Modelling the t(6:9) translocation and MYB-NFIB gene fusion using the Crispr/Cas9 technology: implications for adenoid cystic carcinoma.
Recent advances in genomic technologies have revealed frequent MYB rearrangements in human malignancies. MYB, MYBL1 and MYBL2 belong to a small gene family encoding transcription factors whose role in oncogenesis has always been suspected, but never fully demonstrated. The main goal of the project is to validate the hypothesis that the t(6:9) chromosomal translocation, and formation of the MYB-NFIB fusion gene, is the leading cause of Adenoid Cystic Carcinoma (ACC), a rare and incurable tumour of exocrine glands that will be used as a model of MYB-addicted malignancy. The establishment of animal and cellular models of ACC will be critical for the validation of MYB targeting molecules. A further aim is the understanding of the signalling pathways downstream of MYB that could lead to the identification of new biomarkers and targets for therapy.
1. To create mouse and cellular models of ACC implementing genomic editing technology. The mouse and cellular models will be used to study the molecular pathogenesis of the disease and in preclinical experiments. 2. To study signalling pathways and kinases activated as a result of oncogenic mutation of MYB that could be used as pharmacological targets. 3. To use genomic approaches to distinguish gene signatures common to mouse and human ACCs that could serve as prognostic biomarkers to predict the clinical outcome of ACC patients. 4. To identify and refine MYB small molecule inhibitors and develop them into drugs for the treatment of ACC and other MYB driven cancers.
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This is a self funded topic
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Prof Arturo Sala
- Trained in Biochemistry and Cellular Biology at the University of Rome and the Italian National Institute of Health, I completed a PhD in Biochemistry at the University of Rome “La Sapienza” on the topic of DNA and RNA methylation in relation to muscle cell differentiation. After a short postdoctoral training in the National Institute of Health in Rome, I won an international post-doctoral fellowship from the Italian Association for Cancer Research (AIRC) and moved to the Kimmel Cancer Institute, Thomas Jefferson University Philadelphia. Working in the laboratory of Prof. Bruno Calabretta, I was the first to characterize the transcription factor and oncoprotein B-MYB and establish its relationship with key tumour suppressor genes, such as p53 and retinoblastoma family members. In 2001 I was recruited by the UCL Institute of Child Health as Senior Lecturer and later promoted to Reader. In UCL I continued to pursue the study of oncogenic transcription factors in the context of neuroblastoma, a childhood tumour affecting the peripheral nervous system. I was appointed Professor of Translational Cancer Research and Deputy Director of the Brunel Institute of Cancer Genetics and Pharmacogenomics in September 2011. In 2016 I joined the Synthetic Biology Theme in the Institute of Environment, Health and Societes.