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DOI: 10.1055/s-0029-1237537
© Georg Thieme Verlag KG Stuttgart · New York
Die molekulare Pathogenese des klassischen Hodgkin-Lymphoms
The molecular pathogenesis of classical Hodgkin lymphomaPublication History
eingereicht: 27.4.2009
akzeptiert: 23.7.2009
Publication Date:
16 September 2009 (online)
Zusammenfassung
Obwohl das klassische Hodgkin-Lymphom (HL) als Erkrankung erstmalig vor über 170 Jahren beschrieben wurde, konnten erst in den letzten 15 Jahren wesentliche Fortschritte zu zentralen Fragen seiner molekularen Pathogenese erzielt werden. Der Mangel eines spezifischen Markerprofils in Kombination mit der geringen Anzahl der malignen einkernigen Hodgkin- und mehrkernigen Reed-Sternberg-(HRS-)Zellen in dem betroffenen Gewebe verhinderte lange Zeit sowohl die Identifikation des zellulären Urspungs als auch die Beschreibung genomischer und molekularer Defekte. Durch die Entwicklung von Techniken zur Analyse von Einzelzellen konnte gezeigt werden, dass HRS-Zellen von B-Zellen abstammen. Es ist allerdings deutlich geworden, dass das nomale B-Zell-spezifische Genexpressionsprogramm in HRS-Zellen durch verschiedene molekulare Defekte nachhaltig gestört ist. Zudem konnten in den letzten Jahren molekulare und genomische Defekte verschiedener Signalwege in HRS-Zellen identifiziert werden, u. a. der NF-κB, JAK/STAT und MAPK/AP-1 Signalwege, durch die die HRS-Zellen vor dem programmierten Zelltod geschützt werden. Trotz guter Erfolge in der klinischen Behandlung des HL erfordert die erhebliche Spättoxizität konventioneller Therapien die Entwicklung neuer nicht-genotoxischer Therapiestrategien. Es wird deshalb ein wesentliches Ziel der nächsten Jahre sein, die Kenntnisse zur molekularen Pathogenese klinisch nutzbar zu machen und in die bisherigen Behandlungskonzepte einzubinden.
Summary
Despite the fact that classical Hodgkin lymphoma (HL) has been described more than 170 years ago, only over the last 15 years significant advances regarding its molecular pathogenesis have been achieved. The lack of a specific lineage profile in combination with the low number of the malignant mononuclear Hodgkin- and multinucleated Reed-Sternberg- (HRS-) cells in the affected lymph nodes prevented for a long time both the identification of its cell of origin and of genomic and molecular defects. The development of methods for the analysis of micromanipulated single cells made it possible to demonstrate a B cell origin of HRS cells. However, it has become clear that the normal B cell-specific gene expression program in HRS cells is disrupted by various molecular lesions. Furthermore, molecular and genomic defects of various signaling pathways could be identified in HRS cells, including the NF-κB, JAK/STAT and MAPK-AP-1 signaling pathways, which protect HRS cells from apoptotic cell death. Despite significant advances in the treatment of HL, the considerable long term toxicity of conventional therapies requires the development of new non-genotoxic therapeutic strategies. Therefore, it will be a central aim to develop new treatment strategies based on these insights into HL pathogenesis.
Schlüsselwörter
Hodgkin-Lymphom - HRS-Zellen - B-Zell-Differenzierung - Apoptose
Keywords
Hodgkin lymphoma - HRS cells - B cell differentiation - apoptosis
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Prof. Dr. Bernd Dörken
Medizinische Klinik mit Schwerpunkt Hämatologie und
Onkologie, Charité – Universitätsmedizin
Berlin
Augustenburger Platz 1
13353 Berlin
Phone: 030/450553192
Fax: 030/450553987
Email: bernd.doerken@charite.de