Telomerase Activity and Telomere Length in APL: May Be Proliferative and Prognostic Markers.

Introduction: The telomeric DNA together with its associated proteins protects the chromosome ends from degradation or aberrant recombination. Telomerase and telomere are extensively investigated as potential diagnostic and prognostic markers in human tumors. In this study, we aim to investigate the significance of telomerase activity (TA) and telomere length (TL) in patients with acute promyelocytic leukemia (APL).

Methods: About 300 sequential peripheral blood mononuclear cell (PBMC) samples were collected from 40 patients with APL (32 newly diagnosed and 8 relapsed), at diagnosis, during and after therapy with Arsenic Trioxide. TA was assessed by TRAP-ELISA and -PAGE procedures. Terminal restriction fragment (TRF) length was determined by Southern blot analysis, using a Chemiluminescence-based assay. Quantification of PML-RARα/G6PDH transcripts was carried out by real-time PCR assay.

Results: About 90% of the APL patients had a significant reduction in TRF length (median 3.5, ranged 2.3 to 6.7 kbp) relative to the age-matched control or to that at the time of CR (median 11.37; ranged 8.90 to 14.70 kbp) from the same patients (P<0.0001). A significance positive correlation between telomere length and PML-RARα expression was found in the APL patients (P=0.001). In all the APL patients, telomerase activity was elevated in comparison with normal individuals (P<0.001). The telomerase activity levels were significantly higher in patients with short TRF. The group of patients with shortened TRF and elevated TA had a significantly poorer overall survival. The levels of TA were even significantly higher and the TL size difference of leukemic from non-leukemic was significantly longer in relapsed patients than patients with the primary APL.

Conclusion: Short telomere and high telomerase levels in the APL patients are mainly a consequence of extensive proliferative histories and they correlate with the disease progression. The shortened telomere length and the elevated telomerase activity may serve as prognostic factors for a subset of APL patients with more aggressive disease and poor outcome, and who may not respond favourably to arsenic therapy.