The phosphatase PRL3 as a MYC target and pro-survival oncogene in Acute Lymphoblastic Leukemia

项目总结 发展分子靶向治疗急性淋巴细胞性白血病的必要性 (全部)。缺乏针对这种疾病的有针对性的治疗是一个重要的问题，因为所有这些都是 儿童癌症和强化轮次全身细胞毒化疗有严重和长期的不良反应 对儿童的影响。此外，ALL对细胞毒性化疗无反应的成人和儿童，或 他们复发，由于有限的治疗选择，普遍预后很差。家喻户晓 ALL的驱动因素是错误表达的转录因子，如MYC，这些转录因子在治疗上不容易 靶向对正常细胞无不良副作用。初步数据，建立在体内的一种新的 在MYC诱导的斑马鱼ALL模型中进行移植筛选，证明酪氨酸磷酸酶 PRL3与MYC合作促进白血病进展。利用人体细胞进行的体外和体内研究 研究表明，PRL3与MYC的表达有关，并在ALL的生存中起着关键作用。磷酸酶类 PRL3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癌症患者的临床， 只有一例在临床试验中。本申请的总体目标是清楚地定义致癌作用 MYC驱动的ALL中酪氨酸磷酸酶PrL3的表达及其新的分子靶点的建立 疾病。中心假设是PrL3是MYC的直接转录靶点，并与 MYC在所有细胞中促进有利于生存的表型。这项研究的基本原理是PRL3属于 一种可以选择性抑制的独特的磷酸酶家族；定义了 PRL3促进所有生存将为PRL和其他疾病的发展提供强有力的科学依据 用于癌症患者靶向治疗的磷酸酶抑制剂。这一假设将通过以下方式检验 追求三个具体目标：1)确定MYC通过使用以下机制来调节PRL3表达 用enChIP和生化方法评估MYC与PrL3附近新的增强子区域的相互作用；2) 利用无偏向的生物素连接酶确定PRL3控制的促生存机制 在所有细胞中鉴定PRL3底物方法；以及3)建立对PRL的小分子抑制 家庭是一种有效的治疗策略，通过完成三种新的 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。

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.