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.

项目概要/摘要 尽管进行了强化化疗，仍有 20% 的儿童和超过 50% 的成人患有急性淋巴细胞白血病 (ALL) ALL患者强化化疗后未能达到完全缓解或复发，导致复发 治疗耐药性是治疗这种疾病的最重大挑战。该项目旨在 剖析 NT5C2 的结构和功能，NT5C2 是一种通过功能获得突变激活的胞质核苷酸酶 约 45% 的早期复发 B 前体 ALL 病例和 35% 的早期复发 T-ALL 病例。 NT5C2突变是 与治疗下的早期复发和进展相关，并赋予对 6- 的耐药性 巯嘌呤化疗体外和体内。我们的中心假设是激活突变 NT5C2 通过强制形成类似于以下的组成型活性构型，将 NT5C2 蛋白锁定在活性状态： 由变构激活剂或通过破坏分子内关闭机制诱导的 激活后使酶恢复到其静止的非活性状态。在此背景下，我们将进行详细的 NT5C2突变蛋白的结构-功能分析指导新疗法的开发 治疗复发性和难治性 ALL。