No 25/ November 27, 2005
Embargoed until: Sunday, November 27, 2005, 1 pm EST, 6pm GMT, 19:00 CET
Master Switch for Blood Cell Development Detected
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 Institutes 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
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.
* Lymphoid cell growth and
transformation are suppressed by a key regulatory element of the gene encoding
PU.1 Frank Rosenbauer1,2,9, Bronwyn M Owens1,9, Li Yu3,8,
Joseph R Tumang4,
Ulrich Steidl1,
Jeffery L Kutok5,
Linda K Clayton6,
Katharina Wagner1,8,
Marina Scheller2,
Hiromi Iwasaki7,
Chunhui Liu3, Björn
Hackanson3, Koichi
Akashi7, Achim Leutz2, Thomas L Rothstein4, Christoph Plass3 & Daniel G Tenen1 1Harvard
Institutes of Medicine and Harvard Stem Cell Institute, Room 954, 77 Avenue
Louis Pasteur,
Barbara Bachtler
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