Telomerase is limiting the growth of acute myeloid leukemia cells

Röth, Alexander; Vercauteren, Suzanne; Sutherland, Heather J.; Lansdorp, Peter M.

doi:10.1038/sj.leu.2403177

Cited by 43 publications

(32 citation statements)

References 48 publications

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“…As reported previously, telomerase activity seems to be necessary for the maintenance of critically short telomeres and enables further proliferation of the leukemic cells. 26 However, telomerase activity measured in cell extracts does not necessarily correlate to the telomere length. 38 Our longitudinal data over a period of 18 months with no significant changes in telomere length despite further cell proliferation for one T-PLL patient with progressive disease, would be compatible with the notion that telomerase is able to compensate telomere loss due to cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22] This therapeutic approach was also shown with the use of dominant-negative mutant forms of hTERT, which lead to continuous telomere shortening and subsequent senescence or apoptosis. [23][24][25][26] A novel nonpeptidic, non-nucleosidic inhibitor of the catalytic activity of telomerase is BIBR1532 (2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid). BIBR1532 inhibits telomerase activity, comprising the human telomerase reverse transcriptase and human telomerase RNA components, in a dose-dependent manner, with half-maximal inhibitory concentrations (IC 50 ) of 93 nM by interfering with the processivity of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…In cell culture, numerous studies have established that telomerase inhibition does lead to cell death or cell arrest in both normal and cancerous cells Masutomi et al, 2003). Telomerase inhibition in some cancers thought to arise from immature or progenitor populations, such as AML, also leads to cell death (Roth et al, 2003a). Thus, it is not yet clear whether the inhibition of human telomerase might lead to defects in some cell types, either immediately or perhaps several years after treatment.…”

Section: Future Challenges and Pitfalls In Manipulating Telomere Homementioning

confidence: 99%

Does the reservoir for self-renewal stem from the ends?

Harrington

2004

Oncogene

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Stem cell research is a burgeoning field with an alluring potential for therapeutic intervention, and thus begs a critical understanding of the long-term consequences of stem cell replacement. Operationally, a stem cell may be defined as a rarely dividing cell with the capacity for selfrenewal throughout the lifetime of the organism, and an ability to reconstitute its appropriate lineages via proliferation and differentiation. In many differentiated normal and cancer cell types, the maintenance of telomeres plays a pivotal role in their continued division potential. Taken together with the presence of the enzymatic activity responsible for telomere addition, telomerase, in several progenitor cell lineages, it is presumed that telomere maintenance will be critical for the replenishment of stem cells or their successors. The purpose of this review is to discuss the role of telomere length maintenance in self-renewal, and the consequent challenges and potential pitfalls to the manipulation of normal and cancer-derived stem cells.

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“…20 It is likely that these thresholds apply also in case of patient cells explaining why despite significant hTERT repression induced by the RARa agonist alone no significant effect on telomere length was observed. Moreover, we cannot exclude that some destabilization of telomere structure may accompany hTERT (19) 81 (9) 63 (4) 52 (3) AML5 Pt 11 96 (10) 34 (9) 72 (0.1) 23 (4) CMML Pt 19 45 (19) 52 (19) 53 (14) 35 (19) CML Pt 12 63 (2) 98 (32) 64 (na) 38 (na) CML Pt 14 55 (36) 61 (15) 60 (15) 67 (na) CML Pt 15 12 (8) nd 98 (49) 18 (4) CML Pt 16 90 (1) 100 (38) 30 (11) 44 (18) CML Pt 17 13 (18) 10 (6) 24 (2) 24 ( repression leading to such a rapid shortening in only 11 days. Nevertheless, this observation is the first demonstration that retinoids can efficiently induce telomere shortening in leukemic blast cells.…”

Section: Resultsmentioning

confidence: 99%

“…It is acknowledged that a high level of telomerase activity is detected in acute myeloid leukemia (more than 10-fold compared to normal hematopoietic cells) and during progression of chronic myeloid leukemia (CML). [4][5][6][7][8] Telomere shortening has also been described associated with progression of myelodysplastic syndrome (MDS) to overt leukemia. 9,10 As most cancer cells are reliant on telomerase for their survival, it has become a promising target of anticancer therapy.…”

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confidence: 99%

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL

et al. 2006

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Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor a (RARa) and the retinoic X receptor (RXR). In contrast to differentiationtherapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered. Leukemia (2006) IntroductionTelomerase is a ribonucleoprotein complex responsible for the maintenance of telomeres. Its activity is generally undetectable in normal somatic cells, while it is expressed in approximately 85% of the common cancers. Expression of the catalytic protein component of the telomerase complex, hTERT (human Telomerase Reverse Transcriptase) plays a fundamental role in cellular immortalization. Hematopoietic stem cells express telomerase, 1-3 but not at a sufficient level to fully maintain telomere length. It is acknowledged that a high level of telomerase activity is detected in acute myeloid leukemia (more than 10-fold compared to normal hematopoietic cells) and during progression of chronic myeloid leukemia (CML). [4][5][6][7][8] Telomere shortening has also been described associated with progression of myelodysplastic syndrome (MDS) to overt leukemia. 9,10 As most cancer cells are reliant on telomerase for their survival, it has become a promising target of anticancer therapy. Even though multiple strategies have been described to specifically inhibit telomerase in vitro, 11 most of them have not been tested yet in clinical trials or are not relevant because of their low efficacy and/or a high toxicity.Among myeloid leukemias, acute promyelocytic leukemia (APL) was found to be particularly sensitive to differentiation therapy using pharmacological doses of all-trans retinoic acid (ATRA), which induce remission of APL patients by stimulating differentiation of leukemic cells. [12][13][14] Recently, we identified a new maturation-independent pathway, by which ATRA exerts an antiproliferative activity through hTERT downregulation, leading to telomere shortening and cell death. [15][16][17] The significance and extension of this observation to malignancies resistant to retinoid-induced differentiation is currently unknown. Here, we questioned whether h...

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Telomerase is limiting the growth of acute myeloid leukemia cells

Cited by 43 publications

References 48 publications

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

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

Does the reservoir for self-renewal stem from the ends?

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL

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