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A gene expression signature classifying telomerase and ALT immortalization reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT

Oncogene volume 28, pages 3765–3774 (2009)Cite this article

Abstract

Telomere length is maintained by two known mechanisms, the activation of telomerase or alternative lengthening of telomeres (ALT). The molecular mechanisms regulating the ALT phenotype are poorly understood and it is unknown how the decision of which pathway to activate is made at the cellular level. We have shown earlier that active repression of telomerase gene expression by chromatin remodelling of the promoters is one mechanism of regulation; however, other genes and signalling networks are likely to be required to regulate telomerase and maintain the ALT phenotype. Using gene expression profiling, we have uncovered a signature of 1305 genes to distinguish telomerase-positive and ALT cell lines. By combining this with the gene expression profiles of liposarcoma tissue samples, we refined this signature to 297 genes. A network analysis of known interactions between genes within this signature revealed a regulatory signalling network consistent with a model of human telomerase reverse transcriptase (hTERT) repression in ALT cell lines and liposarcomas. This network expands on our existing knowledge of hTERT regulation and provides a platform to understand differential regulation of hTERT in different tumour types and normal tissues. We also show evidence to suggest a novel mesenchymal stem cell origin for ALT immortalization in cell lines and mesenchymal tissues.

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Acknowledgements

This work was supported by the Cancer Research UK, European Community Grants LSHC-CT-2004-502943, LSHC-CT-2005-0018806 and Health-F2-2007-200950 Glasgow University and Italian Association for Cancer Research.

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Authors and Affiliations

  1. Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Bearsden, Glasgow, UK

    K Lafferty-Whyte, C J Cairney, M B Will, A Bilsland & W N Keith

  2. Institute of Regional Health Services (IRS), Telomere and Aging Group, Southern Denmark University, Vejle, Denmark

    N Serakinci

  3. Department of Experimental Oncology and Laboratories, Unit 10, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    M -G Daidone & N Zaffaroni

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  1. K Lafferty-Whyte
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  2. C J Cairney
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  3. M B Will
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Correspondence to W N Keith.

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Lafferty-Whyte, K., Cairney, C., Will, M. et al. A gene expression signature classifying telomerase and ALT immortalization reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT. Oncogene 28, 3765–3774 (2009). https://doi.org/10.1038/onc.2009.238

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