AP-1 family transcription factors have been implicated in the control of proliferation, apoptosis and malignant transformation. However, their role in oncogenesis is unclear and no recurrent alterations of AP-1 activities have been described in human cancers. Here, we show that constitutively activated AP-1 with robust c-Jun and JunB overexpression is found in all tumor cells of patients with classical Hodgkin's disease. A similar AP-1 activation is present in anaplastic large cell lymphoma (ALCL), but is absent in other lymphoma types. Whereas c-Jun is up-regulated by an autoregulatory process, JunB is under control of NF-kappa B. Activated AP-1 supports proliferation of Hodgkin cells, while it suppresses apoptosis of ALCL cells. Furthermore, AP-1 cooperates with NF-kappa B and stimulates expression of the cell-cycle regulator cyclin D2, proto-oncogene c-met and the lymphocyte homing receptor CCR7, which are all strongly expressed in primary HRS cells. Together, these data suggest an important role of AP-1 in lymphoma pathogenesis.

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. ( It has further been demonstrated that HRS cells contain nonfunctional immunoglobulin (Ig) genes, suggesting that they are derived from germinal center cells that should have been negatively selected but were rescued from apoptosis by cellular transforming events. 3,4 Our previous work has provided evidence that constitutive NF-B activity is a survival factor for HRS cells. [5][6][7][8] We have directly manipulated the NF-B system and overexpressed a dominant-negative version of the inhibitor IB␣. HRS cells depleted of constitutive nuclear NF-B reveal decreased proliferation rates, enhanced apoptotic response, and strongly impaired tumor growth in severe combined immunodeficient mice. 7 To investigate molecular alterations of the NF-B/IB system that might be responsible for constitutive NF-B activity, we have analyzed the IB␣ gene. 9 We and others have demonstrated mutations of the IB␣ gene in a subset of HD cases that contribute to constitutive NF-B activation and are involved in the pathogenesis of HD. 9,10 To evaluate additional molecular mechanisms that lead to constitutive NF-B activity in HRS cells, and because activated Notch signaling has been implicated in the regulation of NF-B, 11-13 we analyzed Notch1 gene expression in cultured and primary HRS cells.Notch1 belongs to a family of transmembrane receptors that control cell proliferation and differentiation in response to extracellular ligands expressed on neighboring cells. 14-18 Notch1 has been isolated as a translocation in human acute T-cell lymphoblastic leukemia-lymphoma, 19 and its constitutively ac...