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.

Public Health Relevance

Acute myeloid leukemia (AML), comprising 20% of childhod leukemias, is treated with very intensive chemotherapy that results in moderate to severe treatment-related toxicities in 80% of patients, a proportion of which do not survive therapy. Our research studies genetic markers that characterize the subpopulation of children with AML who are at risk for severe treatment-related toxicities. Validation of these markers may lead to implementation of upfront screening of children with newly diagnosed AML, and, in cases where a mutation is discovered, a modified treatment regimen with closer monitoring of at-risk organ function in order to reduce the relatively high rates of treatment-related morbidity and mortality in this disease. ! ! ! !

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Subcommittee G - Education (NCI)
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Ojeifo, John O
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Baylor College of Medicine
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Gerbing, Robert B; Alonzo, Todd A; Sung, Lillian et al. (2016) Shorter Remission Telomere Length Predicts Delayed Neutrophil Recovery After Acute Myeloid Leukemia Therapy: A Report From the Children's Oncology Group. J Clin Oncol 34:3766-3772
Bainbridge, Matthew N; Armstrong, Georgina N; Gramatges, M Monica et al. (2015) Germline mutations in shelterin complex genes are associated with familial glioma. J Natl Cancer Inst 107:384
Jalali, Ali; Amirian, E Susan; Bainbridge, Matthew N et al. (2015) Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium. Sci Rep 5:8278
Gramatges, Maria M; Liu, Qi; Yasui, Yutaka et al. (2014) Telomere content and risk of second malignant neoplasm in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Clin Cancer Res 20:904-11
Gramatges, Maria M; Bertuch, Alison A (2013) Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy. Transl Res 162:353-63
Gramatges, M Monica; Rabin, Karen R (2013) The adolescent and young adult with cancer: state of the art-- acute leukemias. Curr Oncol Rep 15:317-24
Gramatges, Maria M; Qi, Xiaodong; Sasa, Ghadir S et al. (2013) A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome. Blood 121:3586-93