About the Project
Under pathogenic challenges, cells of the innate system become epigenetically reprogrammed and establish immune memory. If the myeloid system acquires cellular memory in response to microbial components, could they be similarly reprogrammed by internal pathological signals, namely oncogenes? Could such “oncogene-memory” account for development of drug resistance seen in clinical treatments of myeloid leukaemias?
Chronic myeloid leukaemia (CML) is associated with the BCR-ABL oncogene with 750 patients diagnosed yearly in the UK. Treatment with Imatinib Mesylate (IM), which inhibits the activity of BCR-ABL, has been clinically successful yet ~20% of patients develop drug resistance with imminent death occurring within 12-months.
Given the genetic plasticity of innate immune cells, as well as the clinical observations of drug resistance, it is tempting to speculate that leukaemic myeloid cells can be reprogrammed to become BCR-ABL independent. Definitive proof of such oncogenic programming of the myeloid genome has been lacking.
We established drug resistant clones from the KCL22 cell model; each recapitulating the clinical observations with BCR-ABL activity abolished by IM yet the cells continue to survive. Oncogene-memory was determined by siRNA knockdown approaches whereby targeting of BCR-ABL protein in parental cells induced immediate cell death while drug resistant derivatives continue to grow and survive.
(i) Molecular characterise the newly reprogrammed gene network that establishes oncogene-memory
(ii) Target specific biological pathways of the defined oncogene-memory (cell cycle, metabolism) in attempts to induce apoptosis thus laying the foundation for future generation of novel therapies.
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 BCR-ABL activity and (ii) attempt to rescue the developmental block by restoring the functional activity of these dysregulated 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.
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).
Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.
Applications can be made throughout the year.
Corbin, A. S. et al. Human chronic myeloid leukaemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. The Journal of clinical investigation 121, 396-409, (2011).
Cilloni, D. & Saglio, G. Molecular pathways: BCR-ABL. Clin Cancer Res 18, 930-937, (2012).
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