CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia

Bechter, Oliver; Eisterer, Wolfgang; Dlaska, Margit; Kühr, Thomas; Thaler, Josef

doi:10.1016/s0301-472x(01)00760-3

Cited by 64 publications

(41 citation statements)

References 43 publications

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“…As previously published, ZAP-70 and BCL2 expressions were increased and those of KI-67 and hTERT were decreased (respective ratios: 25.6, 21, 0.26, and 0.04) 12,[16][17][18] (Figure 1B,E). We further showed that levels of hTERT and telomerase activity are correlated in B cells from one patient and one healthy donor ( Figure 1C,D).…”

Section: Resultssupporting

confidence: 85%

Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia

Poncet

Belleville

Roodenbeke

et al. 2008

Blood

113

103

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In this study, we explored the telomeric changes that occur in B-chronic lymphocytic leukemia (B-CLL), in which telomere length has recently been demonstrated to be a powerful prognostic marker. We carried out a transcriptomic analysis of telomerase components (hTERT and DYSKERIN), shelterin proteins (TRF1, TRF2, hRAP1, TIN2, POT1, and TPP1), and a set of multifunctional proteins involved in telomere maintenance (hEST1A, MRE11, RAD50, Ku80, and RPA1) in peripheral B cells from 42 B-CLL patients and 20 healthy donors. We found that, in B-CLL cells, the expressions of hTERT, DYSKERIN, TRF1, hRAP1, POT1, hEST1A, MRE11, RAD50, and KU80 were more than 2-fold reduced (P < .001), contrasting with the higher expression of IntroductionTelomeres are nucleoprotein structures that cap chromosomes and shorten with each division. Telomere structure and functions depend on the telomerase enzyme (hTERT, hTR, DYSKERIN) for elongation, 1 on the shelterin complex (TRF1, TRF2, TIN2, hRAP1, TPP1, POT1) that regulates telomere length and protects them against degradation and fusion, and on a set of multifunctional factors, including RPA1, hEST1A, KU70/KU80 and the RAD50-MRE11-NBS1 complex 2 ( Figure 1A).Telomerase activity is absent or very low in somatic cells and increased in proliferative lymphoid cells. 3 In most cancer cells, the catalytic subunit of telomerase (hTERT) is overexpressed to allow their long-term proliferation. 4 Research in oncogenesis is now focusing on the other telomeric genes, especially the shelterin complex. [5][6][7][8][9][10] Specific changes in the expression of these genes in cancers may provide new knowledge about oncogenesis and useful clinical markers, but would also lead to the development of new therapeutic agents.B-cell chronic lymphocytic leukemia (B-CLL) results from the progressive accumulation of a leukemic clone (for review, see Chiorazzi and Ferrarini 11 ) that shows lower telomerase activity at disease onset 12 and increased activity in advanced stages and bad prognosis group. 13 Telomeres are shorter in B-CLL cells versus normal B cells, and especially short for patients with bad prognosis. Telomere length is thus a powerful prognostic marker for B-CLL. 13,14 In this work, we investigated whether the transcriptional status of the telomeric proteins is modified in B cells from B-CLL patients. Methods Isolation of human B cellsAfter consent was obtained in accordance with the Declaration of Helsinki and according to institutional guidelines, total blood samples were collected from 20 healthy donors (at the "Etablissement Français du Sang" of Lyon and Pitié-Salpétrière Hospital) and from 42 B-CLL patients (at the Lyon Sud and Pitié-Salpétrière Hospitals). Diagnoses were confirmed using morphology and flow-cytometry usual B-CLL characteristics (Matutes score Ն 4). B lymphocytes were purified from peripheral blood by negative selection using the RosetteSep Human B-cell enrichment cocktail (Stem Cell Technologies, Vancouver, BC). The percentage of CD19 ϩ cells was determined by cytometric assay ...

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Section: Resultssupporting

confidence: 85%

Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia

Poncet

Belleville

Roodenbeke

et al. 2008

Blood

113

103

View full text Add to dashboard Cite

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“…One example is the methylation status of the hTERT promoter, which has been reported to repress as well as activate hTERT in various types of cells. 11,12 Histone acetylation has also been found to be involved in the transcriptional regulation of the hTERT gene. [13][14][15] Furthermore, several protooncogene and tumor suppressor gene products have been implicated in the regulation of telomerase activity, including c-Myc, bcl-2, p21, pRb, p53, PKC, Akt/PKB, c-Abl and protein phosphatase 2A (reviewed in 16).…”

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confidence: 99%

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer

Palmqvist

Zhang

et al. 2005

Intl Journal of Cancer

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In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (≥ 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels. © 2005 Wiley‐Liss, Inc.

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“…This region exhibits a high GC content, with two CpG islands important for promoter activity [102,117]. Methylation at the CpG islands correlates with the transcriptional silencing of TERT expression [118]. However, the idea that the TERT promoter is transcriptionally silenced in human somatic cells was questioned when Hahn's group detected an S-phase specific TERT expression, with levels too low for telomere maintenance, in primary human fibroblasts [119].…”

Section: Telomerase Reverse Transcriptase (Tert)mentioning

confidence: 99%

Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies

Trudeau¹,

Wong²

2010

CPPM

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Premature loss of telomere repeats underlies the pathologies of inherited bone marrow failure syndromes. Over the past decade, researchers have mapped genetic lesions responsible for the accelerated loss of telomere repeats. Haploinsufficiencies in the catalytic core components of the telomere maintenance enzyme telomerase, as well as genetic defects in telomerase holoenzyme components responsible for enzyme stability, have been linked to hematopoietic failure pathologies. Frequencies of these disease-associated alleles in human populations are low. Accordingly, the diseases themselves are rare. On the other hand, single nucleotide polymorphisms of telomerase enzyme components are found with much higher frequencies, with several non-synonymous SNP alleles observed in 2-4% of the general population. Importantly, recent advents of molecular diagnostic techniques have uncovered links between telomere length maintenance deficiencies and an increasing number of pathologies unrelated to the hematopoietic system. In these cases, short telomere length correlates to tissue renewal capacities and predicts clinical progression and disease severity. To the authors of this review, these new discoveries imply that even minor genetic defects in telomere maintenance can culminate in the premature failure of tissue compartments with high renewal rates. In this review, we discuss the biology and molecules of telomere maintenance, and the pathologies associated with an accelerated loss of telomeres, along with their etiologies. We also discuss single nucleotide polymorphisms of key telomerase components and their association with tissue renewal deficiency syndromes and other pathologies. We suggest that inter-individual variability in telomere maintenance capacity could play a significant role in chronic inflammatory diseases, and that this is not yet fully appreciated in the translational research of pharmacogenomics and personalized medicine.

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CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia

Cited by 64 publications

References 43 publications

Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia

Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer

Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies

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