Short Telomeres Combined with Low Telomerase Activity Are Associated with a Longer Survival in Patients with Acute Myeloid Leukemia.

Abstract

Telomeres - the terminal regions of human chromosomes, and enzyme telomerase - a ribonucloprotein that synthesizes telomeric DNA onto chromosomal ends, have been thoroughly investigated as potential markers for the prognosis of various cancers including leukemia. However, it is important to consider both parameters and only few studies have investigated the prognostic value of these two combined biomarkers in patients with acute myeloid leukemia (AML). Our work was designed to determine the impact of telomere length together with telomerase activity (TA) on survival in patients with AML. In this current retrospective study, TA (reflected by the quantitative expression of the catalytic subunit of telomerase i.e the hTERT mRNA/18s RNA ratio measured by Q-RT-PCR) and telomere length (determined by southern blot analysis of terminal restriction fragments) were assayed in the bone marrow of 40 patients diagnosed with AML between 1999 and 2003 at Institute Gustave Roussy's division of Hematology. The patients' characteristics are shown on table 1. All patients were treated according to standard AML-type chemotherapy protocols. The median of TA (hTERT mRNA/18s RNA ratio) was 0.0458. TA was not detectable in 4 patients. The median of telomere length was 7.6 Kb (range: 3.5–11.2 Kb). No correlation was found between TA and telomere length. A negative correlation existed between telomere length and age (r= −0.42; p=0.0097). The Kaplan-Meier statistical method and logrank test were used for univariate survival analysis and the Cox proportional hazard regression models for multivariate survival analysis. In multivariate analysis, when adjusted for age (>= 50 years versus younger), cytogenetics findings (poor prognosis versus others) and the nature of leukemia (secondary versus de novo), improved survival was found in patients with a combination of short telomere length (<7.6 Kb) and weak TA (<0.09, cut off point separating the upper tertile) and the worse survival was found in patients with long telomere length (>=7.6 Kb) and high TA (>=0.09) (hazard ratio=9.91; 95% CI: 1.75–56.03; p=0.01). Our results suggest that the combination of telomere length and telomerase activity can be considered as an independent prognostic factor for survival in patients with AML.Table 1:Patients characteristicsSex (no. of patients)M18F22Age (years)Median50Range22–74Leukocyte count (Giga/L)Median24.2Range1.3–360Bone marrow blast percentageMedian76.5Range20–99FAB Classification (no. of patients)M06M19M25M4–M512M4Eo3M61Biphenotypic AL3NK AML1Type of leukemia (no. of patients)De novo31Secondary9*Prognosis (based on karyotype)Good5Intermediate21Poor10Missing4* AML post solid tumor (n=7), post myelodysplastic syndrome (n=1), post chronic myeloid leukemia (n=1)