Blood, 1 May 2002, Vol. 99, No. 9, pp. 3398-3403
NEOPLASIA
Activated Notch1 signaling promotes tumor cell proliferation and
survival in Hodgkin and anaplastic large cell lymphoma
Franziska Jundt,
Ioannis Anagnostopoulos,
Reinhold Förster,
Stephan Mathas,
Harald Stein, and
Bernd Dörken
From Charité, Robert-Rössle-Klinik,
Humboldt University of Berlin; Max Delbrück Center for Molecular
Medicine, Berlin; Institute of Pathology, Klinikum Benjamin Franklin,
Free University of Berlin; Section of Experimental Surgery and
Immunology, Clinic for Surgery, University of Erlangen-Nürnberg,
Germany.
Notch signaling controls cell fate decisions of hematopoietic
progenitors by inhibiting certain steps of differentiation and inducing
either self-renewal or differentiation toward lymphoid or myeloid
lineages. In addition, truncated Notch1 alleles could be associated
with 10% of all cases of human T lymphoblastic leukemia and, when
introduced into mouse bone marrow stem cells, cause T-cell neoplasms.
However, functional links between the abundant expression of intact
Notch1 and oncogenesis are still lacking. Here we show that Notch1 is
highly expressed in B- and T-cell-derived tumor cells of Hodgkin and
anaplastic large cell lymphoma. We demonstrate a novel mechanism for
the oncogenic capacity of Notch1 by showing that the interaction
between intact Notch1 on tumor cells and its ligand Jagged1
dramatically induces proliferation and inhibition of apoptosis in
vitro. We further provide evidence that in Hodgkin and anaplastic large
cell lymphoma, Jagged1 is expressed in malignant and in bystander cells
colocalizing with Notch1-positive tumor cells. Notch1 signaling may
therefore be activated in tumor cells by Jagged1 through homotypic or
heterotypic cell-cell interactions, and it seems likely that these
interactions contribute to lymphomagenesis in vivo. Thus, our data
suggest that activated Notch1 signaling plays an important role in the pathobiology of Hodgkin and anaplastic large cell lymphoma and that it
might be a potential new target for treatment.
