Oncogenic reprogramming of the immune system

Project description

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?

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.

Objectives:

1. Molecular characterise the newly reprogrammed gene network that establishes oncogene-memory
2. 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.

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.

 

References

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

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).

Entry requirements

This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are:

• British Council IELTS - score of 6.5 overall, with no element less than 6. 
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

Applicants with sufficient funding must still undergo a formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

How to apply

Applications can be made at any time. Potential applicants are welcome to contact Dr Peter Laslo with informal enquiries about this research project.

To formally apply for this project applicants should complete a Faculty Scholarship Application form and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly by email.

If you have already applied for other scholarships using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email to inform us you would like to be considered for this scholarship project.