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

描述（由申请人提供）：Maria Monica Gramatges博士是贝勒医学院（Baylor College of Medicine）和德克萨斯儿童癌症中心的儿科助理教授。她目前支持K12补助金，并正在完成她的临床研究硕士学位。她的临床研究导师是Sharon Plon博士，一位领先的癌症遗传学家，她的基础科学导师是Alison Bertuch博士，一位领先的端粒生物学家。丽莎博士和博士迈克尔Andreeff，在临床试验设计和白血病分子生物学的教师专家，分别是她的顾问委员会。来自K23奖的支持将使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赠款的指导。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。在这个应用程序中，Gramatges博士正在研究端粒生物学的作用 急性髓性白血病（AML）和治疗相关毒性。端粒是位于染色体末端的重复DNA-蛋白质结构，其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和对基因组不稳定性的易感性增加。端粒生物学疾病，包括先天性角化不良，是由于端粒相关基因中的种系错义和截短序列突变，并与一系列问题相关，包括再生障碍性贫血和骨髓增生异常和AML的强烈易感性。这些序列变化也在患有恶性血液病的成人中富集，尽管没有研究探索它们与儿科AML或治疗毒性的关联。Gramatges博士已经产生了重要的初步数据，并在ESTA开发了合作，MD安德森癌症中心并通过儿童肿瘤学小组回答两个相关问题：（1）AML儿童携带短生殖系端粒和/或端粒酶相关基因中有害生殖系变异的比例，以及（2）端粒酶缺乏和/或端粒酶相关基因中有害生殖系变异的比例。或短端粒增加了持续骨髓抑制和端粒生物学紊乱特征的其它毒性的可能性。她将通过以下方式测试这些问题：（1）临床和功能表征端粒酶变体，并确定其在当地儿童AML队列中与对照组相比的频率;（2）回顾性比较骨髓恢复延迟与预期骨髓恢复的统一治疗的儿童AML患者中有害端粒酶变体和/或短端粒长度的比例，和（3）前瞻性地确定儿童和年轻成人AML患者化疗后有害的端粒酶变体和短端粒长度的发生率，并将这些结果与特定的治疗并发症相关联。目的3是第一个评价端粒生物学对AML毒性和结局影响的研究。这项研究的结果将支持未来与联合治疗研究相关的生物学工作，并可能导致筛查，更密切的毒性监测和治疗调整，从而降低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.