The research, funded by BBSRC, Cancer Research UK and the MRC, revealed that mice missing two key genes develop an aggressive form of leukaemia similar to Acute Lymphoblastic Leukaemia, the most common form of leukaemia in children. Without these genes, the mice are unable to produce ‘silencer’ proteins, which normally regulate the activity of other genes to ensure the development of a healthy individual.
How cells grow and multiply is controlled by a set of instructions stored by the DNA inside the cell’s nucleus. These instructions are copied into messengers (messenger RNA or mRNA), which deliver instructions from the nucleus for the production of proteins which control cell behaviour. It is known that mRNA has to be copied from DNA at the right speed – too fast or slow and diseases like cancer can occur. This research shows for the first time that ‘silencer’ proteins acting directly on specific mRNAs also provide critical control against cancer. It demonstrates the significance of regulation at the post-transcriptional level (the destruction and inactivation of mRNA) and reveals that defects in this regulation lead to the development of malignancy. This new knowledge may pave the way for new medicines and therapeutic strategies to tackle cancer.
The researchers identified this new pathway by looking at relatively unknown genes, which produce proteins that ensure the timely destruction of specific mRNAs after they have successfully delivered their message to the cell’s machinery responsible for growth. The two genes, Zfp26l1and Zfp26l2, produce ‘silencer’ proteins, which regulate gene expression by acting on mRNA the critical intermediate between DNA and protein. Without these ‘silencer’ proteins the ‘messenger’ produces excessive amounts of protein. In this case the target mRNA directs the production of a protein called Notch1, which plays a key role in the development of a type of white blood cell called the T cell. Absence of the silencers therefore causes higher levels of Notch1 to be produced than is needed for normal growth; consequently the cells multiply out of control, leading to leukaemia.
Dr Martin Turner, Head of Babraham’s Laboratory of Lymphocyte Signalling & Development and senior study author said, “This is a completely new mechanism for the control of normal T cell development that, when corrupted, causes leukaemia.”
Dr Daniel Hodson, a Cancer Research UK Clinical Research Fellow and lead author said, “We have known for some time that switching on Notch1 is an important step in the development of leukaemia, but this ‘missing silencer’ is a completely new step through which Notch1 is controlled. We need to now identify whether this aspect of Notch1 control is faulty in human leukaemia and in other types of human cancer.”
Dr Lesley Walker, Director of cancer information at Cancer Research UK said, “Acute Lymphoblastic Leukaemia is the most common form of leukaemia in children but it also occurs in adults. It can be difficult to treat because cancer cells spread throughout the body so surgery is not an option. This exciting work, finding how the control of Notch 1 levels can lead to leukaemia in mice, could provide scientists with important new leads for treatments.”
It is known that the expression of such silencer proteins is suppressed in a number of human cancers, including breast cancer, so this may be a mechanism contributing to the pathogenesis of other different malignancies. Manipulating the stability and destruction of mRNA may therefore be a useful strategy for developing anti-cancer agents and the treatment of human leukaemia.
Notes to editors
Publication details: Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukaemia. Daniel J Hodson, Michelle L Janas, Alison Galloway, Sarah E Bell, Simon Andrews, Cheuk M Li, Richard Pannell, Christian W Siebel, H Robson MacDonal5, Kim De Keersmaecker, Adolfo A Ferrando, Gerald Grutz & Martin Turner.The DOI for this paper will be 10.1038/ni.1901.
Acute lymphoblastic eukaemia is a cancer that affects white blood cells called lymphocytes; it develops when the bone marrow produces too many lymphocytes. More information about the causes, diagnosing and treating acute lymphoblastic leukaemia can be found on our patient help website www.cancerhelp.org.uk.
About the Babraham Institute
The Babraham Institute is an institute of the Biotechnology and Biological Sciences Research Council (BBSRC) located near Cambridge, undertaking international quality research to support the biomedical aspects of the BBSRC’s mission. The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. The latest technologies are being used to study the basis of conditions such as neurodegenerative disorders, birth defects, cancer and diseases of the immune and cardiovascular systems. With a strategic focus on ‘healthy ageing’, novel approaches for tackling chronic diseases and public health concerns like obesity and inflammatory disorders are being discovered. www.babraham.ac.uk.
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