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Title: Biomarkers predictive of clinical outcome in chronic myeloid leukaemia
Author: Lucas, Claire Marie
ISNI:       0000 0004 2737 2664
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2011
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Imatinib has undoubtedly revolutionised the treatment of chronic myeloid leukaemia (CML) and hence has become first-line treatment. At the time of carrying out this work, the only data available on the efficacy of imatinib for newly diagnosed CML patients were from a single clinical trial, IRIS. In a complete population study in our geographical area, following two years of imatinib treatment, the complete cytogenetic response (CCR) rate w:£s only 51 %, which is considerably worse than IRIS. / Clinical decisions would be greatly facilitated if it was possible to accurately ! predict a patient's probability of achieving a CCR, and in particular to identify those destined to subsequently progress to blast crisis while on imatinib treatment. In identifying patients likely to achieve a CCR on imatinib treatment the most promising biomarker investigated was the pCrkLlCrkL ratio. 100% of patients with a pCrkLlCrkL ratio of less than 25 achieved a CCR, whilst no patient with a ratio greater than 25 achieved a CCR; the latter all required a change in treatment. A patient's BCR-ABLl transcript type can provide additional information, but neither this or the pCrkLlCrkL ratio are predictive of blast crisis. The role of ALOX5 was investigated for the first time in human CML. In contrast to published data in a mouse model, ALOX5 expression appears down-regulated in CML due to low levels of the LTB4 receptor BLTl. These data suggest caution when extrapolating mouse model data to human CML. PP2A is a phosphatase and tumour suppressor which regulates cell proliferation, differentiation and survival. The predictive value of assessing PP2A and/or its inhibitory proteins was investigated. CIP2A is a novel inhibitor of PP2A. Patients with a high CIP2A protein level at diagnosis have a ] 00% probability of progressing to blast crisis, with the mean time to progression being 13 months; this contrasts with a zero progression rate in patients with low diagnostic CIP2A protein levels. CIP2A acts by inhibiting PP2A, resulting in the stabilisation of c-Myc. Via its role in cell cycle promotion and cellular proliferation, c-Myc may then contribute to disease progression by promoting aneuploidy. In summary, CIP2A is a prospective biomarker of blast crisis in CML and may be a useful therapeutic target. As a result of this study identification of patients who will subsequently progress into blast crisis is now possible.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral