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

Abstract

Telomere maintenance is a prerequisite for immortalisation, and in most malignant cells is carried out by telomerase, an enzyme that synthesises new telomeric repeats on the chromosome ends. In normal or reactive tissues with a high regenerative capacity, telomerase is regulated according to the telomere loss that occurs during proliferation. To evaluate the interaction of proliferation and telomerase activity in malignant lymphomas, we quantified telomerase expression in different non-Hodgkin lymphomas in comparison to normal or reactive lymph nodes. Surprisingly, the activity levels were the same in most of the lymphomas analysed as compared to reactive lymph nodes. Significantly higher activity was detected only in Burkitt's lymphoma. Telomerase activity correlated well with hTERT and c-myc expression, but was independent of proliferation. To evaluate interactions of telomere-binding protein expression on telomerase expression in non-Hodgkin lymphoma, the mRNA levels of TRF1, TRF2, tankyrase and hPif1 were assessed by real-time RT -PCR. We demonstrate here that the magnitude of telomerase upregulation does not necessarily reflect the requirement of telomere compensation caused by proliferation. Telomerase regulation in non-Hodgkin lymphomas is therefore uncoupled from proliferative stimuli found in reactive lymphoid tissue. We suggest that the upregulation of specific telomere-binding proteins like TRF2 may contribute to telomere maintenance in malignant lymphoma.

Telomere dysfunction and its role in haematological cancer

“…Analysis of the telomere binding proteins revealed that TERF1, TERF2, and tankyrase expression was similar across the benign tissue and the malignant samples although, interestingly, levels of the helicase hPif1, known as a telomerase inhibitor, were increased in the BL samples. Klapper et al (2003) suggested that the likely reason for the discrepancy in their findings to the previously published studies was due to the use of non-quantitative TA assay in the earlier studies. Their method used an internal control to produce a semi-quantitative measurement that was then further investigated by analysing TERT expression (Klapper et al, 2003).…”

“…Klapper et al (2003) suggested that the likely reason for the discrepancy in their findings to the previously published studies was due to the use of non-quantitative TA assay in the earlier studies. Their method used an internal control to produce a semi-quantitative measurement that was then further investigated by analysing TERT expression (Klapper et al, 2003).…”

“…They further identified cases of MCL with 5p13.33 translocations, though not involving immunoglobulin loci (Nagel et al, 2010). Using the same semi-quantitative method as described by Klapper et al (2003), they demonstrated that the cases with translocations involving 5p13.33 showed increased TA when compared to B-cell malignancies without this translocation. It seems plausible therefore to conclude that one mechanism for the increased TA in lymphomas or other B-cell malignancies may be due to chromosomal translocations involving the TERT locus that leads to its over-expression.…”

“…In contrast Klapper et al (2003) investigated telomerase levels in mantle cell lymphoma (MCL), follicular lymphoma (FL) and DLBCL and found that they were comparable to activity levels found in benign lymphoid tissue. The only lymphoma they found to harbour increased TA was Burkitt lymphoma (BL).…”

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

“…Dysfunctional telomeres may arise either from critically short telomeres or by disruption of the shelterin complex [28]. In some hematologic malignancies, altered expression of shelterin proteins might disrupt the telomere structure, contributing to malignant transformation [13,[28][29][30][31]. Particularly in MCL, to our knowledge, there is only one report on the expression levels of TRF1, TRF2, TNKS, and PIF1 in a limited number of patients (7-8 cases) [30] and no differences in gene expression were found in comparison to lymph nodes.…”