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.

描述（由申请人提供）：Maria Monica Gramatges博士是贝勒医学院（BCM）和德克萨斯州儿童癌症中心的儿科助理教授。目前，她获得了K12赠款的支持，并正在完成临床调查的硕士学位。她的临床研究导师是领先的癌症遗传学家莎朗·普隆（Sharon Plon）博士，她的基础科学指导者是领先的端粒生物学家艾莉森·伯图奇（Alison Bertuch）博士。 Lisa Bomgaars博士和临床试验设计教师专家Michael Andreeff博士分别在她的咨询委员会任职。 K23 Award的支持将使Gramatges博士能够获得更多的研究技能，并在执行研究项目的同时获得创作出版物和开发研究赠款的指导。 Gramatges博士的目标是成为小儿肿瘤学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 在急性髓样白血病（AML）和与治疗相关的毒性中。端粒是染色体末端的重复DNA蛋白结构，可保护染色体完整性。端粒复制缩短，导致细胞化学敏感性增加和对基因组不稳定性的敏感性。端粒生物学疾病，包括症状症状，是由于端粒酶相关基因中的种系错线和截断序列突变引起的，并且与包括性障碍性贫血在内的一系列问题有关，以及骨髓增生性肿瘤和AML的强烈易感性。这些序列变化也富含血液学恶性肿瘤的成年人，尽管没有研究探讨了他们与儿科AML或治疗毒性的关联。 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端粒生物学疾病的抑制和其他毒性特征。 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端粒酶变体和小儿AML患者化学疗法后的端粒变体和短端粒长度，并将这些结果与特定的治疗并发症相关联。 AIM 3是评估端粒生物学对AML毒性和结果的影响的第一项研究。这项研究的结果将支持与财团治疗研究的生物学相关的未来工作，并可能导致筛查，近距离毒性监测和修饰，从而降低与AML治疗相关的发病率和死亡率。