Progressive telomere shortening in aplastic anemia.
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.
Ball
S E
SE
Division of Haematology, Department of Cellular and Molecular Sciences, St George's Hospital Medical School, London, UK.
Gibson
F M
FM
Rizzo
S
S
Tooze
J A
JA
Marsh
J C
JC
Gordon-Smith
E C
EC
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000741:Anemia, Aplastic / Q000097:blood / Q000235:genetics*; D001772:Blood Cell Count; D001853:Bone Marrow / Q000473:pathology; D002455:Cell Division; D002648:Child; D018450:Disease Progression; D005199:Fanconi Anemia / Q000097:blood / Q000235:genetics; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000209:etiology / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis; D012306:Risk; D016615:Telomere / Q000648:ultrastructure*