Genetic research tracking down leukaemia

Life for most white blood cells ends after 8 to 12 days. By this time, they have finished all their tasks and are broken down again. Red blood cells and thrombocytes or platelets also have a limited lifespan. This is why blood stem cells in the bone marrow have to constantly produce new precursor cells from which the various blood cell lines develop. If cell production gets out of synch, the immature cells continue to grow uncontrolled and leukaemia develops. Dr. Frank Rosenbauer of the Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch is studying the genetic regulation of blood cell development and why these regulating programmes sometimes derail.

"Researchers are currently aware of around 20 genetic switches that regulate the development of the various blood cells," explains the young biologist. Previously, Rosenbauer had succeeded in identifying one of the key switches for the genetic regulator PU.1. There, he showed that the super switch URE does not simply turn the genetic switch PU.1 on or off, but rather regulates it very precisely. As a result, certain precursor cells then develop into the two major blood cell lines of B- and T-cells. However, if the URE is missing, leukaemia develops. This may also be the case with the gene IRF8. In healthy people, IRF8 triggers the cell's defence programme which makes defective cells commit suicide. In 80 per cent of the patients suffering from acute or chronic leukaemia, this gene is deregulated. Why this happens is still unclear. Rosenbauer and his staff want to find out how the gene can be turned on again in order to reactive the cell's defence programme. "DNA methylation", which modifies DNA by attaching methyl groups, also has an impact on the renewal and maturation of the blood cells. "This is currently one of the hot topics in stem cell research," says Rosenbauer. Using mice, he is studying the role played by this chemical process in the formation of cancer stem cells. In some diseases of the haemopoitec (blood-building) system, sections of the DNA are "deactivated" by the methyl groups. "However, there are reagents that cancel out this DNA methylation and these are already being tested on some cancer patients. The goal is to reverse the immature cancer cells so that they mature and stop their uncontrolled growth."

Frank Rosenbauer also wants to explain how exactly the development of the various blood lines from blood stem cells is regulated. "Blood stem cells themselves initially produce macrophages," he explains. Macrophages (literally "big eaters") are defensive cells that disintegrate the pathogens. "In order to produce B- or T-cells, however, the genes that cause the stem cells to produce macrophages first have to be switched off. Only then do the genes that are responsible for ensuring that the blood stem cells develop into B- or T-cells switch themselves on. We want to find out whether the genes are already switched off in the stem cells or only in the precursor cells." This is based on the hypothesis that cancer is already programmed in the stem cells. Should this prove to be the case, it could also have consequences for cancer therapy.