LIMR Haematology: Oncogenic reprogramming of immune cells

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 the development of drug resistance seen in clinical treatments of myeloid leukaemias?

<p>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.</p> <p>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.</p> <p>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.</p> <p>Objectives:</p> <ol> <li>Molecular characterise the newly reprogrammed gene network that establishes oncogene-memory</li> <li>Target specific biological pathways of the defined oncogene-memory (cell cycle, metabolism) in attempts to induce apoptosis thus laying the foundation for future generations of novel therapies.</li> </ol> <p>The 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.</p> <p>References:</p> <ul> <li>Laslo P and Stopka T. Transcriptional and epigenetic regulation in the development of myeloid cells: normal and diseased myelopoiesis. Book Chapter. “Epigenetics and Human Health” Springer, 2014</li> <li>Corbin, A. S.<em> et al.</em> Human chronic myeloid leukaemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. <em>The Journal of clinical investigation</em> 121, 396-409, (2011).</li> <li>Cilloni, D. & Saglio, G. Molecular pathways: BCR-ABL. <em>Clin Cancer Res</em> 18, 930-937, (2012).</li> </ul> <p><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support your application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme’s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine, Health & Human Disease as your planned programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting LIMRPhD@leeds.ac.uk.</p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p>