of the Max - MDC

Structure of the Group
Group Leader
Prof. Dr. Bernd Dörken
Scientists
Dr. Stephan Mathas
Dr. Martin Janz
Dr. Franziska Jundt
Dr. Sophie Cayeux
Dr. Stephan Kreher
Dr. Andreas Lietz
Dr. Sabine Friedl
Dr. Rolf Schwarzer
Dr. Özlem Acikgöz
Dr. Thorsten Stühmer*
Graduate Students
Björn Lamprecht
Ursula Ellinghaus
Nina Mielke
Mario Bunse
Branka Cakarun
Dirk Rosentreter
Sarika Jain*
Technical Assistants
Simone Lusatis
Franziska Hummel
Brigitte Wollert-Wulf
Ute Nitschke
Katharina Kley
* part of the period reported
The importance of aberrantly expressed ABF-1 is underlined
by recent studies from our group, in which we showed that
ABF-1 antagonizes the B cell-determining factor E2A in HRS
cells. Furthermore, Notch1 led to enhanced expression of
the macrophage-associated gene colony-stimulating factor
1 (c-fms) and T cell-associated transcription factors T-bet
and TCF-1. These data suggest that Notch determines the
unique HRS cell phenotype through aberrant expression of
B lineage-inappropriate genes. In order to find regulatory
mechanisms of the Notch1 signaling pathway, we analyzed
the expression of Deltex-1, a key modulator and cytoplasmatic
inhibitor of Notch1. Deltex-1 downregulates Notch1
via beta-arrestin and is known to be expressed in germinal
center B cells. We showed that Deltex-1 is not expressed in
B-cell derived neoplastic cells in Hodgkin lymphoma. Taken
together, our data suggest that Notch1 contributes to plasticity
of B cells in Hodgkin lymphoma and that its aberrant
activation is partly caused by absence of its inhibitor
Deltex-1.
Novel therapeutic approach to the treatment of
lymphoma / leukemia by targeting minor histocompatibility
antigens
Sophie Cayeux (in cooperation with W. Uckert, MDC)
In the treatment of leukemia allogeneic bone marrow transplantation
is an effective therapeutic option with curative
potential. In relapsing disease post-transplantation, it has
become evident that donor lymphocyte infusions can potentially
induce clinical remissions by generating a graft-versus-leukemia
reaction in patients. More recently, minor histocompatibility
antigens have been shown to play a clear
role in this effect. The ability to isolate T cell receptors that
bind specifically to defined minor histocompatibility antigen
expressed on tumour cells and subsequently clone them
in retroviral vectors has rendered feasible their transfer to
donor or patient T cells. The resulting genetically modified T
cells can be used as therapy to eliminate tumour cells.
We have developed a single cell PCR method that enables a
high throughput approach and facilitates the cloning of
specific mouse T cell receptors from single T cells. In parallel,
an in vivo mouse model was established using MHC
matched strains differing in the minor histocompatibility
antigen H13. Following allogeneic bone marrow transplantation,
relapsing disease was detected by means of a noninvasive
in vivo bioluminescence imaging technique and
treatment with donor lymphocyte infusions targeting H13
on host tumour cells was performed. The efficacy of the
anti-H13 therapeutic approach and the induction of a graftversus-tumour
reaction were investigated.
Selected Publications
Lietz, A, Janz, M, Sigvardsson, M, Jundt, F, Dörken, B, Mathas S.
(2007). Loss of HLH transcription factor E2A activity in primary
effusion lymphoma confers resistance to apoptosis. Br J
Haematol. 137, 342-348.
Mathas*, S, Janz*, M, Hummel, F, Hummel, M, Wollert-Wulf, B,
Lusatis, S, Anagnostopoulos, I, Lietz, A, Sigvardsson, M, Jundt,
F, Jöhrens, K, Bommert, K, Stein, H, Dörken, B. (2006). Intrinsic
inhibition of E2A by overexpressed ABF-1 and Id2 is involved in
reprogramming of the neoplastic B cells in classical Hodgkin
lymphoma. Nature Immunol. 7, 207-215. *contributed equally
Janz, M, Hummel, M, Truss, M, Wollert-Wulf, B, Mathas, S,
Jöhrens, K, Hagemeier, C, Bommert, K, Stein, H, Dörken, B,
Bargou, RC. (2006). Classical Hodgkin lymphoma is characterized
by high constitutive expression of activating transcription
factor 3 (ATF3) which promotes viability of Hodgkin/Reed-
Sternberg cells. Blood. 107, 2536-2539.
Jundt, F, Raetzel, N, Müller, C, Calkhoven, CF, Kley, K, Mathas,
S, Lietz, A, Leutz, A, Dörken, B. (2005). A rapamycin derivative
(everolimus) controls proliferation through down-regulation of
truncated CCAAT enhancer binding protein β and NF-κB activity
in Hodgkin and anaplastic large cell lymphomas. Blood. 106,
1801-1807.
Mathas, S, Jöhrens, K, Joos, S, Lietz, A, Hummel, F, Janz, M,
Jundt, F, Anagnostopoulos, I, Bommert, K, Lichter, P, Stein, H,
Scheidereit, C, Dörken, B. (2005). Elevated NF-{kappa}B p50
complex formation and Bcl-3 expression in classical Hodgkin,
anaplastic large cell, and other peripheral T cell lymphomas.
Blood. 106, 4287-4293.
Cancer Research 125