'Chromosome instability', which can cause whole chromosomes or large parts of a chromosome to be lost, is a feature of many cancers, including leukaemia. Dr MacKinnon has published a model which explains one mechanism by which chromosome instability in AML can occur. This model also helped predict the gene on chromosome 20, and predicts that there are other cancer-causing genes on chromosomes 5 and 17. It also helps explain why age and chemical exposure are risk factors for AML and MDS.
Dr MacKinnon uses specialised multicolour DNA probes to study the genes and chromosome abnormalities. The position of genes can be found on chromosomes by using a microscope and special fluorescent tags that light up the genes. Other fluorescent 'paints' colour the whole chromosome. These techniques can identify many of the abnormal changes to the chromosomes, such as split, moved, lost or amplified genes.
Microarray technologies have more recently been developed that perform similar tasks but with a much higher power and resolution. They can identify cancerous changes that are too small to be found by microscopy.
The project will help determine how these new technologies can be used to help improve the diagnosis and treatment of AML, MDS and other cancers.
Dr MacKinnon’s model looks at the role of centromeres in creating the genetic instability that causes cancer.
A centromere is like a handle by which newly divided chromosomes are pulled to the daughter cells when the cell divides in two. Some cancer cells have abnormal chromosomes with two “handles”, resulting in a tug-of-war between the two cells that can break the chromosome.
This type of abnormal chromosome is known to occur in cancer, but Dr MacKinnon has shown that these chromosomes with two centromeres are a much more common cause of chromosome 20 abnormalities than is thought – and could play a major role in causing abnormalities of other chromosomes.
Telomeres cap the ends of chromosomes and stop them from eroding away (think of the ends of a shoelace). External factors such as chemical exposure or chemotherapy can destroy these telomeres. This is thought to be the cause of some cases of cancer but the evidence that this is the case in leukaemia has been poor.
Dr MacKinnon now has direct evidence that telomere erosion is sometimes responsible for AML and MDS. Showing that this is the case may provide a rationale for leukaemia prevention, by identifying treatments and behaviours that repair telomeres, or preventing them from being damaged, particularly by chemotherapy. If Dr MacKinnon can show that these abnormal chromosomes are common it will help confirm her model and enable us to better understand mechanisms that produce gene errors in leukaemia.
This could also help explain chromosome abnormalities in other cancers.
These chromosomes have been labelled with different colours to determine their content and organisation.
Gene gains and losses can be determined in very fine detail by cutting the chromosomes into tiny pieces and applying them to DNA microarrays.