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

描述(由申请人提供)：玛丽亚·莫妮卡·格拉马吉斯博士是贝勒医学院(BCM)和德克萨斯州儿童癌症中心的儿科学助理教授。她目前获得了K12助学金，正在完成临床调查硕士学位。她的临床研究导师是领先的癌症遗传学家莎伦·普隆博士，她的基础科学导师是领先的端粒生物学家艾莉森·贝尔图赫博士。丽莎·邦加尔斯博士和迈克尔·安德里夫博士分别是临床试验设计和白血病分子生物学方面的教职专家，他们是她的顾问委员会的成员。K23奖项的支持将使Gramatges博士在执行她的研究项目时获得更多的研究技能，并在撰写出版物和开发研究拨款方面获得指导。Gramatges博士的目标是成为儿科肿瘤学转化性研究的独立研究员和领导者。在这项应用中，Gramatges博士正在研究端粒生物学的作用 在急性髓细胞白血病(AML)和治疗相关的毒性中。端粒是位于染色体末端的重复的DNA-蛋白质结构，保护染色体的完整性。端粒随着DNA的复制而缩短，导致细胞对化学药物的敏感性增加，对基因组不稳定的敏感性增加。端粒生物学疾病，包括先天性角化不良，是由于端粒酶相关基因的胚系错义和截断序列突变引起的，并与一系列问题有关，包括再生障碍性贫血和骨髓发育不良和急性髓细胞白血病的强烈易感性。这些序列变化在患有恶性血液病的成人中也很丰富，尽管还没有研究探讨它们与儿童急性髓细胞白血病或治疗毒性的关系。Gramatges博士生成了重要的初步数据，并通过BCM、MD Anderson癌症中心和儿童肿瘤学小组开展了合作，以回答两个相关问题：(1)患有AML的儿童中，有多大比例的儿童存在端粒酶相关基因中的短生殖线端粒和/或有害的生殖线变异；(2)端粒酶缺乏和/或端粒短是否会增加出现持续性骨髓抑制和其他端粒生物学紊乱所特有的毒性的可能性。她将通过以下方式测试这些问题：(1)临床和功能鉴定端粒酶变异，并确定其在儿童AML局部队列中的频率，与对照组进行比较；(2)回顾性比较接受统一治疗的儿童AML患者中有害端粒酶变异和/或端粒短长度的比例，这些患者的骨髓恢复延迟于预期；以及(3)前瞻性确定儿童和年轻AML患者化疗后有害端粒酶变异和端粒短长度的发生率，并将这些结果与特定治疗并发症相关联。目的3是第一个评估端粒生物学对急性髓细胞白血病毒性和预后影响的研究。这项研究的结果将支持未来关于与联合治疗研究相关的生物学研究的工作，并可能导致筛查、更密切的毒性监测和治疗改进，从而降低与AML治疗相关的发病率和死亡率。

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.