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Telomere Stability Is Frequently Impaired in High-Risk Groups of Patients with Myelodysplastic Syndromes¹

First Department of Internal Medicine, Tokyo Medical College, Tokyo 160-0023, Japan [J. H. O., H. I., N. Y., K. A., S. H., K. O.], and Department of Cell Biology and Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-9039 [J. W. S.]

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 in MDS patients, we compared telomere dynamics to the recently established International Prognostic Scoring System (IPSS) risk groups for MDS. We measured the terminal restriction fragments (TRFs) of 93 patients with MDS at the time of diagnosis, and telomerase activity was analyzed in 62 patients with MDS using the PCR-based telomeric repeat amplification protocol (TRAP) assay. A total of 53 of 93 MDS patients had TRFs within the age-matched normal range, and the remaining patients showed shortened TRFs (35 patients) or elongated TRFs (5 patients). MDS patients with shortened TRFs had a significantly low hemoglobin concentration (P = 0.04), a high percentage of marrow blasts (P = 0.02), and a high incidence of cytogenetic abnormalities (P < 0.05). The incidence of leukemic transformation was significantly high in patients with shortened TRF length (P < 0.05). In addition, patients with shortened 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 activity, suggesting that changes in TRF length rather than telomerase activity may more accurately reflect the pathophysiology of MDS. MDS patients with shortened TRF length had a very poor prognosis (P < 0.01), suggesting that telomere dynamics may be linked to clinical outcome in MDS patients. Thus, an abnormal mechanism of telomere maintenance in subgroups of MDS patients may be an early indication of genomic instability. This study demonstrates that telomere stability is frequently impaired in a high-risk group of MDS patients and suggests that, in combination with the IPSS classification system, measurement of TRFs may be useful in the future to stratify MDS patients according to risk and manage the care of MDS patients.

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