Highlight Publication July 2010

Hodson DJ, Janas ML, Galloway A, Bell SE, Andrews SA, Li CM, Pannell R, Siebel CW, MacDonald HR, De Keersmaecker K, Ferrando AA, Grutz G, Turner M
Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T-lymphoblastic leukaemia.
Nature Immunology Vol 11: 717-724
http://dx.doi.org/10.1038/ni.1901

See comment by Nedjic J, Aifantis I (2010) RNA-binding proteins come out of the shadows.
Nature Immunology 11 697-698 http://dx.doi.org/10.1038/ni0810-697

Link to press release relating to this publication

Lay description

This paper describes the discovery of a completely new mechanism behind the development of a certain type of leukaemia. 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.

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.

About the lead author

Dan Hodson is a clinical haematologist whose main interest is in lymphoid malignancy. He joined Martin Turner’s lab as a McElwain CRUK Clinical Research Fellow in 2006 to undertake a PhD. His career plan is to combine clinical medicine and academic research into lymphoid malignancy. Dan is currently back working as a hospital clinician and is due to move to USA in November to take up a post-doctoral fellowship with Louis Staudt's group at the National Cancer Institute, NIH.