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.
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