent leukemia initiating cells (LICs) by using arsenic to inhibit the function of PML. Our findings support the notion that PML-ablation by arsenic may be an effective tool to render CML-initiating cells more sensitive to anti-tumor therapy. This work has the potential to have a significant impact on the treatment of CML. Tyrosine kinase inhibitors are successful at suppressing the malignant clone in the majority of CML patients. However, the disease recurs upon discontinuation of therapy, and a subset of patients develops disease that is resistant to TKI therapy. In this proposal, we will evaluate the effect of combining arsenic with TKI therapy, with goal of targeting the LICs in order to result in curative rather than suppressive therapy for this disease. The elucidation of the mechanisms by which PML regulates the maintenance of the LIC pool could in turn lead to novel therapeutic approaches to treat leukemia.