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Hodgkin Lymphoma – New Characteristics Discovered

Cytokines Help Tumor Cells Evade the Immune System

Researchers are still discovering new characteristics of Hodgkin lymphoma, a common form of cancer of the lymphatic system. The malignant cells are derived from white blood cells (B cells), but have lost a considerable part of the B cell-specific gene expression pattern. The phenotype and the characteristics of Hodgkin lymphoma cells are therefore unique. Björn Lamprecht and Dr. Stephan Mathas (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch and Charité – Universitätsmedizin Berlin, Germany) have demonstrated the production of interleukin 21 (IL-21) in the tumor cells of Hodgkin lymphoma. IL-21, a signaling molecule (cytokine) of the immune system, promotes the growth of cancer cells and helps them evade immune system detection (Blood*, Vol. 112. N0. 8, 2008, 3339-3347).

Until now
IL-21 was thought to be produced only by T cells, another group of immune
cells. Blocking IL-21 production could lead to the development of new therapy
strategies for Hodgkin lymphoma in the future, according to the researchers in
Professor Bernd Dörken’s laboratory, who collaborated with researchers at the University
Tor Vergata, Rome (Italy).

It was not
until 1994, some 160 years after Hodgkin’s lymphoma (HL) was first described by
the British physician Thomas Hodgkin (1832), that – using molecular biological
methods – scientists discovered that the disease originates from the white
blood cells, the B cells. They noticed, however, that the malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin
lymphoma (HL) exhibit a phenotype and characteristics that are considerably altered.
Although HRS cells are derived from B cells, they have lost the expression of
most of the B cell genes due to reprogramming.

research hypothesis of the just-published paper was that the tumor cells, due
to the loss of many B-cell specific genes, need alternative signaling pathways
to maintain their malignant growth. As Dr. Mathas explained, “Reprogramming can
provide the cells of Hodgkin ymphoma with this survival advantage.” Hence, the
researchers were searching for factors that normally do not originate from B
cells. They found what they were looking for in the gene for the cytokine

Different Functions of IL-21

It has
only been a few years since IL-21 was discovered in T cells. The function of
IL-21, however, varies greatly depending on the kind of cell. In some cell types
IL-21 stimulates the body’s protection program, which researchers call
programmed cell death or apoptosis. Each cell contains this apoptosis program
so that it will self-destruct when it is altered or defective. This prevents
the defective cell from damaging the entire organism.

IL-21 stimulates the T cells of the immune system and, for instance, drives
cells of the chronic-lymphatic leukemia of the B-cell type (B-CLL) to
apoptosis. By contrast, in T-cell leukemias, IL-21 does just the opposite and
stimulates malignant growth. For the first time, the researchers from Berlin
and Rome were able to show that IL-21 is produced by lymphatic cells originally
derived from B cells. IL-21 activates a specific signaling pathway (STAT3),
thus up-regulating the expression of a group of specific genes in HRS cells
which support the unchecked growth and survival of HRS cells.

IL-21 also activates a chemoattractant for
cells which suppress the immune system

On top of
that, according to further findings of the researchers, IL-21 activates a
protein (MIP-3 alpha) in the HRS cells that attracts a group of T cells to the
tumor which suppress the immune system. In the healthy organism, these
regulatory T cells keep the immune system in check and prevent excessive immune

proximity to the HRS cells there are a large number of these regulatory T
cells. Attracted by MIP-3-alpha, they can suppress an effective immune defense
of the body against the HRS cells. The production of such chemoattractants
could, according to the researchers, also be a cause for why Hodgkin lymphoma
contains so few tumor cells. They comprise merely 0.1 to one percent of the

experiments have shown that in immunological diseases like rheumatoid arthritis
and lupus erythematosus, a disease accompanied by symptoms such as skin changes
and inflammation of blood vessels and joints, these symptoms can be
significantly improved if IL-21 is inhibited. “If we could block IL-21 or also
MIP-3 alpha in human tumor cells,” Dr. Mathas added, “this might be a new
therapeutic approach for Hodgkin lymphoma.” The present cure rate for the
disease – also in its advanced stages – is 80 to 90 percent, particular when
chemotherapy is used. However, these therapy regimens might have severe side
ffects including the risk of therapy-induced secondary malignancies.

recently Dr. Mathas and Dr. Martin Janz were distinguished for their research
on Hodgkin ymphoma with the Curt Meyer Memorial Prize of the Berlin Cancer

*Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells
regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3 alpha

Björn Lamprecht1,2, Stephan Kreher1,2, Ioannis
Korinna Jöhrens4,
Giovanni Monteleone3,
Franziska Jundt1,2,
Harald Stein4,
Martin Janz1,2,
Bernd Dörken1,2 and Stephan Mathas1,2

1Max-Delbrück-Center for Molecular
Medicine, Robert-Rössle-Str. 10, 13125 Berlin;2Hematology, Oncology and
Tumorimmunology, Charité, Medical University Berlin, CVK, Augustenburger Platz
1, 13353 Berlin; 3Dipartimento di Medicina Interna e
Centro di Eccellenza per lo Studio delle Malattie Complesse e Multifattoriali,
Università Tor Vergata, Rome, Italy; 4Institute for Pathology, Charité,
Medical University Berlin, CBF, Hindenburgdamm 30, 12200 Berlin, Germany;
prepublished online August 6, 2008; DOI 10.1182/blood-2008-01-134783

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax:  +49 (0) 30 94 06 - 38 33

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