Leuven – Medical science has been at a total loss regarding the origin or cause of some forms of leukemia, or cancer of the bone marrow − including T-cell acute lymphatic leukemia, or T-ALL. But now, researchers from the Flanders Interuniversity Institute for Biotechnology (VIB), connected to the Catholic University of Leuven, have discovered the possible cause of the disease in 6% of the T-ALL patients. The scientists have found small circular DNA fragments in the cells of these patients that contain the ABL1 cancer gene. ABL1 also plays an important role in other forms of leukemia. The good news is that ABL1 is counteracted with the drug Glivec, and so this medication can now also provide help to a number of T-ALL patients.
T-ALL: T-cell acute lymphatic leukemia In normal circumstances, our white blood cells combat foreign intruders, like viruses and bacteria. However, in leukemia, there is a breakdown in the formation of white blood cells. The cells in the bone marrow that should develop into white blood cells multiply out of control without fully reaching maturity. These blood cells function inadequately, disrupting the production of normal blood cells. Among other effects, this makes patients more susceptible to infections. Leukemia appears in several forms − in the case of T-ALL, a large accumulation of immature white blood cells occurs within a very short time. This is the most common type of cancer in children under the age of 14 − striking children between two and three years of age, in particular. At present, an optimal treatment, with chemotherapy, cures over half of these children.
ABL1 plays a prominent role in several forms of leukemia
ABL1 is a kinase, a type of protein that catalyzes a number of processes in the cell − in the case of ABL1, this is the process of cell division. It is crucial that kinases function in a very controlled manner within our cells. Loss of control of their functioning disturbs the normal functioning and division of cells. Thus, such disorders in the functioning of ABL1 are a major cause of certain forms of leukemia.
Existing drug now used with T-ALL patients Research performed by Jan Cools and his colleagues, under the direction of Peter Marynen, shows for the first time that ABL1 also lies at the root of T-ALL − which has a direct effect on the treatment of T-ALL patients. Indeed, a drug exists − called Glivec − that suppresses the action of ABL1. Glivec has already been successfully administered to patients with other forms of leukemia in which ABL1 plays a role. The new research results show that Glivec can also provide a better treatment for a small group of T-ALL patients. Jan Cools has already successfully conducted the first laboratory tests with Glivec on the cancer cells of these patients.
The team of Jan Cools and Peter Marynen, along with Carlos Graux and colleagues from the Centre for Human Heredity under the direction of Anne Hagemeijer, noticed that the ABL1 gene was present in greater quantities in the white blood cells of 6% of the T-ALL patients. The genetic code of ABL1 is at chromosome 9. Through a flaw at the ABL1 gene, a piece of DNA is split off and 'takes on a life of its own' as it were. This fragment contains the ABL1 gene, connected to another gene. Due to this fusion, ABL1 works non-stop − stimulating cell growth unremittingly. This process leads to an uncontrolled growth of immature white blood cells and thus to T-ALL. With these findings, the researchers have revealed a new mechanism for the formation of active cancer genes on circular DNA fragments.
The researchers are now concentrating their efforts on discovering the role of ABL1 and other kinases in all T-ALL patients. In the future, they hope to be able to administer Glivec, and other kinase inhibitors, to treat these patients as well.
Relevant scientific publications
The research of the VIB scientists from Peter Marynen's group appears on 1 October in the authoritative journal, Nature Genetics (Graux C, Cools J et al., Nature Genetics, 36(10):1084-1089 (2004)) and is online on the journal's website: http://www.nature.com/naturegenetics.
Message posted by: Frank S. Zollmann
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