Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia

Abstract

To test the role of telomere biology in T-cell prolymphocytic leukemia (T-PLL), a rare aggressive disease characterized by the expansion of a T-cell clone derived from immuno-competent post-thymic T-lymphocytes, we analyzed telomere length and telomerase activity in subsets of peripheral blood leukocytes from 11 newly diagnosed or relapsed patients with sporadic T-PLL. Telomere length values of the leukemic T cells (mean7s.d.: 1.5370.65 kb) were all below the 1st percentile of telomere length values observed in T cells from healthy agematched controls whereas telomere length of normal T-and B cells fell between the 1st and 99th percentile of the normal distribution. Leukemic T cells exhibited high levels of telomerase and were sensitive to the telomerase inhibitor BIBR1532 at doses that showed no effect on normal, unstimulated T cells. Targeting the short telomeres and telomerase activity in T-PLL seems an attractive strategy for the future treatment of this devastating disease.

Telomeres and prognosis in patients with chronic lymphocytic leukaemia

“…However, CLL cells with short telomeres and high telomerase activity defined a small group of patients with a worse prognosis. Similarly, T-prolymphocytic leukaemia (T-PLL) cells have short telomeres and high telomerase activity, and T-PLL is associated with a poor prognosis [39]. Currently, telomerase inhibitors are being explored as a possible therapy for patients with T-PLL.…”

Telomere dysfunction and its role in haematological cancer

“…In a small study looking at 11 patients with T-cell prolymphocytic leukaemia (T-PLL), a rare and aggressive form of leukaemia, Roth et al (2007) demonstrated that the malignant T-cells have markedly shortened TL of 1AE53 kb as measured by flow-FISH. In comparison, the patients' normal T cells had a TL of 5 kb.…”

“…Furthermore, analysis of the T-PLL cells showed that they had markedly increased levels of TA that correlated with an increase in TERT. Finally, they were able to demonstrate that the telomerase inhibitor (BIBR1532) led to selective death of the malignant T-PLL cells in vitro (Roth et al, 2007). T-PLL therefore is a disease with both high TA and markedly low TL that would logically make the ideal target for anti-telomerase therapy.…”

How I treat prolymphocytic leukemia

“…Extremely short telomeres and high levels of telomerase activity have been reported in T-PLL, and T-PLL cells are sensitive to telomerase inhibition in vitro. 43 Other therapeutic targets. Other intracellular signaling pathways, such as JAK-STAT and IRF, also offer potential targets for inhibition.…”