Bone marrow failure and the telomeropathies.
Blood. 2014 Sep 18;
Authors: Townsley DM, Dumitriu B, Young NS
Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and acquired disease is not so clearly delineated, as lesions in some genetic pathways cause stereotypical childhood syndromes and also act as risk factors for development of clinical manifestations in adult life. Dyskeratosis congenita and the telomere diseases are a prominent example of this relationship. Accelerated telomere attrition is the result of mutations in telomere repair genes and in genes encoding components of the shelterin complex and related proteins. Genotype-phenotype correlations show genes responsible for X-linked (DKC1) and severe recessive childhood dyskeratosis congenita (NOP10, TINF), typically with associated mucocutaneous features, and others (TERC, TERT) for more subtle presentation as telomeropathy in adults, in which multiorgan failure may be prominent. Telomerase mutations also are etiologic in familial pulmonary fibrosis and cryptic liver disease. Detection of a telomere disease requires awareness in the clinic, appropriate laboratory testing of telomere content, and genetic sequencing. In treatment decisions, genetic screening of related donors for hematopoietic stem cell transplantation is critical, and androgen therapy may be helpful. Telomeres shorten normally with aging as well as under environmental circumstances with regenerative stress and oxidative damage. Telomere biology is complexly related to oncogenesis: telomere attrition is protective by enforcing senescence or apoptosis in cells with a long mitotic history, but telomere loss also can destabilize the genome by chromosome re-arrangement and aneuploidy. Basic laboratory experiments, animal models, genome wide surveys, clinical studies of specific diseases, and population-based epidemiology link accelerated telomere attrition and cancer, including in constitutional and acquired aplastic anemia.
PMID: 25237198 [PubMed - as supplied by publisher]