Telomere length and telomerase activity in malignant lymphomas at diagnosis and relapse

Abstract

Telomere length maintenance, in the vast majority of cases executed by telomerase, is a prerequisite for long-term proliferation. Most malignant tumours, including lymphomas, are telomerase-positive and this activity is a potential target for future therapeutic interventions since inhibition of telomerase has been shown to result in telomere shortening and cell death in vitro. One prerequisite for the suitability of anti-telomerase drugs in treating cancer is that tumours exhibit shortened telomeres compared to telomerase-positive stem cells. A scenario is envisioned where the tumour burden is reduced using conventional therapy whereafter remaining tumour cells are treated with telomerase inhibitors. In evaluating the realism of such an approach it is essential to know the effects on telomere status by traditional therapeutic regimens. We have studied the telomere lengths in 47 diagnostic lymphomas and a significant telomere shortening was observed compared to benign lymphoid tissues. In addition, telomere length and telomerase activity were studied in consecutive samples from patients with relapsing non-Hodgkin's lymphomas. Shortened, unchanged and elongated telomere lengths were observed in the relapse samples. The telomere length alterations found in the relapsing lymphomas appeared to be independent of telomerase and rather represented clonal selection random at the telomere length level. These data indicate that anti-telomerase therapy would be suitable in only a fraction of malignant lymphomas. © 2000 Cancer Research Campaign

Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation

“…In these studies, increased telomerase activity was found in B-NHL compared to reactive lymph nodes. Furthermore, a positive correlation of telomerase activity with the rate of proliferation in the B-NHL was found (Norrback et al, 1996;Brousset et al, 1997;Ely et al, 2000;Remes et al, 2000;Lin et al, 2001). In contrast to these studies, we did not find an upregulation of telomerase activity in most of the NHL compared to reactive lymph node tissue (Norrback et al, 1996).…”

“…Thus, tumours with low telomerase activity also can be sensitive to telomerase inhibition if (ii) telomeres of the tumour are significantly shorter than telomeres of normal tissue, especially of stem cells. In this case, inhibition of telomerase activity would shorten tumour telomeres faster to a critical length than in normal tissue and would therefore induce cell death selectively in tumour cells (Remes et al, 2000). Adding a new layer of complexity, we demonstrate, that telomere-binding protein expression varies in NHLs.…”

“…In other words, a high number of proliferating cells in a tumour would require relatively high telomerase activity compared to tumours with low proliferation. As the telomere length in most malignancies, including B-NHL, is shorter than in the corresponding normal tissue, a further shortening due to insufficient telomerase activity would lead to cell death (Remes et al, 2000). Thus, maintenance of telomere integrity seems even more critical for malignant than for normal cells.…”

“…As no specific test for the ALT exists that can be applied to tissue samples, so far only indirect evidence can be obtained from the telomere length pattern (Bryan et al, 1995;Dunham et al, 2000). However, studies of telomere length pattern in B-NHL suggest that most of the lymphomas have telomeres that point to a telomerase-dependent pathway of telomere maintenance (Remes et al, 2000). The lack of correlation in telomerase activity and proliferation in B-NHL found in this study, led us to examine telomere-binding protein expression.…”

Telomerase activity and hTERT mRNA expression can be heterogeneous and does not correlate with telomere length in soft tissue sarcomas

“…40 In our study, 8 tumors were treated before sampling. Remes et al 41 showed that telomere length and TA in relapsing malignant lymphomas may vary significantly after the administration of radiotherapy or chemotherapy as compare to nontreated tumors. In another study, 42 TA (but not hTERT) has been shown to be downregulated after chemotherapy or radiotherapy.…”