Elevated Telomerase Activity Research Articles

Telomerase activity and the expression of telomerase components in acute myelogenous leukaemia.

In 95 leukaemic cell samples from 66 patients with acute myelogenous leukaemia (AML) (47 de novo and 19 secondary AML) telomerase activity was determined and the expression of the telomerase components: telomerase reverse transcriptase (hTERT), telomerase RNA template (hTR) and telomerase-associated protein (TP1) evaluated by RT-PCR. Compared to peripheral blood mononuclear cells (PBMC) from normal adult 87% (82/95) of patient samples exhibited elevated telomerase activity hTERT, but not hTR and TP1 expression strongly correlated with the levels of telomerase activity (r=0.47, P<0.0001). The levels of telomerase activity were significantly higher at time of relapse or progression than at time of diagnosis (P=0.003), and correlated to CD34 expression and chromosomal abnormalities of leukaemic cells (P=0.01 and P=0.001 respectively). The rate and duration of complete remission (CR) did not correlate with the levels of telomerase activity at diagnosis. Among eight patients in first relapse, however, two of three with low levels of telomerase activity re-entered CR. whereas none of five patients with high telomerase activity achieved a second CR. Taken together, telomerase activation/up-regulation in AML is a disease progression-associated event. Undifferentiated status and chromosomal aberration also lead to the up-regulation of telomerase activity in AML.

Elevated levels of telomerase activity in malignant pheochromocytoma

Although malignant pheochromocytoma is a life-threatening illness, there is no excretory profile that is predictive of malignancy. Reliable prediction of malignant behavior on the basis of histopathology is also notoriously difficult. Although DNA ploidy can be a helpful indicator, aneuploidy per se is not considered to be a specific marker of malignancy. Mutations in p53 have been reported to occur frequently in cases of benign pheochromocytoma. Thus, molecular analysis of this protein is not a useful diagnostic tool. The authors analyzed telomerase activity in benign and malignant pheochromocytomas and assessed its utility as a prognostic marker. Telomerase activity was estimated in 16 benign pheochromocytomas, 3 malignant pheochromocytomas, and 16 normal adrenal medullae by the fluorescence-based telomeric repeat amplification protocol. The telomerase activities of each group of samples were compared. No telomerase activity was detected in any of the normal adrenal medullae or the benign pheochromocytomas. By contrast, all of the three malignant pheochromocytomas had elevated telomerase activity. The telomerase activity in each tumor was determined to be 87.6 units, 71.2 units, and 180.3 units, respectively. The expression of telomerase activity in pheochromocytoma clearly suggests the malignant behavior of the component cells. Analysis of telomerase activity appears to be a powerful tool for the diagnosis of malignant pheochromocytoma.

Immortalized mouse mammary cells in vivo do not exhibit increased telomerase activity.

The acquisition of immortalization is an early and carefully documented event in mouse mammary tumorigenesis. Activation of telomerase activity is one hypothesis to explain the acquisition of immortalization. We examined the activity of telomerase in well-defined immortalized, non-tumor cell populations of mouse mammary tissue in vivo. The results indicated that normal virgin and mid-pregnant mammary gland had low to moderate levels of telomerase activity, respectively. In comparison with the levels detected in pregnant mammary gland, telomerase activity was elevated in mammary tumors in situ and in established mammary cell lines in vitro, both tumorigenic and nontumorigenic; however, hyperplastic alveolar preneoplastic mammary outgrowths and non-tumorigenic ductal outgrowths, both in vivo immortalized populations, had telomerase activity <12% of the levels detected in normal pregnant mammary gland. These results suggest that elevated telomerase activity is not necessary for the immortalization phenotype in in vivo mouse mammary cell populations and that elevated telomerase activity occurs as a late event in mammary tumorigenesis. Furthermore, the data suggest that low levels of telomerase activity are characteristic for mouse mammary epithelial cells and not sufficient for immortalization. These data suggest that other factors play more important roles in the induction and/or maintenance of the immortalization state in mammary cell populations.

Telomerase reactivation in leukemia cells

We utilized fluorescent-labeled primers and modified the telomeric repeal amplification protocol (TRAP) to assess telomerase activity during the process of in vitro establishment in four different leukemia cell lines. We demonstrate that three of four leukemia cell lines had elevated telomerase activity, shortened telomeres, and the appearance of either dicentric chromosomes or acentric fragments. By contrast, one leukemia cell line (HAL-01) had high levels of telomerase activity, stable telomeres, but no obvious additional cytogenetic rearrangements. These experiments indicate that there may be several pathways involving telomerase activity in the establishment of leukemia cell lines.