of the Max - MDC

Biology and Targeted
Therapy of Lymphoma
Bernd Dörken
Studying the molecular mechanisms underlying B cell development and differentiation is one of
the key approaches to understanding the pathways leading to disease. We are particularly interested
in terminally differentiated B cells that give rise to hematologic malignancies like Hodgkin lymphoma
and multiple myeloma. Hodgkin- and Reed-Sternberg cells are tumor cells of classical
Hodgkin lymphoma (cHL). In most cases, they are derived from germinal center B cells. However,
they do not express immunoglobulins and typical B cell-specific markers. We focus our work on the
characterization of the molecular basis for the dedifferentiated B cell phenotype of Hodgkin lymphoma
and aim to identify molecular defects that are responsible for tumor cell transformation and differentiation.
We further evaluate molecular defects in lymphomas related to Hodgkin lymphoma like
anaplastic large cell lymphoma (ALCL), primary effusion lymphoma (PEL) or multiple myeloma. It is
the ultimate aim of our work to identify targets for the development of new treatment strategies.
Characterization of deregulated transcription
factor networks in Hodgkin lymphoma
S. Mathas, M. Janz in cooperation with H. Stein (Charité)
Using classical Hodgkin lymphoma (cHL) as a model system,
we are investigating the role of transcription factors in
lymphoma development. Malignant transformation of
hematopoietic cells is associated with profound alterations
in the transcriptional program resulting in deregulated proliferation,
differentiation, and apoptosis. Using oligonucleotide
microarrays, we have generated expression profiles
of cHL-derived cell lines as well as non-Hodgkin B cell lines.
These data facilitate the identification of differentially
expressed genes and transcription factor networks specifically
deregulated in the malignant Hodgkin-/Reed-
Sternberg (HRS) cells. Our work revealed in HRS cells a
functional disruption of the B cell-specific transcription factor
network, which is composed of the transcription factors
E2A, EBF, and Pax5. In particular, the B cell-determining
transcription factor E2A is inhibited by its overexpressed
antagonists activated B cell factor 1 (ABF-1) and inhibitor
of differentiation 2 (Id2). Both helix-loop-helix (HLH) proteins
are specifically overexpressed in HRS cell lines and primary
tumor cells. Importantly, these factors are able to
down-regulate the expression of B cell-specific genes and to
allow up-regulation of B lineage-inappropriate genes. These
data provide an explanation for the unique phenotype of
cHL tumor cells. In addition, we showed that the loss of the
B cell phenotype in primary effusion lymphoma (PEL) is
based on similar molecular mechanisms. In these cells,
reconstitution of B-cell specific E2A activity resulted in
induction of apoptosis. These data support the concept that
the loss of lineage-specific transcription factors in lymphoid
cells might be linked to the process of malignant transformation.
Thus, further understanding of the dedifferentiation
process in lymphoid cells provides a basis for the development
of novel targeted therapeutics for lymphoma
therapy.
Identification of survival pathways of lymphoma
cells for the development of new therapeutic
strategies
M. Janz, S. Mathas
In continuation of earlier work of our group, we focus on the
analysis of the NF-κB and AP-1 transcription factor system
with respect to apoptosis resistance and proliferation. These
pathways are investigated not only in HRS of cHL, but also
in related lymphoma entities such as anaplastic large cell
lymphoma (ALCL) and multiple myeloma. Recent results
show that overexpression of the NF-κB/IκB family member
Bcl-3 constitutes a novel molecular defect of the NF-κB system
in cHL and ALCL. Bcl-3 might be involved in apoptosis
protection of these cells. Furthermore, we have shown that
AP-1 is involved in the dedifferentiation process of HRS cells
by maintaining high expression of the E2A antagonist
inhibitor of differentiation 2 (Id2). The AP-1 activity might
further be enhanced by a specific overexpression of the
CREB family member ATF3. ATF3 is specifically overexpressed
in HRS and ALCL tumor cells and protects at least HRS cells
Cancer Research 123