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New Key Element Discovered in Pathogenesis of Burkitt Lymphoma

MDC Scientists Develop Model for New Treatments

Burkitt lymphoma is a malignant, fast-growing tumor that originates from a subtype of white blood cells called B lymphocytes of the immune system and often affects internal organs and the central nervous system. Now Dr. Sandrine Sander and Professor Klaus Rajewsky of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have identified a key element that transforms the immune cells into malignant lymphoma cells. They developed a mouse model that closely resembles Burkitt lymphoma in humans and that may help to test new treatment strategies (Cancer Cell, http://dx.doi.org/10.1016/j.ccr.2012.06.012)*.

Burkitt
lymphoma typically develops in childhood and occurs most frequently in equatorial
Africa and South America. This tumor originates from germinal centers of the
lymphoid organs (Peyer’s patches in the small intestine, lymph nodes and spleen).
The germinal center reaction is initiated by mature B cells upon detection of a
foreign substance (antigen). These B cells modify their DNA in the course of
the reaction, resulting finally in a highly specific antibody response against
the antigen.

The B cell
receptor (BCR), an antibody presented on the surface of mature B cells, plays a
crucial role in the germinal center reaction. In order to optimally recognize
the respective antigen and initiate an appropriate immune response, the DNA
segments encoding the antibody need to be modified and rearranged. While the
processes are complex, DNA breaks occur and error-prone repair mechanisms may
lead to genetic mutations associated with cancer development.

It is well
established that in Burkitt lymphoma, mistakes in the repair of DNA breaks
result in the translocation of the c-MYC oncogene. This gene regulates cell
division, and thus its expression is tightly controlled in normal cells. The
c-MYC translocation leads to its deregulation, and the affected cells divide in an
uncontrolled manner. However, c-MYC overexpression also leads to massive cell
death. Therefore c-MYC deregulation by itself is unable to transform normal cells
into cancer cells. In Burkitt lymphoma, the apoptosis induction of elevated
c-MYC expression must be overcome by additional mutations preventing cell
death.

Recently,
Professor Rajewsky and his colleagues showed that an enzyme called PI3K is critical
for the survival of mature B cells. It activates a signaling pathway that regulates
cell growth and counteracts programmed cell death. Based on these findings Dr.
Sander and Professor Rajewsky investigated an interaction of c-MYC and PI3K in mouse
tumorigenesis in their present study. They demonstrated that PI3K is a key
element in Burkitt lymphoma development which enables c-MYC to turn germinal
center B lymphocytes into lymphoma cells that divide continuously and escape
apoptosis.

However,
not every B cell co-expressing c-MYC and PI3K transforms into a lymphoma cell, thus
the researchers suspected additional genetic mutations that may play a role in
Burkitt lymphomagenesis. Indeed they could identify such aberrations in their
mouse model, and a study in human Burkitt lymphoma by Professor Louis Staudt
(National Cancer Institute, Bethesda, Maryland, USA), which was published
simultaneously in Nature (DOI:
10.1038/nature11378), confirmed these results. Staudt and colleagues showed
that Burkitt lymphoma patients, besides having mutations resulting in the
activation of the PI3K signaling pathway, carry genetic mutations that resemble
those in the mouse.

“In
addition to c-MYC deregulation, the activation of the PI3K signaling pathway is
a key element in the development of Burkitt lymphoma,” said Dr. Sander and
Professor Rajewsky. “The inhibition of this signaling pathway could therefore
be an effective strategy for treating the disease.”

*Synergy between PI3K signalling and MYC in Burkitt lymphomagenesis

Sandrine Sander,1,2 Dinis P. Calado,1,2 Lakshmi
Srinivasan,1 Karl Köchert,2 Baochun Zhang,1
Maciej Rosolowski,3 Scott J. Rodig,4 Karlheinz Holzmann,5
Stephan Stilgenbauer,6 Reiner Siebert,7 Lars Bullinger,6
and Klaus Rajewsky 1,2,#

1 Program
of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease
Institute, Harvard Medical School, Boston, MA 02115, USA

2 Max
Delbrück Center for Molecular Medicine, Berlin-Buch 13092, Germany

3
Institute for Medical Informatics, Statistics and Epidemiology, University of
Leipzig, Leipzig 04107, Germany;

4
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA

5
Microarray Core Facility, University of Ulm, Ulm 89081, Germany

6
Department of Internal Medicine III, University Hospital of Ulm, Ulm 89081,
Germany

7
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus
Kiel/Christian-

Albrechts University Kiel, Kiel 24105,
Germany;

Contact:
Barbara
Bachtler

Press Department

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

in the Helmholtz Association
Robert-Rössle-Straße
10; 13125 Berlin, Germany
Phone:
+49 (0) 30 94 06 - 38 96; Fax:  +49 (0)
30 94 06 - 38 33
e-mail:
presse@mdc-berlin.de

http://www.mdc-berlin.de/

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