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: 8721725
• 负责人: Maria Monica Gramatges
• 金额: $ 16.88万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721725
• 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; 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; 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; genetic variant; 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.

简介（由申请人提供）：Maria Monica Gramatges博士是贝勒医学院（BCM）和德克萨斯州儿童癌症中心的儿科助理教授。她目前在K12资助下获得支持，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方面的专家，也是她的顾问委员会成员。K23奖的支持将使Gramatges博士获得额外的研究技能，并在执行她的研究项目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学转化研究的独立研究者和领导者。在这个应用中，Gramatges博士正在研究端粒生物学的作用