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 尽管进行了强化化疗，但有20％的小儿和超过50％的成人急性淋巴细胞白血病（全部） 所有患者在加强化疗后无法完全缓解或复发，使复发 抗药性是治疗该疾病的最重大挑战。这个项目试图 剖析NT5C2的结构和功能，NT5C2，一种通过功能突变激活的胞质核苷酸酶 早期复发的早期复发中，大约有45％的全部和35％的早期复发t-all病例。 NT5C2突变是 在治疗下的早期复发和进展方面具有特殊性，并赋予6-- 体外和体内胃嘌呤化学疗法。我们的中心假设是激活突变 NT5C2通过强迫组成性主动构型与类似 变构激活剂或通过破坏分子开关的破坏机制引起的 激活后将酶返回其静止状态。在这种情况下，我们将执行详细 NT5C2突变蛋白的结构功能分析，以指导开发新疗法 治疗复发和难治性。