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New research moves forward the fight against leukaemia

European 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. In a study published in the jou...

European 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. In a study published in the journal Nature Genetics, researchers from the Netherlands and the United Kingdom suggest that there are three crucial steps required to transform normal blood cells into leukaemic ones, each one subverting a different cellular process. By mapping out the route towards cancer, the study identifies processes that might serve as targets for new treatments to halt the cancer's development. Acute myeloid leukaemia is a rare but devastating disease, which can take hold in a matter of just days or weeks. Four out of every five patients with acute myeloid leukaemia die from their disease. 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. This study moves forward our knowledge of how NPM1 functions, showing 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 identifies 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, 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,' says Dr George Vassiliou, one of the leading authors of the study. 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 NPM1 mutations 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 3 out of every 10 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. 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 that 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. 'These findings give a much clearer view of how this difficult cancer develops and propagates,' says Allan Bradley, another author of the study. 'Our studies 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.For more information, please visit:Wellcome Trust Sanger Institute:http://www.sanger.ac.uk/

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Netherlands, United Kingdom

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