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-Delbrьck
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 Charitй 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, Bjцrn
Hackanson3, Koichi Akashi7, Achim Leutz2, Thomas L Rothstein4,
Christoph Plass3 & Daniel G Tenen1


1 - Harvard Institutes of Medicine and Harvard Stem Cell Institute, Room
954, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.


2 - Max Delbrьck Center for Molecular Medicine, Robert-Rцssle-Str. 10,
13092 Berlin, Germany.


3- Internal Medicine, Division of
Hematology/Oncology, The Ohio State University, Columbus,
Ohio,USA.


4 - Department of Medicine, Evans Memorial Department of
Clinical Research, Boston University Medical Center, Boston,
Massachusetts, USA.


5 - Department of Pathology, Brigham and
Women's Hospital, Boston, Massachusetts, USA.


6 - Laboratory of
Immunobiology and Department of Cancer Immunology and AIDS,
Dana Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts, USA.


7 - Present addresses:

Department of
Hematology, Hemostaseology and Oncology, Hannover Medical
School, University of Hannover, Hannover, Germany (K.W.);

Department of Hematology, 301 General Hospital of PLA, Beijing,
China (L.Y.).


8 - These authors contributed equally to this work.


Max Delbrьck Center for Molecular Medicine(MDC) Berlin-Buch

Robert-Rцssle-Str. 10

13125 Berlin

Germany

e-mail: bachtlermdc-berlin

mdc-berlin