The role of the protein tyrosine phosphatase PRL3 in leukemia development

蛋白酪氨酸磷酸酶 PRL3 在白血病发展中的作用

• 批准号: 8618454
• 负责人: Jessica S. Blackburn
• 金额: $ 17.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618454
• 关键词: Acute; Acute T Cell Leukemia; Adult; Adverse effects; Animals; Award; Behavior; Cancer Model; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Child; Childhood; Chronic Myeloid Leukemia; Clinical; Clinical Treatment; Communities; Coupled; Data; Development; Drug Targeting; Environment; Foundations; General Hospitals; Genes; Genetic Epistasis; Goals; Hand; Health; Human; Image; In Vitro; Induction of Apoptosis; Knowledge; Learning; Life; Malignant Neoplasms; Massachusetts; Mentors; Mentorship; Modeling; Molecular; Molecular Target; Multiple Myeloma; Mus; Nature; Oncogenes; Outcome; Pathway interactions; Patients; Phase; Phosphorylation; Play; Protein Tyrosine Phosphatase; Proteins; Proteomics; Relapse; Research; Research Personnel; Role; Sampling; Solid Neoplasm; Staging; Survival Rate; Techniques; Testing; Therapeutic; Therapeutic Uses; Thymus Gland; Time; Transgenic Animals; Tyrosine; Work; Xenograft Model; Xenograft procedure; Zebrafish; base; cancer type; chemotherapy; defined contribution; gain of function; improved; in vivo; inhibitor/antagonist; innovation; knock-down; leukemia; loss of function; medical schools; mortality; mouse model; new therapeutic target; novel; outcome forecast; preclinical study; research study; small molecule; success; tumor progression

DESCRIPTION (provided by applicant): The aggressive and unpredictable nature of relapsed T-cell acute lymphoblastic leukemia (T-ALL) represents a major clinical challenge, in large part due to highly toxic and ineffective chemotherapies. Further advances in therapy will require a detailed understanding of the molecular underpinnings of T- ALL development and relapse. To this end, I have completed a highly innovative screen in zebrafish to identify genes associated with T-ALL progression and have found that the protein tyrosine phosphotase PRL-3 was commonly amplified in single T-ALL cells as they developed increased ability to form relapse over time. In transgenic animals, PRL-3 over-expression significantly enhanced primary T-ALL development and relapse formation. I have found that PRL-3 amplified in a subset of human T-ALL and is highly expressed by a majority of T-ALL patient samples. These cells are also sensitive to PRL-3 knock-down through the induction of apoptosis. These results imply that PRL-3 activity has an important role in T-ALL malignancy, and that PRL-3 and its substrates may represent novel therapeutic targets for the treatment of T-ALL. The objectives of this proposal are to 1) define the contribution of PRL-3 to T- ALL progression and relapse and 2) identify the mechanism by which PRL-3 drives T-ALL malignancy. This objective will be achieved through two specific aims. During the K99 phase of this award, I will complete Aim 1, where I will examine the effect of PRL-3 gain-of-function and loss-of-function in various stages of T-ALL development in zebrafish, including invasion from the thymus, intravasation, proliferation and relapse, and I will also test the effects of PRL-3 knock-down on human cells in a murine xenograft model. During this phase, I will learn techniques to directly image cancer progression in live animals and to develop orthotopic leukemia xenografts in mice. With this knowledge in hand, during the R00 phase I will complete Aim 2, where I will identify the target substrates of PRL-3 in T-ALL cells, and test the contribution of these genes and pathways to T-ALL malignancy using in vivo and in vitro epistasis experiments. In total, this work will lay the foundation for the development of small molecule PRL-3 and pathway inhibitors for potential therapeutic use in T-ALL. The mentored phase of this award will occur under the guidance of Dr. David Langenau, an expert in zebrafish models of cancer, and Dr. Thomas Look, an internationally recognized leader in the field of leukemia research. Their proven track record of mentorship, coupled with an intensive didactic component and the rigorous and nurturing academic environment offered by the research community of Massachusetts General Hospital and Harvard Medical School offer the best opportunity for my success as I transition to becoming an independent investigator.

描述(申请人提供)：复发性T细胞急性淋巴细胞性白血病(T-ALL)的侵袭性和不可预测性是一个重大的临床挑战，在很大程度上是由于剧毒和无效的化疗。在治疗方面的进一步进展将需要详细了解T-ALL发展和复发的分子基础。为此，我在斑马鱼中完成了一项高度创新的筛选，以确定与T-ALL进展相关的基因，并发现蛋白质酪氨酸磷酸酶PRL-3在单个T-ALL细胞中通常被扩增，因为它们随着时间的推移形成复发的能力增强。在转基因动物中，PRL-3过表达显著促进了原发T-ALL的发展和复发的形成。我发现PRL-3在人类T-ALL的一个子集中扩增，并在大多数T-ALL患者样本中高度表达。通过诱导细胞凋亡，这些细胞对PRL-3基因敲除也很敏感。这些结果提示PRL-3活性在T-ALL恶性中起重要作用，PRL-3及其底物可能成为治疗T-ALL的新靶点。本研究的目的是1)明确PRL-3在T-ALL进展和复发中的作用，以及2)确定PRL-3驱动T-ALL恶性的机制。这一目标将通过两个具体目标来实现。在该奖项的K99阶段，我将完成目标1，在那里我将研究PRL-3功能获得和功能丧失在斑马鱼T-ALL发育的不同阶段的影响，包括胸腺入侵、血管内注入、增殖和复发，我还将在小鼠异种移植模型中测试PRL-3基因敲除对人类细胞的影响。在这个阶段，我将学习在活体动物中直接成像癌症进展的技术，以及在小鼠身上开发原位白血病异种移植的技术。有了这些知识，在R00阶段，我将完成目标2，在那里我将确定T-ALL细胞中PRL-3的目标底物，并使用体内和体外上位实验来测试这些基因和途径对T-ALL恶性肿瘤的贡献。总之，这项工作将为开发小分子PRL-3和潜在治疗T-ALL的途径抑制剂奠定基础。该奖项的指导阶段将在斑马鱼癌症模型专家David Langenau博士和白血病研究领域国际公认的领导者Thomas Look博士的指导下进行。他们可靠的指导记录，再加上马萨诸塞州总医院和哈佛医学院的研究社区提供的严格的教学内容和严谨而有益的学术环境，为我在过渡到成为一名独立研究员的过程中取得成功提供了最好的机会。