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Scientists create model of a blood disorder

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19 Mar 2010

UK scientists have generated the first mouse model of 5q- syndrome, a human blood disorder, demonstrating the feasibility of creating chromosomal deletions in mice in order to study the genetic origins of such conditions.

The researchers, from the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge and the University of Oxford, aimed to track the development of 5q- syndrome, defined by the deletion of a section of chromosome 5.

The condition causes blood disorders such as anaemia, which is characterised by a low red blood cell count, as well as the over-production of both immature red blood cells and platelets. While initially not fatal, it may go on to transform into leukaemia and most patients become transfusion dependent, resulting in significant death rates.

In a study published online in Nature Medicine on 22 November, the scientists, who were funded by the charity Leukaemia & Lymphoma Research and the Medical Research Council, describe how they created a mouse model for the human 5q- syndrome using large-scale chromosomal engineering.

The scientists used a system that allowed them to selectively “knock out” a segment of the mouse genome that corresponds with the deleted region on chromosome 5 associated with 5q- syndrome in humans. When they did this the mice developed all the symptoms of the disease.

The deleted region that defines 5q- syndrome is widely believed to mark the location of genes that control cell growth and division. The scientists think that one such gene, called rps14, is lost in the 5q- deletion, affecting important processes such as growth control and normal red blood cell production. Further research is needed to see whether other genes or mutations are involved.

The researchers went on to show that 5q- syndrome’s development into anaemia also involves the p53 gene. The p53 gene is sometimes called the “guardian of the genome” because of its role in preventing mutations in DNA and is a trigger for ‘apoptosis’ - the programmed cell death of defective cells.

When researchers crossed the 5q- mice with mice that lacked the p53 gene, the blood cells developed normally. The researchers suspect that the initial damage to the blood cells caused by the deletion of part of chromosome 5 causes a “stress response” which triggers increased levels of p53 protein in the blood cells. Thus the two events are both necessary to cause the anaemia.

Dr Andrew McKenzie, of the MRC Laboratory of Molecular Biology, University of Cambridge, said: “Our mouse model exhibits important features of 5q- syndrome such as anaemia, allowing us to investigate in vivo the mechanism underlying the syndrome. It opens the door for further research and we hope it leads to improved treatments in the future.“

Dr Jackie Boultwood, of the University of Oxford, which also contributed to the study, said: “Our demonstration that we can correct the 5q- syndrome in this model by inhibiting p53 is very exciting and offers a realistic approach to successfully treating this disease.”

Dr David Grant, Scientific Director at Leukaemia & Lymphoma Research, said: “This research has already shown how specific genetic changes in blood cells can cause blood disorders in patients. Further understanding of how the disease starts and how it progresses will reveal targets for drugs for this and other forms of blood cancers that have the 5q- deletion.”