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'Cancer-killing gene' found

Monday 14 September 2009

British scientists have identified the “key master gene that can kill cancer”, according to the Daily Mail, which says that the gene is the masterswitch in the body’s battle against cancer. According to the newspaper, the E4bp4 gene triggers the production of natural killer cells from stem cells and could be used to boost the body's defences. The researchers involved are reported to have stumbled across the gene while researching childhood leukaemia.

This exciting research is important for the field of immunology because researchers have characterised the factors involved in the development of natural killer cells. Natural killer cells are part of the immune system that humans are born with (innate), and can destroy tumours and infected cells. It will be some time before the direct relevance of these findings to human immunity is clear as this was a study in mice.

This discovery is an important step in the understanding of how the body may respond to tumours. However, the manufacture of a drug that can boost the production of these natural killer cells will need a lot of further research and then many years of safety and efficacy testing. 

Where did the story come from?

This research was carried out by Dr Duncan Gascoyne and colleagues from University College London, the Medical Research Council National Institute for Medical Research, the University of York, Imperial College London and the Faculdade de Medicina de Lisboa in Portugal. The research was funded by Children with Leukaemia and the Leukaemia Research Fund. The study was published in the peer-reviewed medical journal Nature Immunology.

What kind of scientific study was this?

This laboratory study was a detailed exploration of the mechanisms behind the generation and specialisation of white blood cells called natural killer cells. These important immune cells develop mainly in bone marrow and migrate to organs including the spleen and lymph nodes once they have matured.

Various chemicals are involved in the development of natural killer cells, including a range of transcription factors, which are types of proteins that bind to specific sequences of DNA and help to control the interpretation of genetic material.

Past research has provided detailed descriptions of the chemical pathways for the development of other types of blood cells such as T lymphocytes and B lymphocytes, which are part of the adaptive immune system (where immunity is acquired due to exposure to an antigen). These lymphocytes produce antibodies that can recognise harmful pathogens (disease-causing organisms such as a virus or bacteria) and target their molecules when exposed to them again, providing a specific immune response to a particular pathogen. However, the processes involved in the development of the natural killer cells are not well understood.

Natural killer cells are an important part of the innate immune system and protect the body in a non-specific way. The innate immune system does not recognise or learn the make-up of pathogens but instead provides a broad response to protect the body from infected cells (for example, those infected with viruses) and tumours.

One particular transcription factor protein called E4bp4 has several known functions, including helping  in the growth and survival of motorneurones (nerves that activate muscle movement) and cells responsible for bone development. The study investigated how the gene that codes the manufacture of this transcription factor protein was involved in the development of natural killer cells.

The researchers measured the quantity of the chemical coded by the gene E4bp4 in populations of different mouse immune cells, including B and T lymphocytes, natural killer T cells (that have properties of both T cells and natural killer cells) and natural killer cells themselves. They bred mutant mice that were incapable of producing E4bp4 (because they did not have the E4bp4 gene) and then measured the concentration of the different types of blood cells in the animals’ spleens. They also assessed how the mice responded to immune challenges.

Natural killer cells can be produced outside the body from stem cells that have had particular chemicals applied. The researchers isolated bone marrow from both mutant and normal mice and then compared the production levels of the natural killer cells.

What were the results of the study?

The researchers found high concentrations of two transcription factors called Pax5 and Notch1 in populations of B and T lymphocytes, as was expected. However, in the populations of the natural killer cells and the natural killer T cells, there was eight times as much E4bp4 than in stem cell-rich bone marrow.

In mice that had no E4bp4 genes (and therefore could not make the E4bp4 transcription factor that was implicated in the development of natural killer cells), the concentration of natural killer cells in their spleens was lower than seen in mice that were able to make the chemical.

Further investigation into the role of E4bp4 in the development of natural killer cells confirmed low levels of all types of developing natural killer cells (including immature and mature cells) in the bone marrow of the mutant mice. Stem cells from the bone marrow from mutant mice lacking the E4bp4 gene did not develop natural killer cells outside the body.

What interpretations did the researchers draw from these results?

The researchers conclude that they have identified the first gene to specifically determine the development of natural killer cells. They say that the mutant mice that lack the E4bp4 gene, which they have shown to be crucial in the development of these white blood cells, may provide a model for further analysis of how the natural killer cells contribute to immune response in the context of disease.

What does the NHS Knowledge Service make of this study?

The findings from this laboratory study are important in the field of immunology because scientists have discovered a crucial gene that switches on the development of the natural killer type of white blood cell. The natural killer cells are part of the innate immune system that defend the body in a non-specific way and destroy tumour cells and cells that are infected with viruses.

There are a number of issues to keep in mind when interpreting the results of this study. Firstly, this is a study using animals so how the findings apply to the human body is not clear. More research will be needed .

Second, it is still unclear how the production of these natural killer cells can be enhanced. While some newspapers discuss the idea of a “drug that boosts natural killer cell numbers”, it is not apparent how this might work, and such a development is likely to be some distance in the future. In order to potentially develop these findings into a treatment for cancer, there will first need to be further research into the action of the E4bp4 genes in humans and the technologies to enhance them in living systems, followed by further research if this shows promise.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Key gene 'controls disease fight'

BBC News, 13 September 2009

New hope for cancer cure after scientists identify gene that switches on disease-fighting blood cells

The Daily Telegraph, 14 September 2009

Key master gene that can KILL cancer identified by British scientists

Daily Mail, 14 September 2009

Links to the science

Gascoyne DM, Long E, Veiga-Fernandes H et al.

The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development

Nature Immunology, (Published online) September 13 2009