Researchers from the University of California San Diego School of Medicine and Moores Cancer Centre, California conducted a genome-wide screen in leukaemia cells. They used genome editing to delete thousands of different genes in leukaemia cells and observed which were required for cell survival and proliferation.
'[CRISPR] is an extremely powerful tool that allowed us to identify a multitude of genes that fuel leukaemia growth and find new vulnerabilities that can be targeted in this disease,' said senior author Professor Tannishtha Reya. 'The study also shows, for the first time, that whole-genome CRISPR-based screens can in fact be carried out in a manner that is much more physiologically relevant: using primary cancer cells, and in the setting of the native microenvironment.'
The screen showed several potential genes of interest, many of which regulated the activity of RNA binding proteins. The most promising was Staufen2 (Stau2): a relatively unstudied member of the RNA-binding protein family known to play a role in brain and nervous system development, but not previously thought to promote cancer.
After choosing to focus their attention on Stau2, they developed a mouse model in which Stau2 was genetically deleted. In this 'knock-out' mouse the team observed a profound reduction in cancer growth. The mice in this group also had a markedly improved survival rate.
Cell samples were then isolated from patients with leukaemia and the Stau2 gene deleted. Upon deletion they found the cells would no longer grow. This, therefore, suggests that Stau2 plays a similar, if not the same, role in human cancer as it does in mice.
Finally, the scientists performed a genome-scale computational analysis of Stau2 targets. The results suggested that Stau2 may control a well-known oncogene, Ras, and also the LSD/KDM family of proteins, both of which are potential drug targets currently under investigation.
'This work will be particularly important for the discovery of new treatments,' said lead author Dr Jeevisha Bajaj. 'Our genome-wide screen identified cellular signals critical for the growth of cancer, and in the future, this study will be useful to study the microenvironment, the area around the tumour that includes tissue, blood vessels and important molecular signals related to how the cancer behaves.'
The research was published in Nature Cancer.