Master gene that switches on disease-fighting cells identified by scientists

Imperial-led researchers discover gene that drives blood stem cells to become Natural Killer cells<em> - News Release</em>

Imperial College London news release

For immediate release
Tuesday 15 September 2009

The master gene that causes blood stem cells to turn into disease-fighting 'Natural Killer' (NK) immune cells has been identified by scientists, in a study published in Nature Immunology today. The discovery could one day help scientists boost the body's production of these frontline tumour-killing cells, creating new ways to treat cancer.

The researchers have 'knocked out' the gene in question, known as E4bp4, in a mouse model, creating the world's first animal model entirely lacking NK cells, but with all other blood cells and immune cells intact. This breakthrough model should help solve the mystery of the role that Natural Killer cells play in autoimmune diseases, such as diabetes and multiple sclerosis. Some scientists think that these diseases are caused by malfunctioning NK cells that turn on the body and attack healthy cells, causing disease instead of fighting it. Clarifying NK cells' role could lead to new ways of treating these conditions.

The study was carried out by researchers at Imperial College London, UCL and the Medical Research Council’s National Institute for Medical Research.

Natural Killer cells – a type of white blood cell - are a major component of the human body's innate, quick- response immune system. They provide a fast frontline defence against tumours, viruses and bacterial infections, by scanning the human body for cells that are cancerous or infected with a virus or a bacterial pathogen, and killing them.

NK cells - along with all other types of blood cell, both white and red - are continuously generated from blood stem cells in the bone marrow over the course of a person's lifetime. The gene E4bp4 identified in today's study is the 'master gene' for NK cell production, which means it is the primary driver that causes blood stem cells to differentiate into NK cells.

A Natural Killer cell (red) recognising and embracing a target cancer cell (blue) prior to destroying it (courtesy of Dan Davis' lab, Imperial College London)

The researchers behind today's study, led by Dr Hugh Brady from Imperial College London's Department of Life Sciences, are hoping to progress with a drug treatment for cancer patients which reacts with the protein expressed by their E4bp4 gene, causing their bodies to produce a higher number of NK cells than normal, to increase the chances of successfully destroying tumours.

Currently, NK cells isolated from donated blood are sometimes used to treat cancer patients, but the effectiveness of donated cells is limited because NK cells can be slightly different from person to person.

Dr Brady explains: "If increased numbers of the patient's own blood stem cells could be coerced into differentiating into NK cells, via drug treatment, we would be able to bolster the body's cancer-fighting force, without having to deal with the problems of donor incompatibility."

Dr Brady and his colleagues at the MRC National Institute for Medical Research proved the pivotal role E4bp4 plays in NK production when they knocked the gene out in a mouse model. Without E4bp4 the mouse produced no NK cells whatsoever but other types of blood cell were unaffected. As well as proving their hypothesis about the function of the E4bp4 gene, this animal model will allow medical researchers, for the first time, to discover if NK cell malfunction is behind a wide range of medical conditions, including autoimmune disorders, inflammatory conditions, persistent viral infections, female infertility and graft rejection.

Dr Brady explains: "Since shortly after they were discovered in the 1970s some scientists have suspected that the vital disease-fighting NK cells could themselves be behind a number of serious medical conditions, when they malfunction. Now finally, with our discovery of the NK cell master gene and subsequent creation of our mouse model, we will be able to find out if the progression of these diseases is impeded or aided by the removal of NK cells from the equation. This will solve the often-debated question of whether NK cells are always the 'good guys', or if in certain circumstances they cause more harm than good."

The researchers were initially studying the effect of E4bp4 in a very rare but fatal form of childhood leukaemia when they discovered its importance for NK cells.

The study was funded by the charities CHILDREN with LEUKAEMIA and Leukaemia Research.

-Ends-

For more information please contact:

Danielle Reeves, Imperial College London press office
Tel: +44 (0)20 7594 2198
Out-of-hours duty press office: +44 (0)7803 886248
Email: Danielle.reeves@imperial.ac.uk

Notes to Editors:

1. 'The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development,' Nature Immunology, online publication X September 2009.

Duncan M Gascoyne (1), Elaine Long (1), Henrique Veiga-Fernandes (2), Jasper de Boer (2), Owen Williams (1), Benedict Seddon (3), Mark Coles (4), Dimitris Kioussis (2) and Hugh J M Brady (1,5).

(1) Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.
(2) Division of Molecular Immunology and
(3) Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK.
(4) Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, UK.
(5) Immunology and Infection Section, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College, London, UK.

2. About Imperial College London

Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 13,000 students and 6,000 staff of the highest international quality.

Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.

Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve health in the UK and globally, tackle climate change and develop clean and sustainable sources of energy.

www.imperial.ac.uk

3. About the Medical Research Council

The Medical Research Council is dedicated to improving human health through excellent science. It invests on behalf of the UK taxpayer. Its work ranges from molecular level science to public health research, carried out in universities, hospitals and a network of its own units and institutes. The MRC liaises with the Health Departments, the National Health Service and industry to take account of the public's needs. The results have led to some of the most significant discoveries in medical science and benefited the health and wealth of millions of people in the UK and around the world.

www.mrc.ac.uk

4. About UCL (University College London)

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. UCL is the seventh-ranked university in the 2008 THES-QS World University Rankings, and the third-ranked UK university in the 2008 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. UCL currently has over 12,000 undergraduate and 8,000 postgraduate students. Its annual income is over £600 million.

For further information see: www.ucl.ac.uk

5. About CHILDREN With LEUKAEMIA

CHILDREN with LEUKAEMIA is Britain's leading charity dedicated to the conquest of childhood leukaemia through pioneering research, new treatment and support of leukaemic children and their families.

www.leukaemia.org

6. About Leukaemia Research

Leukaemia Research is the only national charity devoted exclusively to improving treatments, finding cures and learning how to prevent leukaemia, Hodgkin's and other lymphomas, myeloma and the other related blood disorders, diagnosed in 24,500 people in the UK every year. Further information, including patient information booklets, is available from www.lrf.org.uk or call 020 7405 0101.

Over the next five years, Leukaemia Research urgently needs to raise over £100 million to commit to new research across the UK. From basic laboratory research to clinical trials with patients, Leukaemia Research is committed to saving lives by funding high quality, carefully selected research throughout the UK.