Blood cells develop from blood stem cells in the bone marrow. Their development is regulated by roughly 20 gene regulators or transcription factors.
One transcription factor, called PU.1, plays a central role in this vital process. It steers the development of two major blood cell lines of the immune system, namely the lymphocytes and the myeloid blood cells. In addition, PU.1 regulates the blood stem cells own development thereby ensuring that new blood cells are produced as needed.
Yet, the question remains, “What regulates the regulator?”
Now, Dr. Frank Rosenbauer, a cell biologist who recently moved from the Harvard Institute of Medicine (Boston, USA) to the Max-Delbrück Center for Molecular Medicine (MDC) Berlin-Buch supported by the Initiative and Networking Fund of the President of the Helmholtz Association to which the MDC belongs, has detected a master switch which regulates PU.1. This master switch, termed URE (upstream regulatory element), not only turns the gene regulator on or off but also tunes it. As Dr. Rosenbauer demonstrated for the first time, URE can up- and down regulate PU.1, and, thus, determine whether B- or T-cells develop from lymphocyte progenitor cells. Animals that lack URE develop various forms of leukemias and, consequently, die within a few months. The research of Dr. Rosenbauer and his colleagues in the USA and at the MDC has now been published online in the journal Nature Genetics (November 27, 2005, doi:10.1038/ng1679).
With respect to the development of T-cells, Dr. Rosenbauer and colleagues could also show that the master switch is part of the wnt-signalling pathway. This pathway plays a crucial role in the healthy development of complex organisms. It reaches from the cell surface down into the cell nucleus with the genetic control station. If signals cannot be transmitted correctly via this pathway malformations or tumours develop. During T-cell development, this pathway normally is switched off. Thus, the master switch URE turns off the gene regulator PU.1. However, if this signalling pathway is disturbed, PU.1 is not turned off properly and T-cells cannot mature. “The deregulation of PU.1 prepares the platform for further mutations in the blood stem cells and the precursor cells, respectively, and thus for the outbreak of various forms of leukemia”, so Dr. Rosenbauer. Now, together with clinicians from the Charité Medical School Berlin, they plan to study the blood of leukemia patients to see whether the findings in mice also hold true for blood cell development in humans.