Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes

Genomic instability induces an accumulation of genetic changes and may play a role in the pathogenesis of myelodysplastic syndromes (MDS), To clarify the possible association between genomic instability and clinical outcome i n MDS patients, we compared telomere dynamics to the recently established I nternational Prognostic Scoring System (IPSS) risk groups for MDS, We measu red the terminal restriction fragments (TRFs) of 93 patients with MDS at th e time of diagnosis, and telomerase activity was analyzed in 62 patients wi th MDS using the PCR-based telomeric repeat amplification protocol (TRAP) a ssay. A total of 53 of 93 MDS patients had TRFs within the age-matched norm al range, and the remaining patients showed shortened TRFs (35 patients) or elongated TRFs (5 patients). MDS patients with shortened TRFs had a signif icantly low hemoglobin concentration (P = 0.04), a high percentage of marro w blasts (P = 0.02), and a high incidence of cytogenetic abnormalities (P < 0.05), The incidence of leukemic transformation,vas significantly high in patients with shortened TRF length (P < 0.05). In addition, patients with s hortened TRF length were frequently seen in the IPSS high-risk group (P < 0 .01), Most of the MDS patients had normal-to-low levels of telomerase activ ity, suggesting that changes in TRF length rather than telomerase activity may more accurately reflect the pathophysiology of MDS, MDS patients with s hortened TRP length had a very poor prognosis (P < 0.01), suggesting that t elomere dynamics may be linked to clinical outcome in MDS patients. Thus, a n abnormal mechanism of telomere maintenance in subgroups of MDS patients m ay be an early indication of genomic instability. This study demonstrates t hat telomere stability is frequently impaired in a high-risk group of MDS p atients and suggests that, in combination with the IPSS classification syst em, measurement of TRFs may be useful in the future to stratify MDS patient s according to risk and manage the care of MDS patients.