Researchers have found a gene defect that predisposes people to acute myeloid leukemia and myelodysplasia and hope their finding will lead to a genetic test that gives people with a family history of leukemia a chance to find out if they carry the faulty gene before their symptoms emerge. You can read a scientific paper on how Dr. Marshall S. Horwitz, professor of pathology at the University of Washington (UW) in the US, and colleagues, made their discovery, online in the 4 September issue of Nature Genetics.

Horwitz and colleagues comprise an international team of scientists and were able to carry out their research with the help of families from Australia, Canada, and the United States.

They discovered the mutations in a gene called GATA2, which among other roles, controls the process that changes primitive blood-forming cells into white blood cells.

The journey of discovery started after a research participant, a patient from central Washington, was successfully treated for leukemia in 1992 after receiving a bone marrow transplant at UW Medical Center. The patient's family history showed that several members had myelodysplastic syndrome, myeloid leukemia, and intractable mycobacteria infections, and prompted Horwitz to look for a genetic explanation.

Myelodysplastic syndrome (MDS) is where the body has problems producing certain types of blood cell. It starts with a fall in the quantity and quality of blood-forming cells in the bone marrow, the birthplace of blood cells. Patients often have severe anemia and need frequent blood transfusions.

Eventually the bone marrow fails and the blood count worsens, and about one third of patients with MDS develop acute myeloid leukemia (AML), where abnormal white cells accumulate in the bone marrow and screw up production of normal blood cells.

Linking up with colleagues in Australia, Horwitz heard of another family with a similar inherited blood disorder.

After 18 years of painstaking searching for candidate genes, the teams in the US and Australia eventually hit upon GATA2 as the gene whose mutations were most likely responsible for causing leukemia in the two families.

Since then, the researchers have identified faulty GATA2 mutations in more than 20 families and individuals.

In their paper they suggest the mutations could be more common than they first thought. For some, the GATA2 mutation leads to leukemia, but for others it could mean they are susceptible to dangerous bacterial, viral and fungal infections because of the shortage of white blood cells.

There have been a number of papers published recently implicating GATA2 in other diseases, including non-inherited leukemias, which are more common than the familial kind. And another paper in the same issue of Nature Genetics points to similar mutations in the gene being responsible for lymphedema and, in some cases, deafness.

What is puzzling is why similar gene mutations should cause such a range of health problems, and why it is so much harder to find genes for blood cancer than other cancers.

Horwitz told the press that while "several genes have been discovered and linked to solid, malignant tumors such as breast cancer in families susceptible to those types of cancer, so far very few inherited mutations have been uncovered for blood cancers."

Other studies have already linked mutations in the RUNX1 and CEBPA genes to inherited MDS and AML: these bind to DNA and control how it is transcribed to create the code that controls the production of proteins.

So for this study, the researchers looked at families that did not have the RUNX1 and CEBPA mutations and no other explanation for their inherited blood cancers: and this is how they came across GATA2. They also noticed that the mutations made the gene unable to play an effective role in producing healthy white blood cells.

Horwitz said the GATA2 mutations in the DNA sit next to an amino acid that is found to be faulty in some patients with terminal chronic myeloid leukemia. Being so near to each other on the DNA suggests the two locations share the same pathway that is important for several types of myeloid malignancies, said Horwitz.

The researchers hope their discovery will lead to a test where people at risk, because of the family history will be able to find out if they have the faulty GATA2 gene before any symptoms emerge. This could give them and their doctors a head start on getting an early diagnosis and treatment plan.

Another hope is that the discovery will also help the development of new therapies for AML and MDS and other blood disorders. A clinical trial to establish specific treatment options for people with GATA2 mutations is already under way in the US.

Grants from the National Institutes of Health in the US, the National Health and Medical Research Council of Australia, a Dora Lush Postgraduate Award, Leukaemia Foundation of Australia, the Cancer Council of South Australia, and MedVet Pty Ltd, helped pay for the research.

Written by Catharine Paddock PhD