Telomerase-Independent Telomere Length Maintenance in the Absence of Alternative Lengthening of Telomeres–Associated Promyelocytic Leukemia Bodies

Fasching, Clare L.; Bower, Kylie; Reddel, Roger R.

doi:10.1158/0008-5472.can-04-2881

Cited by 89 publications

(76 citation statements)

References 46 publications

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“…Moreover, transfer of telomeric DNA between sister chromatids or different chromosomes (Bailey et al, 2004a) should have only a temporary effect on telomere maintenance and survival in C3-cl6 cells given the homogenous and short size of their telomeres. An ALT cell line that lacks APBs but retains other features of ALT has recently been described (Fasching et al, 2005;Marciniak et al, 2005), strengthening our conclusion that the use of the known ALT markers needs to be reassessed. Most relevant, absence of both telomerase and classical ALT has been reported in a high percentage of human osteosarcomas and found associated with improved patient survival, suggesting that lack of telomere maintenance mechanisms may represent a positive prognostic factor (Ulaner et al, 2003).…”

Section: Discussionsupporting

confidence: 72%

A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT

et al. 2005

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In human somatic cells proliferation results in telomere shortening due to the end replication problem and the absence of adequate levels of telomerase activity. The progressive loss of telomeric DNA has been associated with replicative senescence. Maintenance of telomere structure and function is, therefore, an essential requisite for cells that proliferate indefinitely. Human cells that have acquired the immortal phenotype mostly rely on telomerase to compensate for telomere shortening with cell division. However, a certain percentage of immortalized cell lines and human tumors maintain their telomeres by Alternative Lengthening of Telomeres (ALT), a mechanism not fully understood but apparently based on homologous recombination. Here, we report the isolation of an immortal human cell line that is derived from an ALT cell line but maintains telomeres in the absence of key features of ALT and of telomerase. The properties of these cells suggest that the identification of ALT cells may not be reliably based on known ALT markers. This finding is of relevance for discriminating between the mortal and immortal phenotype among telomerase-negative cells in vitro and in vivo, particularly in regard to the development of pharmacological approaches for cancer treatment based on telomerase inhibition.

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Section: Discussionsupporting

confidence: 72%

A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT

et al. 2005

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“…24,39 -41 Recent studies also demonstrated alternative telomere maintenance mechanisms in human cells, although these seem to be operative much less frequently, particularly in epithelial carcinomas. [41][42][43][44][45][46] In this study, we investigated hTERT expression in benign and malignant thyroid tumors using three measures. We first measured total hTERT transcript levels using a PCR probe that did not discriminate between alternative splice variants.…”

Section: Discussionmentioning

confidence: 99%

Telomere Length Is Related to Alternative Splice Patterns of Telomerase in Thyroid Tumors

Wang

Meeker

Kowalski

et al. 2011

The American Journal of Pathology

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Telomere dysfunction and aberrant telomerase expression play important roles in tumorigenesis. In thyroid tumors, three possibly inhibitory splice variants of the active full-length isoform of human telomerase reverse transcriptase (hTERT) may be expressed. These variants might regulate telomerase activity and telomere length because it is the fraction of the full-length isoform, rather than the total transcript level, that correlates with enzymatic activity. Telomerase reactivation may be critical in the early stages of tumorigenesis, when progressive telomere shortening may be limiting cell viability. The aim of this study was to investigate the relationship between telomere length and hTERT splice variant expression patterns in benign and well-differentiated malignant thyroid tumors. Telomere lengths of 61 thyroid tumors were examined by fluorescence in situ hybridization, comparing tumors with adjacent normal thyroid tissue on the same slide. Expression patterns of hTERT splice variants were evaluated by quantitative and nested RT-PCR. Telomere length was inversely correlated with percentage of full-length hTERT expression rather than with total hTERT expression levels. Short telomeres and high fractions of full-length hTERT transcripts were associated with follicular and papillary thyroid carcinomas, whereas long telomeres and low levels of full-length hTERT were associated with benign thyroid nodules. Intermediate levels of full-length hTERT and telomere length were found in follicular variant of papillary thyroid carcinomas and follicular adenomas.

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“…It has been shown that APBs are not always associated with the ALT phenotype (Fasching et al, 2005) and although candidate genes have been suggested (Jiang et al, 2007), no molecular markers for the detection of ALT have yet been confirmed. Previous work in cell line models highlighted an association of trimethyl K20 of histone H4 with both telomerase gene promoters in ALT cell lines, suggesting that chromatin modifications may have potential as novel markers of the ALT phenotype (Atkinson et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

et al. 2008

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Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel þ ); ALT positive; ALTÀ/TelÀ. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel þ compared to ALTÀ/TelÀ samples and increased hTERT in Tel þ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients.

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Telomerase-Independent Telomere Length Maintenance in the Absence of Alternative Lengthening of Telomeres–Associated Promyelocytic Leukemia Bodies

Cited by 89 publications

References 46 publications

A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT

A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT

Telomere Length Is Related to Alternative Splice Patterns of Telomerase in Thyroid Tumors

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

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