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（由申请人提供）：复发性T细胞急性淋巴细胞白血病（T-ALL）的侵略性和不可预测性质代表了一个主要的临床挑战，这在很大程度上是由于高毒且无效的化学疗法。治疗的进一步进展将需要详细了解T-所有发育和复发的分子基础。为此，我在斑马鱼中完成了一个高度创新的筛选，以识别与T-All进展相关的基因，发现蛋白质酪氨酸磷酸酶PRL-3通常在单个T-ALL细胞中扩增，因为它们随着时间的推移而增强了复发的能力。在转基因动物中，PRL-3过表达显着增强了原发性T-ALL发育和复发形成。我发现PRL-3在人类T-ALL的一个子集中放大，并且大多数T-ALL患者样品都高度表达。这些细胞也对通过诱导细胞凋亡对敲击的prl-3敏感。这些结果表明，PRL-3活性在T-All恶性肿瘤中具有重要作用，并且PRL-3及其底物可能代表了T-All治疗的新型治疗靶标。该提案的目标是1）定义PRL-3对T-所有进展和复发的贡献，以及2）确定PRL-3驱动T-All恶性肿瘤的机制。这个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AIM 1，在那里我将研究Zebrafish T-All Development的PRL-3功能获得和功能丧失的影响，包括胸腺的入侵，侵入，增殖，增殖和复发，我还将测试PRL-3敲除对人类细胞Murine Xenoff in Murine Xeneroff模型的影响。在此阶段，我将学习直接成像活动物中癌症进展并发展小鼠的原位白血病的技术。借助此知识，在R00阶段，I将完成AIM 2，我将在T-ALL细胞中识别PRL-3的靶标底物，并使用体内和体外Epistasis实验测试这些基因的贡献以及T-ALL恶性肿瘤的贡献。总的来说，这项工作将奠定小分子PRL-3和途径抑制剂的基础，以在T-ALL中潜在的治疗用途。该奖项的指导阶段将在斑马鱼模型的专家David Langenau博士和白血病研究领域的国际认可领导者Thomas Look博士的指导下发生。他们的良好指导记录，再加上密集的教学成分以及马萨诸塞州综合医院和哈佛医学院研究界提供的严格而培养的学术环境，为我的成功提供了最佳机会，因为我过渡到成为独立研究员。