Molecular characterization and targeting of NT5C2 mutations in acute lymphoblastic leukemia

急性淋巴细胞白血病 NT5C2 突变的分子特征和靶向

• 批准号: 10221633
• 负责人: Adolfo A. Ferrando
• 金额: $ 38.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221633
• 关键词: 5' -Nucleotidase; 6-Mercaptopurine; Acute Lymphocytic Leukemia; Adopted; Adult Acute Lymphocytic Leukemia; Anabolism; Animal Model; Automobile Driving; Biological Assay; Catalysis; Cell model; Cells; Cessation of life; Characteristics; Chemoresistance; Childhood; Development; Disease; Disease Progression; Disease remission; Enzymes; Failure; Genes; Goals; Guanosine; Hematologic Neoplasms; In Vitro; Inosine; Lymphoid; Maintenance; Malignant - descriptor; Mediating; Metabolic; Molecular; Molecular Conformation; Mutation; Nucleotidases; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Protein Dephosphorylation; Proteins; Purines; Refractory; Relapse; Resistance; Rest; Role; Salvage Therapy; Structural Models; Structure; Testing; Therapeutic; biochemical model; chemotherapy; cytotoxic; exome sequencing; gain of function mutation; high risk; improved; in vitro activity; in vivo; inhibitor/antagonist; insight; leukemia; leukemia relapse; lymphoblast; mutant; novel therapeutic intervention; novel therapeutics; protein structure; relapse risk; response; small molecule; stem cells; targeted treatment; therapy resistant; thiopurine; treatment strategy; xanthosine; xanthosine monophosphate

Project Summary/Abstract Despite intensive chemotherapy, 20% of pediatric and over 50% of adult acute lymphoblastic leukemia (ALL) ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making relapse and resistance to therapy the most significant challenge in the treatment of this disease. This project seeks to dissect the structure and function of NT5C2, a cytosolic nucleotidase activated by gain of function mutations in about 45% of early relapse B-precursor ALL and 35% of early relapse T-ALL cases. NT5C2 mutations are characteristically associated with early relapse and progression under therapy and confer resistance to 6- mercaptopurine chemotherapy in vitro and in vivo. Our central hypothesis is that activating mutations in NT5C2 lock the NT5C2 protein in an active state either by forcing a constitutively active configuration similar to that induced by allosteric activators or via disruption of intramolecular switch off mechanisms responsible for returning the enzyme to its resting inactive state after activation. In this context, we will perform detailed structure-function analysis of NT5C2 mutant proteins to guide the development of new therapies for the treatment of relapse and refractory ALL.

项目总结/摘要 尽管进行了强化化疗，20%的儿童和超过50%的成人急性淋巴细胞白血病（ALL） ALL患者在强化化疗后未能达到完全缓解或复发， 并且对治疗的抗性是治疗这种疾病的最重要的挑战。本项目谋求 分析NT 5C 2的结构和功能，NT 5C 2是一种细胞溶质核苷酸酶，由细胞内的功能突变激活， 约45%的早期复发B前体ALL和35%的早期复发T-ALL病例。NT 5C 2突变是 特征性地与治疗下的早期复发和进展相关，并赋予对6-羟色胺的耐药性 巯基嘌呤化疗的体外和体内研究。我们的中心假设是，激活突变， NT 5C 2将NT 5C 2蛋白锁定在活性状态，或者通过迫使类似于 由变构激活剂诱导或通过破坏分子内关闭机制， 使酶在活化后返回其静止的非活性状态。在此背景下，我们将详细介绍 NT 5C 2突变蛋白的结构-功能分析，以指导新疗法的开发。 复发和难治性ALL的治疗。