Telomeres are essential for the maintenance of genomic integrity. Dyskeratosis congenita (DC) is a cancer- prone syndrome characterized by short telomeres. Affected patients have an increased risk for developing hematologic malignancies, specifically myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While DC is an inherited Mendelian disorder, germline mutations in telomerase and telomere components are identifiable in only two-thirds of families, leaving the causal mutations in the remaining cases uncharacterized. Mutations in DC genes also underlie inheritance in a subset of MDS and AML families. This fact, along with the observation that MDS-AML patients have short telomeres, has suggested an intimate role for telomere length in the genetics of these disorders. This project examines two aspects of DC genetics and biology of relevance to understanding MDS-AML pathogenesis.
We aim to identify novel genes that are critical for telomere maintenance by studying genetically uncharacterized DC families in a registry we have established. Given the known limitations of traditional linkage approaches in small kindreds, the cohort we have compiled provides an ideal setting to apply next-generation sequencing technologies for the purpose of gene discovery.
In Aim 2, we examine the biology by which short telomeres promote MDS-AML in an animal model of DC we have characterized. This murine model uniquely recapitulates human telomere length dynamics. The proposed studies in DC have particular significance for understanding the biology of MDS-AML since the telomere defect found in DC patients is universally acquired with aging, and the biology that underlies the increasing incidence of MDS-AML with age is not understood. Broadly, they have implications for understanding fundamental questions regarding the role of telomere length in cancer risk and progression.

Public Health Relevance

This proposal aims to understand the genetics that predispose to myelodysplastic syndromes and acute myeloid malignancies. Both disorders account for as many as 20,000 deaths in the United States alone and treatment options are limited and toxic. Our goal is to improve the understanding of the inherited factors that predispose to these disorders with aging with the goal of improving their prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160433-03
Application #
8609555
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$302,535
Indirect Cost
$115,785
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Armanios, Mary (2013) Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest 123:996-1002
Alder, Jonathan K; Parry, Erin M; Yegnasubramanian, Srinivasan et al. (2013) Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum Mutat 34:1481-5
Jonassaint, Naudia L; Guo, Nini; Califano, Joseph A et al. (2013) The gastrointestinal manifestations of telomere-mediated disease. Aging Cell 12:319-23