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Title: Predictors of imatinib response in patients with chronic myeloid leukaemia
Author: Crossman, Lucy C.
ISNI:       0000 0001 3398 5369
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2006
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The majority of patients with chronic myeloid leukaemia (CML) achieve a complete cytogenetic response (CCR) on imatinib. However, we cannot predict which patients will have a suboptimal response. We set out to investigate ways of predicting poor cytogenetic response to imatinib in patients with CML. We examined patients with CML for the possession of particular alleles of the rs2290573 and IL-I P +3953 polymorphisms because these polymorphisms had been linked with the rate of achievement of a major cytogenetic response (MCR). Following the discovery of a polymorphism (K247R) within the P-Ioop of BCR-ABL, we determined its frequency within both CML patients and healthy blood donors, and used in vitro biochemical and cellular assays to test its drug sensitivity. We examined patients with primary cytogenetic resistance to imatinib for the expression of genes associated with drug transport (hOCT 1, MDR 1, ABCG2, ABCCl, ABCA2, ABCC2, ABCC3, ABCC6 and MVP) and compared this to patients who achieved a complete cytogenetic response to imatinib. We used gene expression profiling of CML unselected white cells, and of CML CD34+ cells, to look for genes associated with poor cytogenetic response. We could not find a correlation between the possession of the rs2290573 and IL-I p +3953 polymorphisms, and rate of MCR in our patients. The K247R polymorphism was rare, but 3 out of 5 patients with the arginine allele failed to achieve a major MCR. Despite its position in the P-Ioop, in vitro assays showed K247R to have a drug sensitivity phenotype highly similar to wild type BCR-ABL. Imatini b non-responders had significantly lower pre imatinib gene expression levels of hOCT 1, and significantly higher levels of ABCC3. compared to responders. In addition, in imatinib non-responders we found that the expression level of a variety of drug transport genes changed with time on imatinib, but these changes did not reach statistical significance. Gene expression profiling of CML total white cells revealed that imatinib responders and non-responders had highly similar gene signatures, and that the noise created by different sample source, handling and cell phenotype limited the detection of changes in gene expression. We successfully developed a technique for selecting CD34+ cells from cryopreserved CML mononuclear cells, and preliminary analysis of the CD34+ cell microarray data does not identify any genes that are significantly differentially expressed between cytogenetic responders and non-responders. Possession of the rs2290573 and IL-βI+3953 polymorphisms did not aid prediction of achievement of MCR in our CML popUlation. In patients with CML, possession of the arginine allele of K247R should not be confused with the development of a kinase domain mutation, and the failure of 3 out of 5 patients to achieve a MCR is likely to be a chance finding in a small cohort, but further collection of response data on patients with K247R is required. Differences in drug transport gene expression may influence patients' responses to imatinib, by potentially causing inadequate intracellular imatinib concentrations. Gene expression profiling of CML unselected WBC does not allow prediction of response to imatinib, and work is ongoing to see if the technique proves more useful when using RNA derived from CML CD34+ cells.
Supervisor: Not available Sponsor: Clinical Training Fellowship, Leukaemia Research Fund ; British Journal of Haematology Research Trust ; Elimination of Leukaemia Fund
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available