hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia - associations with immunophenotype and cytogenetic subgroup.

OBJECTIVE: Telomere maintenance, of importance for long term cell survival and malignant transformation, is directed by a multitude of factors including epigenetic mechanisms and has been implicated in the outcome for patients with leukemia. In the present study the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase (hTERT) gene in childhood acute lymphoblastic leukemia. PATIENTSANDMETHODS: A cohort of 169 childhood acute lymphoblastic leukemias (ALL) was investigated for telomere length, hTERT gene promoter methylation status, genomic aberrations, immunophenotype and clinical outcome. RESULTS: Methylation of the core promoter of the hTERT gene was demonstrated in 24 % of diagnostic samples, with a significant difference between B-cell precursor (n=130) and T- cell ALL (n=17) cases (18% and 72%, respectively, p< 0.001). No remission sample demonstrated hTERT promoter methylation (n= 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n=19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51-61 chromosomes) ALL (n=44) (63% and 7% respectively, p< 0.001). hTERT mRNA levels were negatively associated with methylation status and in the t(12;21) group methylated cases had shorter telomeres (p= 0.017). In low-risk B-cell precursor patients (n=101) long telomeres indicated a worse prognosis. CONCLUSIONS: The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups.