New player in the development T-cell acute lymphoblastic leukemia

Apr 16 2007

Leukemia, or cancer of the bone marrow, strikes some 700 Belgians each year. Scientists are still searching for the cause of many forms of leukemia, including T-cell acute lymphoblastic leukemia, or T-ALL.

Now, VIB researchers connected to the Katholieke Universiteit Leuven have identified a new player in the development of some 10% of the T-ALL cases: MYB. The scientists have discovered that patients in this group have a duplication of the MYB gene, which increases MYB concentrations. Further research has indicated that MYB might well be an important target for therapies for this group of T-ALL patients.

T-cell acute lymphoblastic leukemia (T-ALL)

Our bodies' white blood cells combat foreign intruders such as viruses and bacteria. However, in leukemia, the formation of white blood cells is disrupted. The cells in the bone marrow that should develop into white blood cells multiply out of control without fully maturing. These blood cells do not function properly and thus jeopardize the production of normal blood cells. Among other consequences, this makes patients more susceptible to infections. T-ALL is a certain form of leukemia in which immature T-cells (a specific type of blood cells) build up very rapidly. T-ALL is the most prevalent form of cancer in children under 14 years of age, striking children between the ages of 2 and 3 in particular. Today, with optimal treatment using chemotherapy, more than half of the children are cured.

Combined action of several players

The search for the mechanisms that cause T-ALL goes on ceaselessly. Discovering these mechanisms will enable the development of targeted therapies, which are preferred over chemotherapy. Scientists know that T-ALL arises only when defects occur in several genes simultaneously. So it is not only important to identify the genes that underlie T-ALL, but also to discover which combinations trigger the disease. This is an important step in the development of specific combination therapies, which are much more effective than therapies that focus on just one target.

A new player

Idoya Lahortiga and Jan Cools in Peter Marynen's group, working with colleagues from Ghent (Belgium) and Rotterdam (the Netherlands), have recently identified MYB as a major player in certain T-ALL cases. Studying the DNA of 107 patients, they found that the MYB gene was duplicated in 9 of them. This duplication results in increased MYB concentrations. The MYB transcription factor is important for the proliferation, survival and differentiation of the precursor cells that precede the formation of blood cells. Scientists also know that MYB is involved in several other forms of cancer.

On the way to a new therapy

The researchers are convinced that MYB can be an important target for the development of a new therapy for T-ALL. They are particularly encouraged by the results they obtained when they suppressed the expression of MYB in T-ALL cell lines. This produced a limited - but therapeutically significant - effect on the cancer cells.

They also obtained a much more significant effect by suppressing two genes at the same time: MYB and NOTCH1. NOTCH1 has recently been identified as an important factor in the development of nearly 70% of T-ALL cases. The effect of inhibiting NOTCH1 is currently being tested on T-ALL patients. This is going very well, but the NOTCH1 inhibitors turn out to have toxic side effects, whereby some patients have to stop the treatment. The results from the VIB researchers in Leuven now demonstrate that the combined inhibition of NOTCH1 and MYB in T-ALL cell lines is very effective. These results raise hopes that scientists will be able to develop a very effective combination therapy - in which the concentration of the toxic NOTCH1 inhibitors is reduced - for the group of patients in which MYB and NOTCH1 play a role. The quest for this therapy will also be a part of the further research efforts of Lahortiga, Cools and Marynen.