PROGRESSIVE TELOMERE SHORTENING IN APLASTIC-ANEMIA

Improved survival in aplastic anemia (AA) has shown a high incidence o f late clonal marrow disorders. To investigate whether accelerated sen escence 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 lengt h (TRF) in peripheral blood leukocytes from 79 patients with AA, Fanco ni anemia, or PNH in comparison with normal controls. TRF lengths in t he patient group were significantly shorter for age than normals (P < .0001), Telomere shortening was apparent in both granulocyte and monon uclear cell fractions, suggesting loss at the level of the hematopoiet ic 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 tel omere 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 acqu ired cytogenetic abnormalities, suggesting that telomere erosion may b e relevant to the pathogenesis of MDS in aplastic anemia. (C) 1998 by The American Society of Hematology.