The overall goal of our research is to improve the diagnosis, care, and treatment of patients with bone marrow failure (BMF). One focus of our research is dyskeratosis congenita (DC), a rare inherited form of BMF associated with a classic triad of mucocutaneous features including abnormal pigmentation, dystrophic nail changes, and leukoplakia of the oral mucosa. Mutations in 6 different genes, all involved in the maintenance of telomeres, have been identified in patients with DC. During our last funding period we investigated the frequency, heritability, penetrance, and expressivity of mutations in TERC and in the telomerase catalytic subunit TERT in patients diagnosed with BMF and their families. Our studies identified small but distinctive populations of patients with BMF due to TERC or TERT gene mutations. Disease penetrance and expressivity were highly variable depending on the gene mutated, the nature of the mutation, and the number of generations the mutation had been inherited. Among patients with BMF the measurement of short telomeres in peripheral blood cells was found to be a sensitive though nonspecific method for identifying patients with DC. Our studies and those of other investigators have shown that patients with the classic clinical features of DC are only the "tip of the iceberg" of individuals who have BMF due to defective telomere maintenance. Because of these discoveries there is confusion and disagreement about the clinical significance of short telomeres and mutations in telomere maintenance genes. We hypothesize that premature senescence of hematopoietic stem cells is the basis of BMF in patients with DC and that the major cause of premature senescence is dysfunctional telomeres. In the proposed research we will longitudinally monitor telomere length in patients with BMF and mutations in DC associated genes and determine whether the rate of telomere shortening or telomere length correlates with the severity of BMF. We will investigate the functional consequences of newly identified sequence alterations in DC associated genes on telomerase activity at the telomere end and investigate the pathways that lead to short telomeres and premature senescence in primary cells from patients with the disease. We will test whether an increase in telomerase activity and/or antioxidants will delay the onset of senescence in the mutant cells. These proof-of-principle experiments may identify new treatment options for patients with DC and possibly other related conditions associated with BMF and cancer predisposition.

Public Health Relevance

The bone marrow produces blood cells that serve to fight infections, stop bleeding, and transport oxygen to tissues. Patients with inherited bone marrow failure syndromes (IBMFS) are unable to make sufficient numbers of blood cells, resulting in major disability and early death. Some of these patients have mutations in critical genes that determine the length and integrity of the chromosome end, known as the telomere. Classically these patients present with additional clinical manifestations, including alterations of the skin, white spots on the tongue and brittle fingernails, which led to the disease name, dyskeratosis congenita (DC). Our work and that of others has shown that mutations in these DC associated genes are much more frequent than originally presumed and that the majority of patients do not present with the classic associated manifestations. However, at the time of bone marrow failure (BMF) all patients with DC have short telomeres. There are multiple mechanisms that shorten the telomeres. They all cause cells to stop growing and to age prematurely. The proposed research will characterize the mechanisms that lead to short telomeres in patients with DC and test whether the inhibition of these mechanisms will improve cell growth and prevent or delay premature aging of these cells. These experiments will hopefully identify new treatments for patients with DC and possibly also for patients with other types of BMF.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Nelson, Stefanie A
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Children's Hospital of Philadelphia
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