T-Cells with Extremely Short Telomeres and High Telomerase Activity in T-Cell Prolymphocytic Leukemia (T-PLL): The Ideal Target for Telomerase Inhibition

• Published in: Blood 2006-11, Vol.108 (11), p.497-497
• Main Authors: Roeth, Alexander, Duerig, Jan, Himmelreich, Heike, Siebert, Reiner, Bug, Stefanie, Duehrsen, Ulrich, Lansdorp, Peter M., Baerlocher, Gabriela
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V108.11.497.497

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive lymphoproliferative disease characterized by the expansion of a T-cell clone derived from immuno-competent post-thymic T-lymphocytes. Important mechanisms involved in expansion of human malignant cells are reactivation of telomerase, an enzyme complex, which is able to compensate the loss of telomere repeats by cell division, and maintenance or elongation of telomere length. To investigate the role of telomeres and telomerase we measured telomere length by automated multicolor flow-FISH and telomerase activity by telomeric repeat amplification protocol in subsets of peripheral blood leukocytes from 11 newly diagnosed or relapsed patients with sporadic T-PLL. In addition, we analyzed the effect of the selective telomerase inhibitor BIBR1532 on T-PLL cells in short-term culture assays. The average telomere length in the clonal T-cells of all samples analyzed was extremely short (mean ± std: 1.53 kb ± 0.65 kb) compared to the non-clonal T-cells (5.03 kb ± 0.71 kb; p=0.012). The average telomere length for B-cells in these patients was 6.37 kb ± 0.71 kb (n=6). Telomere length values of the clonal T-cells were all below the 1st percentile of telomere length values observed in T-cells from healthy aged-matched controls whereas non-clonal T-cells and B-cells fell between the 1st and 99th percentile of the normal distribution. Interestingly, telomere length in the clonal T-cells remained stably short at 1.0 kb ± 0.6 kb without further telomere loss in one patient over a period of 18 months. No cell doublets indicative of fused or bridged chromosomes and telomere dysfunction were observed. Clonal T-cells exhibited high levels of telomerase activity almost comparable to levels of the positive control K562 whereas there was no measurable telomerase activity in normal, unstimulated T-cells. Telomerase levels even correlated inversely with telomere length in clonal T-cells (r=−0.91, n=6). In addition, we could induce a dose-dependent cytotoxicity of T-PLL cells with the telomerase inhibitor BIBR1532 (viable cells as percentage of untreated controls (viability index) in % after 10 days of cell culture (mean ± std) with 0, 10, 40, 100 μM BIBR1532: 100 ± 0, 54 ± 14.3, 27.5 ± 11.7, 2.6 ± 1.6, n=6) whereas no effect was observed in normal, unstimulated T-cells (viability index in % (mean ± std) after 10 days with 0, 10, 40, 100 μM BIBR1532: 100 ± 0, 100.8 ± 8.6, 96.9 ± 7.9, 103.1 ± 22.4, n=3). In summary, clonal T-