Germline Telomere Biology Defects in Pediatric and Young Adult Acute Myeloid Leuk

儿科和年轻人急性髓系白血病的种系端粒生物学缺陷

• 批准号: 8547788
• 负责人: Maria Monica Gramatges
• 金额: $ 16.86万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547788
• 关键词: Acute; Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Adverse event; Advisory Committees; Aplastic Anemia; Basic Science; Biological; Biological Assay; Biology; Bone Marrow; Bone Marrow Suppression; Cancer Center; Characteristics; Child; Childhood; Childhood Acute Myeloid Leukemia; Children' s Oncology Group; Chromosomes; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; DNA; DNA biosynthesis; Data; Defect; Diagnostic; Disease; Disease remission; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Enrollment; Exposure to; Faculty; Fibroblasts; Frequencies; Future; Genes; Genetic Markers; Genetic Variation; Genome Stability; Genomic Instability; Goals; Grant; Hematologic Neoplasms; Hematopoietic; Hepatic; In Vitro; Incidence; Lead; Length; Longevity; Lung; Lymphocyte; Malignant Neoplasms; Marrow; Master' s Degree; Measures; Medical Records; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Modification; Molecular; Molecular Biology; Monitor; Morbidity - disease rate; Mutation; Myelogenous; Neutropenia; Newly Diagnosed; Oncology Group; Organ; Outcome; Patients; Pediatric Oncology; Pediatrics; Phase; Population; Population Control; Population Database; Predisposition; Protocols documentation; Publications; Recovery; Relative (related person); Remission Induction; Research; Research Personnel; Research Project Grants; Risk; Role; SECTM1 gene; Sampling; Scientist; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; Texas; Therapy-Related Acute Myeloid Leukemia; Tissues; Toxic effect; Training; Translational Research; Treatment Protocols; Validation; Variant; Whole Blood; Work; chemotherapy; cohort; college; design; leukemia; mortality; professor; protein structure; research study; screening; skills; telomere; toxicity characteristics; young adult

DESCRIPTION (provided by applicant): Dr. Maria Monica Gramatges is an Assistant Professor of Pediatrics at Baylor College of Medicine (BCM) and Texas Children's Cancer Center. She is currently supported on a K12 grant and is completing her Master's degree in Clinical Investigation. Her Clinical Research Mentor is Dr. Sharon Plon, a leading cancer geneticist, and her Basic Science Mentor is Dr. Alison Bertuch, a leading telomere biologist. Dr. Lisa Bomgaars and Dr. Michael Andreeff, faculty experts in clinical trial design and leukemia molecular biology, respectively, are on her advisory committee. Support from the K23 award will enable Dr. Gramatges to gain additional research skills and receive mentorship in authoring publications and developing research grants while performing her research project. Dr. Gramatges' goal is to become an independent investigator and leader in pediatric oncology translational research. In this application, Dr. Gramatges is studying the role of telomere biology in acute myeloid leukemia (AML) and treatment-related toxicities. Telomeres are repetitive DNA-protein structures at chromosome ends which protect chromosome integrity. Telomeres shorten with DNA replication, causing increasing cellular chemosensitivity and susceptibility to genomic instability. Telomere biology disorders, including dyskeratosis congenita, are due to germline missense and truncating sequence mutations in telomerase-associated genes and are associated with a spectrum of problems including aplastic anemia and a strong predisposition for myelodysplasia and AML. These sequence changes are also enriched in adults with hematologic malignancies, though no studies have explored their association with pediatric AML or treatment toxicities. Dr. Gramatges has generated significant preliminary data and developed collaborations at BCM, MD Anderson Cancer Center and through the Children's Oncology Group to answer two related questions (1) what proportion of children with AML harbor short germline telomeres and/or deleterious germline variants in telomerase-related genes and (2) does telomerase deficiency and/or short telomeres increase the likelihood of persistent bone marrow suppression and other toxicities characteristic of telomere biology disorders. She will test these questions by (1) clinically and functionally characterizing telomerase variants and determining their frequency in a local cohort of pediatric AML compared to controls (2) retrospectively comparing the proportion of deleterious telomerase variants and/or short telomere length in uniformly-treated pediatric AML patients with delayed vs. expected bone marrow recovery, and (3) prospectively determining the incidence of deleterious telomerase variants and short telomere length following chemotherapy in pediatric and young adult AML patients and correlating these results with specific treatment complications. Aim 3 is the first study to evaluate the effects of telomere biology on toxicities and outcomes in AML. Results of this research will support future work on a biological correlate to a consortium treatment study, and may result in screening, closer toxicity monitoring, and therapy modification, thereby reducing AML treatment-related morbidity and mortality.

描述（由申请人提供）：Maria Monica Gramatges 博士是贝勒医学院 (BCM) 和德克萨斯儿童癌症中心的儿科助理教授。她目前获得 K12 助学金的支持，并正在完成临床研究硕士学位。她的临床研究导师是领先的癌症遗传学家 Sharon Plon 博士，她的基础科学导师是领先的端粒生物学家 Alison Bertuch 博士。 Lisa Bomgaars 博士和 Michael Andreeff 博士分别是临床试验设计和白血病分子生物学领域的专家，也是她的顾问委员会成员。 K23 奖项的支持将使 Gramatges 博士能够获得额外的研究技能，并在执行研究项目的同时获得撰写出版物和开发研究资助的指导。 Gramatges 博士的目标是成为儿科肿瘤转化研究的独立研究者和领导者。在此应用中，Gramatges 博士正在研究端粒生物学的作用 急性髓系白血病（AML）和治疗相关毒性。端粒是染色体末端的重复 DNA 蛋白质结构，可保护染色体的完整性。端粒随着 DNA 复制而缩短，导致细胞化学敏感性增加和对基因组不稳定性的敏感性增加。端粒生物学疾病，包括先天性角化不良，是由种系错义和端粒酶相关基因的截短序列突变引起的，并与一系列问题相关，包括再生障碍性贫血以及骨髓增生异常和 AML 的强烈易感性。这些序列变化在患有血液系统恶性肿瘤的成人中也很丰富，但没有研究探讨它们与儿科 AML 或治疗毒性的关联。 Gramatges 博士已生成重要的初步数据，并与 BCM、MD 安德森癌症中心以及儿童肿瘤学小组开展合作，以回答两个相关问题 (1) 患有 AML 的儿童中，有多少比例的 AML 儿童在端粒酶相关基因中存在短种系端粒和/或有害种系变异，以及 (2) 端粒酶缺陷和/或短端粒是否会增加骨髓持续存在的可能性 端粒生物学疾病的抑制和其他毒性特征。她将通过以下方式测试这些问题：(1) 临床和功能上表征端粒酶变异，并确定其在当地儿科 AML 队列中与对照组相比的频率；(2) 回顾性比较接受统一治疗的骨髓恢复延迟与预期骨髓恢复的儿科 AML 患者中有害端粒酶变异和/或短端粒长度的比例；(3) 前瞻性确定有害端粒酶变异和/或短端粒长度的发生率。 研究儿童和年轻成人 AML 患者化疗后的端粒酶变异和端粒长度缩短，并将这些结果与特定的治疗并发症相关联。 Aim 3 是第一项评估端粒生物学对 AML 毒性和结果影响的研究。这项研究的结果将支持未来与联合治疗研究的生物学相关性的工作，并可能导致筛查、更密切的毒性监测和治疗修改，从而降低 AML 治疗相关的发病率和死亡率。