A key step in understanding the nature of the fight for superiority between mutated genes and normal genes could lead to new therapies to combat leukaemia, say researchers from the University of Birmingham and Newcastle University.
The study, published in Cell Reports, investigated Acute Myeloid Leukaemia to understand why leukemic cells are not able to develop normally into mature blood cells.
Stem cells in the bone marrow generate billions of different blood cells each day. The process resembles a production line with genes acting as regulators to control each step of the blood formation.
Leukaemia arises when the DNA encoding regulators in the stem cells is changed by a mutation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted with drastic consequences.
A chain reaction occurs, with the function of other regulators in the process being altered. The new cells no longer develop into normal blood cells, but leukemic cells that multiply and begin to take over the body.
Professor Constanze Bonifer, of the University of Birmingham, explained, “This particular leukaemia is characterised by a mutation in a gene that produces a rogue regulator. That is, one that is not normally made and behaves in a different way. The knock-on effect of that one mutation is huge.”
The team showed that this aberrant regulator switches off hundreds of other genes, many of them regulators themselves, by using state of the art technology that looks at the activity of all genes within a cell. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells are formed.
Professor Bonifer added, “Understanding how these rogue regulators operate is essential. Because all cells contain two copies of each gene, one from the mother and one from the father, these leukemic cells have one mutated gene and one unchanged one that would make the normal regulator.”
“What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time. This is compounded by the normal regulator which tries to compensate for defeat, and in doing so changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”
Crucially, the team identified that removing the mutated regulator allowed the cells to resume their normal behaviour and the production line returns to the regular process.
Professor Olaf Heidenreich, of Newcastle University, said, “This one aberrant regulator reprograms thousands of genes. If targeting it can reverse the changes it is making to the cellular production line then it would ultimately point towards new avenues for a more precise treatment of leukaemia.”
“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab that it is in the human body. But now we know how this works we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”
Professor Heidenreich is leading on turning this breakthrough discovery into therapies that could provide new ways of combatting leukaemia.
The project was funded by Leukaemia and Lymphoma Research, Cancer Research UK, and the Medical Research Council.
ENDS
Notes to editors
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Read the full paper (PDF - 4.4Mb): ‘Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal’ Cell Reports 2014.
University of Birmingham
The University of Birmingham has been named The Times and The Sunday Times University of the Year 2013/4.
The University of Birmingham is ranked amongst the world’s top 100 institutions, its work brings people from across the world to Birmingham, including researchers and teachers and more than 4,000 international students from nearly 150 countries.
Newcastle University
- Newcastle University is a Russell Group University
- Ranked in the top 1% of universities in the world (QS World University Rankings 2014)
- Ranked in the top 20 of UK universities in The Sunday Times 2013 University Guide and in the 2015 Complete University Guide
- Amongst our peers Newcastle is:
- Joint 6th in the UK for student satisfaction o Ranked 8th in the UK for Medical research power o Engineering and Physical Sciences Research Council (EPSRC) top 20 strategic partner
- 93.7% of our students are in a job or further training within six months of graduating
- We have a world-class reputation for research excellence and are spearheading three major societal challenges that have a significant impact on global society. These themes are: Ageing, Sustainability, and Social Renewal
- Newcastle University is the first UK university to establish a fully owned international branch campus for medicine at its NUMed Campus in Malaysia which opened in 2011
- Our international students put Newcastle University in the world's top 50 (ISB 2013) of global universities.
- Newcastle University Business School is one of 20 Triple Accredited Business Schools in the UK
The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms.