Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

The gene processes that drive acute myeloid leukaemia

28.03.2011
Researchers find genetic conspirators in the development of acute myeloid leukemia

Researchers have described how the most common gene mutation found in acute myeloid leukaemia starts the process of cancer development and how it can cooperate with a well-defined group of other mutations to cause full-blown leukaemia.

The researchers suggest that three critical steps are required to transform normal blood cells into leukaemic ones, each subverting a different cellular process. By charting the route towards cancer, the study identifies processes that might serve as targets for new treatments to halt the cancer's development in its tracks and even reverse it.

Acute myeloid leukaemia is a rare but devastating disease, which can take hold in a matter of just days or weeks. Every year, 2,000 adults in the UK are diagnosed with acute myeloid leukaemia: only about three in ten adults survive for five years.

In recent years researchers have identified a number of genes involved in the development of acute myeloid leukaemia. The most common is NPM1, a gene with many known functions. The new research shows that mutation in NPM1 is a key event in the development of a large proportion of cases of acute myeloid leukaemia and that it exerts its effect by helping cells to self-renew, a process that can be thought of as the first step towards leukaemia. The team also identify two subsequent events that are required to cooperate with NPM1 to drive cells to become cancerous.

"We have used targeted gene disruption to look at the way acute myeloid leukaemia develops in mice," says Dr George Vassiliou, Consultant Haematologist, cancer researcher and first author on the study from the Wellcome Trust Sanger Institute, "and have found critical steps that take place when the cancer develops. Identifying the biological steps in turn means we can look for new drugs to reverse the process."

The team started by developing a strain of mice that contained a 'control switch', that allowed the researchers to turn on mutations in the acute myeloid leukaemia gene Npm1.

When they switched on the Npm1mutations in the mice, the team saw that the mutation gave normal blood cells the ability to renew themselves more efficiently and boosted the production of a group of blood cells known as myeloid cells.

However, the team found that, despite mutations in this most frequently mutated leukaemia gene, only three out of every ten mice developed leukaemia and the disease developed only after a long time. The results suggest that the Npm1 mutation can start the leukaemic process but cannot, on its own, drive cells towards cancer.

To try to find the events that conspire to cause acute myeloid leukaemia, the team studied the same mice using a technique called 'insertional mutagenesis', in which tagged DNA is inserted into the mouse genome. Using this specialised technique, researchers can accelerate the development of cancers by causing mutations in genes at random, while at the same time 'tagging' the altered genes, making them easy to identify. When the process hits a gene that drives cancer, it leads to tumours in the mice – the team can then use the tag to see which genes were mutated.

By applying the technique to the mice that already had the Npm1 mutation, the team could search for additional genes that work with Npm1 to promote cancer development. As they had anticipated, the team found that more than four in five of these mice rapidly developed acute myeloid leukaemia.

Looking at the new gene mutations, the team identified three distinct processes that the mutated genes seemed to govern. While the team were able to confirm the role of Npm1 mutations in cellular self-renewal, they found other genes, which were routinely involved in one of two other processes. The first group of genes controlled the way that cells proliferate; the second group played a role in orchestrating the genetic activity in the cells.

"In our mice two or, in most cases, all three of these cellular processes were subverted," says Allan Bradley, from the Sanger Institute and senior author on the paper. "In concert, these genetic mutations, which were concentrated on a tiny number of genes, transformed normal to leukaemic cells. These findings give a much clearer view of how this difficult cancer develops and propagates.

"Our studies in the mouse, using novel methods to alter genes, complement the work of human cancer genomics. Together, we can more rapidly give biological context about just how genetic changes can cause the disease."

Researchers can now look in closer detail at the processes identified and divide them into complementary groups, a crucial first step to developing effective anti-cancer drugs.

"The two main therapeutic options for acute myeloid leukaemia have remained unchanged for more than 20 years," says Brian Huntly, MRC Senior Clinical Fellow at the University of Cambridge. "Although our ability to better use existing agents has led to modest improvements in patient survival, we desperately need new treatments to combat this disease and this relies heavily on us understanding the biological processes behind leukaemia development.

"The research by Vassiliou et al signals new hope in the search for new treatments to combat this devastating disease."

Notes to Editors

Publication Details

Vassiliou GS, et al. (2011) Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice. Nature Genetics.

Published online at doi: 10.1038/ng.796.

Selected websites

George Vassiliou profile:
http://www.sanger.ac.uk/research/faculty/gvassiliou/
George Vassiliou lab:
http://www.sanger.ac.uk/research/projects/haematologicalcancers/
Funding
This work was supported by a Clinician Scientist Fellowship from Cancer Research UK.

Participating Centres

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
The Netherlands Cancer Institute, Amsterdam, The Netherlands
Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, United Kingdom.

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease. http://www.sanger.ac.uk

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. http://www.wellcome.ac.uk

Jenny Cameron | EurekAlert!
Further information:
http://www.sanger.ac.uk

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>