Gene Expression Analysis of Telomerase Related Genes in Myeloid Malignancy

Campbell, Lisa Jane (2012). Gene Expression Analysis of Telomerase Related Genes in Myeloid Malignancy. PhD thesis The Open University.



Telomere shortening and an increased telomerase activity are associated with poor prognosis and disease progression in many cancers. In Chronic Myeloid Leukaemia (CML) telomere shortening has a strong correlation with disease progression. Expression of hTERT, the catalytic component of telomerase, was evaluated in the CD34+ cells of CML patients. This revealed that expression of hTERT was significantly reduced in chronic phase CML and decreased with disease progression to accelerated phase and blast crisis. It could therefore be concluded that reduced hTERT expression contributes to reduced telomere length in CML. Additionally, expression of c-Myc, which increases hTERT transcription, correlated with hTERT expression suggesting decreased hTERT is partly caused by reduced c-Myc. hTERT promoter methylation and mutation status were investigated and this revealed that the hTERT promoter was not methylated and mutation rates were low suggesting that these are not contributing to reduced hTERT expression. cDNA microarrays were used to analyse gene expression in neutrophils of patients with Essential Thrombocythaemia (ET) harbouring the JAK2 V617F mutation which, like the BCR/ABL translocation in CML, results in an activated kinase. Neutrophils of ET patients exhibited a gene expression profile close to that of controls despite the presence of the mutation. Affymetrix microarrays were used to investigate the role of telomerase related genes in Myelodysplastic Syndromes (MDS). Genes decreased in patients with del(5q) include positive regulators of telomere length and genes with higher expression were associated with increased telomerase activity. Inferring that in these patients telomere length would be reduced but counteracted by increased expression of genes promoting telomerase activity. Genes that could differentiate between RA and RAEB2 subtypes were mostly related to telomere maintenance. These results demonstrate the complex role of telomerase and telomere length in malignancy and challenge the view that hTERT is always increased in cancer.

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