hTERT expression in AML is heterogeneous and is of likely prognostic significance
Jordanides NE., Keith WN., Hills RK., Wheatley K., Luong QT., Burnett AK., Holyoake TL., Drummond MW.
Molecular events in AML (e.g. Flt3-ITD) may be exploited as prognostic indicators or therapeutic targets. The cancer- and stem/ progenitor cell-related enzyme telomerase is central to maintaining the immortal phenotype. We investigated whether levels of telomerase expression are of prognostic value in AML. Following validation of the assay in a range of telomerase positive and negative cell lines and tissues, 300 samples of archived peripheral blood MNC RNA (MRC AML12 study) were analysed blindly by Q-PCR (Light- Cycler) for hTERT (the catalytic component of telomerase). Internal QA utilised Q-PCR for the control gene PBGD. Only samples generating 4103 PBGD transcripts were analysed. Results were expressed as hTERT/PBGD transcripts (%) and as either hTERT positive or negative, or high, intermediate or low (43.2%, 40.7o 3.2, o0.7, respectively, according to levels detected in normal CD341 PBSC and PBL MNC, median of 3.2% and 0.7%, respectively) to facilitate statistical analysis. 1169 samples were analysed, with hTERT transcripts undetectable in 75 (hTERT range 0?255.9%, median 0.17%, mean 4.3%). When analysed on an hTERT-positive or negative basis, there was no correlation between hTERT levels and cytogenetic risk group, FAB subgroups, white cell count or age. Using multivariate regression analysis, adjusted for the known prognostic factors (as previous, plus performance status), there was no evidence of differences in CR rate (OR 1.14, 95%CI 0.43?3.02, p50.8), but borderline evidence of worse overall survival (OS) and disease-free survival (DFS) among hTERT positive patients (5 year OS: 39% vs 53% HR 1.54 (95%CI 0.97?2.45), p50.07; 5 year DFS: 42% vs 54% HR 1.62 (95%CI 0.96?2.74), p50.07). Classifying hTERT as high, intermediate or low, 5 year OS was 34%, 50% and 47% (p50.5 for trend). hTERT expression in AML is heterogeneous and may be of prognostic significance. Larger studies are required to investigate further these findings.