Modelling the (6:9) translocation and MYB-NFIB gene fusion using the Crispr/Cas9 technology: implications for adenoid cystic carcinoma
Adenoid Cystic Carcinoma, also known as ACC, is a rare tumour of the salivary glands that can also originate in the breast, sinonasal tract, bronchoalveolar tree and other exocrine glands. In spite ACC is a slow growing tumour, it is relentless and most of the patients with metastatic disease do not survive after 10 years. This is also due to the fact that ACC responds very poorly to chemotherapy, radiotherapy and other treatments.
A major breakthrough in ACC research has been the identification of a molecular aberration in tumours in which two genes encoding the transcription factors MYB and NFIB are fused, forming a chimeric product. This new product, called MYB-NFIB, is thought to be the primary cause of the disease. Finding drugs specifically inhibiting this molecule could thus hold the promise for a more effective and personalised therapeutic approach for this cancer. However, the creation of a faithful cellular and animal model of the fusion is an essential prerequisite for the development of specific drugs targeting the oncogene.
Using a new technology called DNA editing we have been able to demonstrate that it is possible to modify the genome of mouse cells to induce the formation of a MYB-NFIB fusion gene that is identical to the corresponding human lesion observed in ACCs. We propose to complete and extend this pilot study by inducing the formation of the MYB-NFIB fusion gene in cells and tissues relevant to ACC to assess whether this causes tumourigenesis in living mice.
Given the great similarity of the mouse and human systems the in vitro and in vivo models developed in this study will be invaluable for the understanding of the molecular causes of the disease and the validation of new drugs.
Meet the Principal Investigator(s) for the project
Professor 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.
Related Research Group(s)
Inflammation Research and Translational Medicine - Driving scientific innovation and discovery for diagnosis, treatment, and management of cardiovascular disease, inflammatory and immune disorders, microbial resistance, and cancer.
Genome Engineering and Maintenance - Diverse research network focused on molecular, cellular, organismal and computational aspects of genome biology.
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Project last modified 21/11/2023