Accelerated telomere shortening and telomerase activation in Fanconi's anaemia

Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure that often evolves towards acute leukaemia, FA also belongs to a group of chromosome instability diseases. Because tel omeres are directly involved in chromosomal stability and in cell prolifera tion capacity, we examined telomere metabolism in peripheral blood mononucl ear cells (PBMC). Telomere length was significantly shorter in 54 FA patien t samples, compared to 51 controls (P < 0.0001). In addition, mean telomere terminal restriction fragment lengths (TRF) in nine heterozygous patient s amples did not differ from those of controls. In 14 samples from FA patient s with severe aplastic anaemia (SFA), telomere length was significantly sho rter than in 22 samples of age-matched FA patients with moderate haematolog ical abnormalities (NSFA) (P < 0.001). However, no correlation was found be tween TRF length and the presence of bone marrow clonal abnormalities in 16 additional, separately analysed, patient samples. Sequential measurement o f TRF in six FA patients showed an accelerated rate of telomere shortening. Accordingly, telomere shortening rate was inversely correlated with clinic al status. Telomerase, the enzyme that counteracts telomere shortening, was 4.8-fold more active in 25 FA patients than in 15 age-matched healthy cont rols, A model for the FA disease process is proposed.