Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) are related blood cancers, which can occur at any age, but most often over the age of 65. The incidence of these diseases is rising, partly because of better success at treating other cancers. Up to 10% of cancer survivors develop therapy-related AML or MDS within 5 years of their previous cancer as a direct result of chemotherapy.
Although some people inherit cancer-promoting genetic errors (mutations), most cancer is caused by gene errors that arise in healthy tissue. To understand the causes of leukaemia and other cancers we need to determine which genes are responsible, and understand how and why these gene errors occur.
These diseases are often associated with massive genetic change and reorganisation – known as a 'complex karyotype' – in bone marrow cells. Thousands of genes can be affected. Environmental factors such as benzene and radiation exposure can also cause this type of AML and MDS, which has an extremely poor prognosis. Patients rarely survive a year after diagnosis, and new treatments are desperately needed. Because of the complexity of the genetic changes, these leukaemias are poorly understood.
Telomeres and centromeres are parts of a chromosome that can play a central role in the formation of these complex karyotype abnormalities, but the study of these features in large scale cancer genome projects is limited. Our research includes a focus on these regions and their relevance to leukaemia.
Continue reading for Aims and Benefits of the project.
This project studies some of the poorly studied gene errors in complex karyotype AML and MDS. It also aims to identify some of the mechanisms causing them. A better understanding of gene errors that occur in these diseases will help researchers understand how they are caused, identify preventive measures, and develop drugs that target the specific genetic abnormalities with greater efficacy and fewer side-effects than current treatments.
1. Investigate genome errors in AML and MDS patients:
- Obtain data by studying the gene and chromosome abnormalities of leukaemia specimens
- Identify new leukaemia-causing genes
- Identify abnormalities in leukaemia-causing genes
2. Pursue causes of genome abnormalities in patients:
- Further develop an already published model which explains one mechanism by which chromosome instability in AML can occur
- Further investigate risk factors for AML and MDS
- Investigate identified risk factors for AML and MDS patients in other forms of cancer
The genetic knowledge gained through this research will help Dr MacKinnon, her collaborators and other researchers achieve:
1. Identification and further development of specific cancer treatments including:
- Drugs to target faulty genes
- Avenues for preventing damage to AML- and MDS-causing genes
2. Development and application of specific treatments for other cancers to:
- Reduce side-effects of existing cancer treatments
- Increase efficacy of existing cancer treatments
AML or MDS accompanied by complex abnormalities of the genes has a particularly poor prognosis. While cancer survival rates are improving, cancer survivors who have had chemotherapy have a significant risk of developing this therapy-related leukaemia as a result of the DNA damage caused by the drugs which so effectively destroyed the original cancer.
Dr MacKinnon’s work will help explain related chromosome instability, and will potentially be useful for identifying other genes causing leukaemia and other cancers.
Most AML and MDS patients are elderly, and usually cannot tolerate standard chemotherapy treatments. Identification of the genes causing these cancers will make it possible to develop new drugs that are designed to specifically target the abnormal molecules in the cancer cells, with fewer side-effects. This will lead to improved treatments and outcomes for these patients and impact significantly on research into other cancers.
Genome sequencing is becoming faster and cheaper, and multimillion dollar international sequencing consortia are attracting more cancer research dollars. Sequencing analyses the genes down to the smallest unit and can detect very small changes. But gene sequence is not the only important consideration, and these large scale studies do not focus on chromosome organisation.
Dr MacKinnon’s approach is distinctive in analysing not only genes but also chromosome organisation, information that is largely lost during sequencing. This is particularly important when studying centromeres and telomeres, which are specialised regions of DNA that can destabilise the chromosomes. These regions are not analysed by high resolution sequencing and microarray technologies.
A complex karyotype
A normal set of chromosomes can be arranged in matching pairs. This complex leukaemia karyotype is highly abnormal.
The Victorian Cancer Cytogenetics Service (VCCS) at St Vincent’s Hospital (Melbourne) is the largest diagnostic cancer cytogenetics laboratory in Australia, specialising in the analysis of chromosomes of cancer patients. This is the ideal environment to explore the mechanisms and consequences of chromosome aberrations in leukaemia.
VCCS Director Associate Professor Lynda Campbell has had a long-standing interest in the cytogenetics of acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS), and is a member of the International Working Group on MDS Cytogenetics. Assoc Prof Campbell was an editor of the international guidelines for cytogenetic nomenclature.
Dr Ruth MacKinnon is a Research Fellow at the VCCS, researching the chromosome abnormalities in AML and MDS. Because these chromosome changes can be very complex, they are poorly understood. By studying some of the patterns of gene changes in these diseases she is working towards a better understanding of the mechanisms that cause this type of leukaemia.
Dr MacKinnon and Assoc Prof Campbell
The funding of this research is imperative to pursue the increasing benefits and findings of Dr MacKinnon’s work to date.
Without funding, these important findings in the 'cancer cure' arena may be lost or stagnate to the disadvantage of the population at large.
This proposal allows Dr MacKinnon’s research to continue in a cost-effective way. Your support will provide a significant and valuable impact on UNDERSTANDING LEUKAEMIA, with an added benefit of better understanding and addressing the nature and possible treatments for all forms of cancer.