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

项目摘要 急性淋巴细胞白血病的分子靶向治疗亟待发展 （全部）。缺乏针对这种疾病的靶向治疗是一个重要的问题，因为ALL主要是一种 儿童癌症和密集轮的一般细胞毒性化疗具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 复发的患者由于治疗选择有限，预后普遍较差。知名 ALL的驱动因子是错误表达的转录因子，如MYC，其不易治疗。 对正常细胞没有不良副作用。初步数据，建立在一种新的体内 在斑马鱼MYC诱导的ALL模型中进行的移植筛选表明，酪氨酸磷酸酶 PRL 3与MYC合作促进白血病进展。使用人细胞的体外和体内研究 结果显示，PRL 3与MYC表达相关，并在ALL生存中起关键作用。磷酸酶样 PRL 3作为肿瘤抑制因子最为人们所熟知，尽管有新的证据表明某些磷酸酶 具有致癌能力，目前临床上没有磷酸酶抑制剂用于癌症患者， 只有一个在临床试验中。本申请的总体目标是明确定义 酪氨酸磷酸酶PRL 3在MYC驱动的ALL中的作用，并确定它是一种新的分子靶点， 疾病核心假设是PRL 3是MYC的直接转录靶点，并且与MYC协同作用。 MYC促进ALL细胞中的促存活表型。这项研究的基本原理是，PRL 3属于 一个独特的磷酸酶家族，可以被选择性抑制;定义了 PRL 3促进ALL生存将为PRL和其他疾病的发展提供强有力的科学依据。 磷酸酶抑制剂用作癌症患者的靶向治疗。这一假设将由以下人员进行检验： 追求三个具体目标：1）通过使用MYC来定义MYC调节PRL 3表达的机制， enChIP和生物化学方法评估MYC与PRL 3附近的新增强子区域的相互作用; 2） 通过利用无偏生物素连接酶确定由PRL 3控制的促存活机制 鉴定ALL细胞中PRL 3底物方法;和3）建立PRL的小分子抑制 家庭是一个有效的治疗策略，在所有完成全面的临床前测试的三个新的 PRL抑制剂和FDA批准的酪氨酸磷酸酶抑制剂。这项研究具有创新性 因为使用新的方法来确定磷酸酶在肿瘤中的致癌作用与现状不同， 癌拟议中的研究也具有重大意义，因为它有望纵向推进和扩大 了解磷酸酶在癌症进展中的作用。最终，这些知识 有可能推动急性淋巴细胞白血病患者新型靶向治疗的发展 白血病和其他MYC驱动的癌症。

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.