Chronic Myeloid Leukaemia (CML) represents 15% of all adult leukaemias and is associated with the t(9:22) chromosome translocation which fuses the BCR and ABL1 genes. The oncogene product, BCR-ABL, is the driving mutation of CML and its constitutive tyrosine kinase activity is central for its pathology. Targeting the tyrosine kinase activity of BCR-ABL for therapeutic application was first suggested in 1992 and these findings spawned the generation of Imatinib Mesylate (IM) 4-years later. The clinical success in treating CML with IM is a major success in targeted molecular therapy.
However, in some patients the disease turns aggressive and patients rapidly become resistant to current drug therapies. Development of resistance to drug therapies represents a significant hindrance to the effective treatment of cancer patients. Currently there is no effective non-surgical option for these patients with fatality occurring within 12-months.
Development of drug resistant BC-CML remains a clinical challenge and there is an urgent need to develop novel therapies for this pathology. The most widely studied mechanism by which leukaemic cells acquire IM-resistance is acquisition of point mutations within the tyrosine kinase domain of BCR-ABL. However, such mutations account for ~40% of patients, with a majority of drug resistant patients harbouring a wild-type BCR-ABL allele.
These clinical observations demonstrate that CML can become BCR-ABL kinase independent. Yet, how do leukaemic cells continue to survive and grow in the absence of BCR-ABL kinase activity?
To understand how CML cells have learnt to be kinase independent our lab has established a pre-clinical model that phenocopies this transition. Specifically, these drug-resistant derivatives recapitulate the clinical observations in that the activity of BCR-ABL is significantly diminished in the presence of IM yet the cells continue to grow and survive unperturbed.
This model system is a powerful model to gain insight into the molecular basis of this disease and can be used as platforms for drug screens.
The PhD project will employ a systems-biology approach (genome wide expression analysis, bio-informatics and shRNA technology) with the specific aims to (i) identify regulatory factors whose expression is dysregulated as a direct consequence of acquisition of drug resistance and (ii) attempt to rescue the developmental block by restoring the functional activity of these dsyregulated genes.
The PhD student will gain experience in a broad range of molecular and cell biology techniques including standard recombinant DNA procedures, gene expression profiling, micro-array analysis, bio-informatics, shRNA and general tissue culture practice with culturing of both primary and established cell lines.
Informal enquiries to Dr. Peter Laslo, email: [email protected]
The Section of Experimental Haematology is a vigorous and highly interactive department. The Section consists of faculty members studying the molecular regulation of cell fate specification and differentiation during blood cell development. This is complimented by studies on the dysregulation of haematopoiesis in cancers (leukemias and lymphomas).
You will join the Leeds Institute of Cancer and Pathology, a world-class multi-disciplinary research institute, dedicated to defining the molecules involved in human diseases. Further details of the Institute’s research: