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: 9750649
• 负责人: Adolfo A. Ferrando
• 金额: $ 37.12万
• 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/9750649
• 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; 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; Stem cells; Structural Models; Structural Protein; 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; lymphoblast; mutant; novel therapeutics; protein structure; relapse risk; response; small molecule; 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.

项目摘要/摘要 尽管进行了密集化疗，20%的儿童和超过50%的成人急性淋巴细胞白血病(ALL) 所有患者在强化化疗后未能达到完全缓解或复发，导致复发。 而抵抗治疗是治疗这种疾病最大的挑战。这一项目旨在 解剖NT5C2的结构和功能，NT5C2是一种由基因功能突变获得激活的胞质核苷酸酶 约45%的早期复发B-前体ALL和35%的早期复发T-ALL病例。NT5C2突变是 与治疗中的早期复发和进展有关，并使人对6-羟色胺产生耐药性 体外和体内的巯基嘌呤化疗。我们的中心假设是激活基因突变 NT5C2将NT5C2蛋白锁定在活性状态，方法是强制使用类似于 由变构激活剂或通过破坏分子内开关机制引起的 激活后使酶回到静止的非活性状态。在此背景下，我们将详细执行 分析NT5C2突变蛋白的结构与功能，以指导新药的开发 复发和难治性急性淋巴细胞白血病的治疗。