Progressive Telomere Shortening in Aplastic Anemia

Abstract

Improved survival in aplastic anemia (AA) has shown a high incidence of late clonal marrow disorders. To investigate whether accelerated senescence of hematopoietic stem cells might underlie the pathophysiology of myelodysplasia (MDS) or paroxysmal nocturnal hemoglobinuria (PNH) occurring as a late complication of AA, we studied mean telomere length (TRF) in peripheral blood leukocytes from 79 patients with AA, Fanconi anemia, or PNH in comparison with normal controls. TRF lengths in the patient group were significantly shorter for age than normals (P < .0001). Telomere shortening was apparent in both granulocyte and mononuclear cell fractions, suggesting loss at the level of the hematopoietic stem cell. In patients with acquired AA with persistent cytopenias (n = 40), there was significant correlation between telomere loss and disease duration (r = −.685; P < .0001), equivalent to progressive telomere erosion at 216 bp/yr, in addition to the normal age-related loss. In patients who had achieved normal full blood counts (n = 20), the rate of telomere loss had apparently stabilised. There was no apparent association between telomere loss and secondary PNH (n = 13). However, of the 5 patients in the study with TRF less than 5.0 kb, 3 had acquired cytogenetic abnormalities, suggesting that telomere erosion may be relevant to the pathogenesis of MDS in aplastic anemia.

Accelerated telomere shortening and telomerase activation in Fanconi's anaemia

“…A correlation between telomere length (or shortening rate) and severity of pancytopenia -but not with bone marrow clonal anomaly -was also observed. These results complement a previously published report showing decreased telomere length in a heterogenous group of patients with aplastic anaemia, including six with FA (Ball et al, 1998).…”

An update on the management of severe idiopathic aplastic anaemia in children

“…Haematopoietic stem cells, which must retain proliferative capacity, maintain telomere integrity via the telomerase ribonucleoprotein complex consisting of telomerase reverse transcriptase (TERT) and its integral RNA template (TERC). Abnormal telomere shortening in haematopoietic cells occurs in some patients with idiopathic AA (Ball et al, 1998). Telomere shortening is consistent with the concept of haematopoietic progenitor cell exhaustion, and suggests that defective telomerase maintenance might have a role in the aetiology of sAA.…”

Accelerated telomere shortening in Fanconi anemia fibroblasts – a longitudinal study

“…This explanation might be valid for a whole category of diseases, such as acquired aplastic anemias, in which telomere shortening could be demonstrated [18]. FA, however, is an inherited disease characterized by chromosomal instability.…”