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Title: The erythropoietin receptor in TEL-AML1 positive acute lymphoblastic leukaemia
Author: Breen , Marie Elizabeth
ISNI:       0000 0004 2742 2801
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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The TEL-AMLl fusion is the result of t(12;21) (p13;q22), the most frequent chromosomal translocation in childhood B-cell ALL. Recent studies have found a positive correlation with TEL-AMLl and EpoR expression. Three possible mechanisms of up-regulation were investigated in this study: Gene expression analysis, DNA methylation and microRNAs. Microarray analysis compared TEL-AMLl positive and negative gene expression profiles to identify differentially expressed genes. Genes with well known roles in haematopoiesis were also examined. GATA-2 showed a similar expression profile to EpoR, with a higher expression found in TEL-AMLl positive cells. Over-expression of GATA-2 increased EpoR expression further in TEL-AMLl positive cells providing evidence of a link between GATA-2 and EpoR expression in the presence of the fusion protein. DNA methylation analysis of EpoR and GATA-2 promoter regions showed a much higher level of methylation in TEL-AMLl negative cells. After treatment with a demethylating agent EpoR levels did not increase indicating EpoR expression was not epigenetically controlled. However, demethylation of GATA-2 increased expression in both TEL-AMLl positive and negative samples indicating a direct role for DNA methylation with GATA-2 expression. MicroRNAs are short non-coding RNA molecules with the ability to post-transcriptionally regulate genes by binding to the 3•UTR. Taqman microRNA arrays allowed simultaneous analysis of 667 commonly found microRNAs in both TEL-AMLl positive and negative cells. Arrays were analysed and compared with target prediction results to identify microRNAs that could target EpoR and GATA-2. Over-expression of miR-362 showed down-regulation of EpoR protein levels. Over-expression of miR-650 showed down-regulation of both GATA-2 and EpoR. Together these results support a theory of an "EpoR friendly" environment in TEL-AMLl positive cells to aid and promote EpoR expression. This includes an increase in GATA-2 and a decrease in DNA methylation and microRNA expression. These factors are reversed in TEL-AMLl negative cells to hinder EpoR expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available