The Phosphatase PRL3 as a MYC Target and Pro-Survival Oncogene in Acute Lymphoblastic Leukemia

原始项目摘要 急性淋巴母细胞瘤的分子靶向治疗亟待发展 白血病(ALL)。缺乏针对这种疾病的针对性治疗是一个重要的问题，因为所有的 主要是儿科癌症，而密集的全身细胞毒性化疗有严重而长期的- 儿童的长期不良反应。此外，ALL对细胞毒性不起反应的成人和儿童 由于治疗选择有限，化疗或复发患者的预后普遍较差。 众所周知，ALL的驱动因素是错误表达的转录因子，如myc，它们不容易 具有治疗靶向性，对正常细胞无不良副作用。初步数据，这是建立在 新的体内移植筛选在MYC诱导的斑马鱼ALL模型中，证明了酪氨酸 磷酸酶PRL3与MYC合作促进了白血病的进展。体外和体内研究使用 人类细胞研究表明，PRL3与MYC的表达有关，并在所有生存中发挥关键作用。 像PRL3这样的磷酸酶是众所周知的肿瘤抑制因子，尽管有新的证据表明，一些 磷酸酶具有致癌能力，目前还没有磷酸酶抑制剂用于临床治疗 癌症患者，只有一人在临床试验中。此应用程序的总体目标是清楚地定义 酪氨酸磷酸酶PrL3在MYC驱动的ALL中的致癌作用及其新发现 这种疾病的分子靶点。中心假设是PrL3是MYC的直接转录靶点，并且 与MYC协同作用，促进所有细胞中有利于生存的表型。这项研究的基本原理是 PRL3属于一种独特的磷酸酶家族，可以选择性地抑制；定义了 通过PRL3促进所有人的生存将为发展 PRL和其他磷酸酶抑制剂，用于癌症患者的靶向治疗。这一假设将是 通过追求三个具体目标进行测试：1)定义MYC调节PRL3表达的机制 通过使用enChIP和生化方法评估MYC与一个新的增强子区域的相互作用 PRL3；2)利用无偏见的生物素确定由PRL3控制的促生存机制 连接酶方法来鉴定所有细胞中PRL3底物；以及3)建立对 PRL家族是一种有效的治疗策略，通过完成三项全面的临床前测试 新的PRL抑制剂和FDA批准的一组酪氨酸磷酸酶抑制剂。本研究具有创新性。 因为它与现状不同，使用新的方法来定义磷酸酶在肿瘤中的致癌作用 癌症。拟议中的研究也具有重要意义，因为预计它将垂直推进和扩展 了解磷酸酶在癌症进展中所起的作用。归根结底，这种知识具有 为急性淋巴细胞白血病患者开发一种新的靶向治疗的潜力 白血病和其他由MYC引起的癌症。

ORIGINAL PROJECT SUMMARY There is a great need for the development of molecularly targeted therapies in Acute Lymphoblastic Leukemia (ALL). The lack of targeted therapies for this disease is an important problem because ALL is primarily a pediatric cancer, and intensive rounds of general cytotoxic chemotherapy have severe and long- term adverse effects in children. Additionally, adults and children whose ALL does not respond to cytotoxic chemotherapy, or who develop relapse, have a universally poor prognosis due to limited treatment options. The well-known drivers of ALL are mis-expressed transcription factors, such as MYC, which are not easily therapeutically targeted without undesirable side-effects on normal cells. Preliminary data, which built on a novel in vivo transplantation screen in a MYC-induced ALL model in zebrafish, demonstrated that the tyrosine phosphatase PRL3 collaborated with MYC to enhance leukemia progression. In vitro and in vivo studies using human cells showed that PRL3 is linked with MYC expression, and plays a critical role in ALL survival. Phosphatases like PRL3 are most well-known as tumor suppressors, and despite emerging evidence that some phosphatases have oncogenic abilities, there are currently no phosphatase inhibitors used in the clinic for cancer patients, and only one in clinical trial. The overall objective of this application is to clearly define the oncogenic role of the tyrosine phosphatase PRL3 in MYC-driven ALL and to establish that it is a novel molecular target in this disease. The central hypothesis is that PRL3 is a direct transcriptional target of MYC, and synergizes with MYC to promote a pro-survival phenotype in ALL cells. The rationale for this research is that PRL3 belongs to a unique family of phosphatases that can be selectively inhibited; defining the mechanisms through which PRL3 promotes ALL survival will provide a strong scientific rationale for the development of PRL and other phosphatase inhibitors for use as targeted therapy for cancer patients. This hypothesis will be tested by pursuing three specific aims: 1) Define a mechanism through which MYC regulates PRL3 expression by using enChIP and biochemical approaches to assess MYC interaction with a novel enhancer region near PRL3; 2) determine the pro-survival mechanisms that are controlled by PRL3 by utilizing an unbiased biotin ligase approach to identify PRL3 substrates in ALL cells; and 3) establish that small molecule inhibition of the PRL family is a potent therapeutic strategy in ALL by completing comprehensive pre-clinical testing of three new PRL inhibitors and a panel of FDA-approved tyrosine phosphatase inhibitors. This research is innovative because it departs from the status quo to use new methods to define an oncogenic role for a phosphatase in cancer. The proposed research is also significant because it is expected to vertically advance and expand understanding of the role that phosphatases play in cancer progression. Ultimately, this knowledge has the potential to drive the development of a new class of targeted therapy for patients with acute lymphoblastic leukemia and other MYC-driven cancers.