They also found that advanced leukaemic stem cells that had become resistant to treatment could be 're-sensitised' to treatment by suppressing the same protein. Professor Eric So, who led the study at the Department of Haematology at King's College London, says the findings, published today in the journal Cancer Cell, represent a 'critical step forward' in the search for more effective treatments for aggressive forms of leukaemia.
The role that beta-catenin plays in the development and drug-resistance of stem cells in acute leukaemia was previously unknown. This study, funded by the Association for International Cancer Research (AICR), Cancer Research UK and the Kay Kendall Leukaemia Fund, reveals its significance and highlights it as a potential therapeutic target that could allow selective eradication of leukaemic stem cells.
King's scientists looked at leukaemic stem cells found in types of leukaemia that involve mutations of the MLL gene. This accounts for around 70 per cent of infant leukaemias and 10 per cent of adult acute leukaemias. The prognosis for this type of leukaemia in children is not good – only 50 per cent survive past two years after receiving standard anti-leukaemia treatment.
To understand how the disease develops, the King's team carried out a series of experiments to look at how pre-leukaemic stem cells (which do not always develop into leukaemia) are different to leukaemic stem cells, which sustain the disease and are likely to be responsible for relapse. They carried out studies in mice, in cultured human cells derived from cord blood, and on human leukaemic cells obtained from two leukaemia patients.
The studies in mice showed that pre-leukaemic cells developed into leukaemic stem cells and induced leukaemia, in part by activation of beta-catenin. But suppression of beta-catenin in leukaemic stem cells reduced leukaemic cell growth, delayed the onset of leukaemia and reversed the stem cells to a pre-leukaemic stage. Furthermore, when beta-catenin was completely inactivated in mice with pre-leukaemic cells, the mice did not develop leukaemia, even though they carried MLL gene mutations.
Researchers then wanted to see how suppression of the beta-catenin protein impaired human leukaemic cells. They found that suppression of the protein in MLL leukaemic cells again diminished their ability to proliferate and renew themselves (an essential part of how leukaemia develops). This confirmed the important role of beta-catenin in the human disease.
The study also revealed a previously unrecognized critical function of beta-catenin in mediating drug resistant properties of leukaemic stem cells. Leukaemic stem cells can become resistant to treatment in some cases but, crucially, this study showed that suppression of beta-catenin in human MLL leukaemic cells made them sensitive again.
Professor Eric So, who led the study at King's, said: 'These results are extremely exciting and represent a critical step forward in the search for more effective treatments for this devastating form of leukaemia. The findings provide compelling evidence that this protein could be exploited to develop an effective therapeutic target for this form of the disease.
'Most of the current anti-cancer therapies used to treat leukaemia attack healthy blood cells as well as cancerous ones. Interestingly, beta-catenin is not required for normal blood stem cells. So if we can specifically target beta-catenin in the bone marrow, we can have potentially a more effective and less toxic anti-leukaemia therapy that can efficiently eradicate leukaemic stem cells but spares healthy blood stem cells.
'Much more research needs to be done before we can adopt this approach in treating people with leukaemia, but the findings of this study do look promising. We will now investigate the mechanisms behind these molecular changes to find out why beta-catenin is so important in the development of MLL leukaemia, and if we can apply the principle to other types of leukaemia.'
Dr Mark Matfield, AICR's scientific co-ordinator said: 'The whole field of cancer stem cell research is relatively new, but this discovery has the potential to be one of the most useful in this rapidly-advancing area, because it shows us directly how a new treatment could be developed.'
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For further information please contact Emma Reynolds, Press Officer at King's College London, on 0207 848 4334 or email emma.reynolds@kcl.ac.uk
Notes to editors:
King's College London
King's College London is one of the top 25 universities in the world (2010 QS international world rankings), The Sunday Times 'University of the Year 2010/11' and the fourth oldest in England. A research-led university based in the heart of London, King's has nearly 23,000 students (of whom more than 8,600 are graduate students) from nearly 140 countries, and some 5,500 employees. King's is in the second phase of a £1 billion redevelopment programme which is transforming its estate.
King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.
King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe; no university has more Medical Research Council Centres.
King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: www.kingshealthpartners.org.
The Association for International Cancer Research (AICR)
AICR is the largest Scottish-based cancer charity, currently funding 207 active projects, at a cost of £36,765,555. Of those, 91 are in the UK and 116 are overseas. They include 12 prostate and nine bowel cancer projects.
Twenty three countries currently hold grants from AICR. Those are: (Overseas) Australia 15; Belgium 1; Denmark 1; Finland 3; France 13; Germany 6; Greece 5; Hong Kong 1;India 1; Israel 4; Italy 25; Netherlands 20; New Zealand 1; Portugal 2; Singapore 1; Spain 9; Sweden 3; Switzerland 3; USA 2. In the UK there are 67 in England; 1 in Northern Ireland; 21 in Scotland and 2 in Wales.
Since the charity was established in St Andrews, in Fife, Scotland, 30 years ago, its overall spend on research has totalled £137,957,566. That money has been spent on 1762 projects, throughout 32 different countries.
For more information on AICR please visit www.aicr.org.uk
The Kay Kendall Leukaemia Fund
The Kay Kendall Leukaemia Fund awards grants for research on aspects of leukaemia and for relevant studies on related haematological malignancies. Grants are awarded for first class research on innovative proposals, particularly those close to the care of leukaemia patients or the prevention of leukaemia or related diseases. Programme/Project grants are awarded twice yearly, and Senior, Intermediate, and Junior Fellowships of 3 – 5 years are awarded annually. The Fund also considers support for capital projects that will have direct benefit to leukaemia patient care. For more information please see Kay Kendall Leukaemia Fund website www.kklf.org.uk .
About Cancer Research UK
Cancer Research UK is the world's leading cancer charity dedicated to saving lives through research The charity's groundbreaking work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. This work is funded entirely by the public. Cancer Research UK has been at the heart of the progress that has already seen survival rates double in the last forty years. Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses. Together with its partners and supporters, Cancer Research UK's vision is to beat cancer.
For further information about Cancer Research UK's work or to find out how to support the charity, please call 020 7121 6699 or visit www.cancerresearchuk.org
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