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Analysis of gene rearrangements and protein expression of the tumour suppressor genes, RB1 and p16, in acute myeloid leukaemia: Possible roles in leukaemogenesis

Jamal, A. Rahman A.; (1996) Analysis of gene rearrangements and protein expression of the tumour suppressor genes, RB1 and p16, in acute myeloid leukaemia: Possible roles in leukaemogenesis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Carcinogenesis is multi-step process involving the activation of oncogenes and/or inactivation of tumour suppressor genes. One of these tumour suppressor genes is the human retinoblastoma susceptibility gene, RB1, which encodes for a 110 kilodaltons (kDa) nuclear phosphoprotein, pRB. The hypophosphorylated form of pRB inhibits the progression of a cell from the G1 to the S phase of the cell cycle. Phosphorylation of pRB is mediated by the cyclin dependent kinase-4 (CDK4) and the latter is inhibited by a 16kDa protein, the product of another tumour suppressor gene, p16. It has been shown that a negative feedback loop exists between pRB and p16 protein in cell lines. The roles of RB1 and p16 in the pathogenesis of acute myeloid leukaemia (AML) were investigated. Using Southern blotting analysis, none of the 106 patients analysed had gross rearrangements in the RB1 gene. Fourteen patients showed the presence of polymorphic bands. The protein analysis revealed that 31% of 86 cases studied had abnormal pRB expression. Although, AML patients with normal pRB showed a higher complete remission rate and a longer median survival compared to those with abnormal pRB, the differences were not statistically significant. Using quantitative Southern blotting analysis, none of the 70 samples analysed were found to have p16 gene deletions. No point mutations were found in 25 cases analysed using single strand conformational polymorphism technique, p16 protein expression was investigated by western blotting in 60 cases. Six (10%) were found to have a reduced expression. There was no methylation of the 5' CpG island found in these 6 cases. Another six cases (10%) had overexpression of the p16 protein and four of these had abnormal expression of pRB providing further evidence that the reciprocal relationship between p16 and pRB also exists in primary tumours. However this interaction does not seem to occur universally as in cell lines.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Analysis of gene rearrangements and protein expression of the tumour suppressor genes, RB1 and p16, in acute myeloid leukaemia: Possible roles in leukaemogenesis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10104095
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