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Scientists at the Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch shed new light on the mechanism that turns healthy white blood cells into cancer cells. They detected a novel function of a gene regulator which steers blood cell development and, when mutated, blocks the transcription of genetic information which can result in leukemia. Playing an important role in this process, the myeloblastose protein (c-Myb), not only regulates proliferation and differentiation of blood cells by binding to the DNA, but, as has now been discovered, also directs DNA packaging into a specific protein structure known as chromatin. The findings of Dr. Xianming Mo, Dr. Elisabeth Kowenz-Leutz, Dr. Yves Laumonnier, Frau Hong Xu, and Prof. Achim Leutz have now been published in the journal Genes and Development online (doi: 10.1101/gad.355405).
Both red and white blood cells originate in the bone marrow. The production and proliferation of blood cells is controlled by a series of gene regulators called transcription factors which regulate the transcription of genes from the DNA molecule. To ensure that blood cells develop and function normally, various genes, whose products (proteins) play an important role in shaping the function of a cell, have to be transcribed at different times and in different amounts.
One such gene regulator that is important for the development of blood cells and present in all vertebrates is the transcription factor c-Myb protein, which coordinates the proliferation of blood precursor cells and their differentiation. Mutations in c-Myb have a strong impact on the development of the blood cells. More than 65 years ago, an avian leukemia virus was isolated that turned out to contain a mutated variant of the myb transcription factor that causes leukemia in poultry. Due to the Myb mutations, the processes of cell division and cell differentiation are no longer coordinated causing uncontrolled proliferation of undifferentiated blood cells. Since then, researchers have been investigating the mechanisms of blood cell development and the development of leukemia using cell biological and molecular biological methods.
Now, MDC researchers have demonstrated for the first time that the normal cellular Myb transcription factor not only controls the transcription of genes by binding to the DNA but also by changing the packaging of DNA into chromatin through its interaction with specific proteins (histones) found in the cell nucleus. Thus myb modulates the density of the chromatin structure, which influences the transcription of genes.
When mutated, Myb fails to assist in changing the structure of chromatin and thus blocks the activation of those genes involved in cell differentiation, resulting in uncontrolled blood cell proliferation and, hence, leukemia cell production. By adding a specific chemical substance, Trichostatin A (TSA) to the leukemia cells, the researchers were able to normalize the cells which then resumed normal differentiation. TSA blocks a specific enzyme, the histone deacetylase (HDAC). This enzyme modifies the activity of histones and also the transcription of genes. So far, cancer researcher test TSA in vitro and in animal experiments. It remains to be seen how these new findings will influence the development of new therapeutic strategies.
*Histone H3-tail Positioning and Acetylation by the c-Myb but not the v-Myb DNA Binding SANT Domain
1 Xianming Mo, Elisabeth Kowenz-Leutz, Yves Laumonnier, Hong Xu, and Achim Leutz1
1Max-Delbrueck-Center for Molecular Medicine, Berlin; Germany
1 Corresponding author: Achim Leutz M e-mail: aleutz@mdc-berlin.de
Press and Public Affairs
Max Delbrück Center for Molecular Medicine(MDC) Berlin-Buch
Barbara Bachtler
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Phone: +49/30/9406-38 96
Fax.: +49/30/9406-38 33
e-mail: bachtler@mdc-berlin.de
http://www.mdc-berlin.de
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