The role of telomere biology in bone marrow failure and other disorders

Abstract

Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest-lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis. The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients be categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.

Figure 1. Telomere lengths in inherited bone marrow failure syndromes

Telomere lengths in lymphocytes were determined by multi-color flow-FISH. Telomere lengths determined on 400 healthy subjects from newborn to 100 years of age were used to determine the normal range. The top line represents the 99th %ile and the bottom line represents the 1st %ile. This figure was derived from previously published data (Alter et al. 2007). A: Telomere lengths in Dyskeratosis Congenita (DC). Red circles indicate patients with DC. Green triangles indicate the Hoyeraal-Hreidarsson Syndrome (HH) and light blue diamonds indicate the Revesz Syndrome (RS) variants of DC. Dark blue squares are silent carriers of gene mutations who remain clinically asymptomatic. B: Telomere lengths in Fanconi Anemia (FA). Red circles indicate patients with FA. The dark blue circle is a patient with FA who underwent bone marrow transplantation. Mosaic FA patients are noted with the light blue circle. C: Telomere lengths in Shwachman Diamond Syndrome. D: Telomere lengths in Diamond Blackfan Anemia.