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Title: Pathogenesis of core binding factor in acute and chronic myeloproliferative disorders
Author: Johan, Muhammad Farid
ISNI:       0000 0001 3590 8463
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2007
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Pathogenesis of leukaemia is a multistep process that involves multiple genetic alterations of normal cells to transform into a malignant phenotype. Mutations in the receptor tyrosine kinase (RTK/RAS) signalling pathway frequently provide a proliferative signal particularly the core binding factors leukaemia. In addition, DNA methylation may playa major role in the pathogenesis of myeloid malignancies where aberrant methylation of the promoter region is a major mechanism for silencing of tumour suppressor genes in cancers. In this study, the role of downstream effectors of RTK/RAS signalling; NRAS, KRAS and PTPNll, two RTKs; PDGFRA and PDGFRB and effectors of JAK/STAT pathway; JAK2 has been investigated to determine if point mutation are involved in pathogenesis of myeloid leukaemia. The role of negative regulators of RTK/RAS signalling; RASSF1A, SHPl and SaCSl was also investigated to determine if aberrant promoter methylation are involved in the pathogenesis of myeloid leukaemia. A total of 326 DNAs from AML, CMML, MDS and JMML patients were screened for mutations . and DNA promoter methylation in these genes. The relative expression of SaCS1 was also analysed using RQ-PCR to confirm the role of saCSl methylation in haematopoietic cell lines. NRAS mutation was found in 20%(8/40) inv(16) AML and 19%(4/21) of t(8;21). KRAS mutation was detected in 3%(1/40) inv(16) AML. PTPNll mutation was detected in 1/67 AML and 1/5 JMML. 1/50 CMML patients possessed a JAK2 p.VaI617Phe. Aberrant RASSF1A methylation was found in 9%(5/55) MDS and in 1/5 JMML. Aberrant SHPl methylation was present in 11%(13/121) AML. SaCSl 'promoter' methylation was present in 11%(8/74) MDS patients. SaCSl 'exon 2' methylation was found in 40%(19/47) AML and is associated with the transcriptional silencing of SaCSl gene in haematopoietic cell lines. Interestingly, 68% of patients with AML arid inv(16) possessed either NRAS or KRAS or RTK mutation (KIT or FLT3) or SHPl aberrant methylation. 92% of class I mutations in AML and inv(16) were not associated with one another, thus suggesting the mutual exclusivity of RTK/RAS signalling pathway mutations. The findings lead to support the two-hit model of leukaemogenesis and moreover for the possibility of targeted therapy for patients with CBF AML especially inv(16).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available