MULTISTEP LYMPHOMAGENESIS

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Lymphogenesis is a complex multi-step process in which dysregulation of lymphocyte signaling pathways, transcriptional regulation, and apoptosis machinery leads to transformation. In the initial period of this grant, we built upon observations from a naturally-occurring bovine pseudo- leukemia syndrome and from studies of human tumor specimens to develop a model system to investigate the role of the regulatory serine studies of human tumor specimens to develop a model system to investigate the role of the regulatory serine-threonine kinase CK2 (formerly termed casein kinase II) in lymphomagenesis. These experiments have shown that dysregulated expression of CK2alpha does in fact predispose to lymphoma, and that CK2alpha over-expression synergizes with deficiency of the tumor suppressor gene p53 to accelerate lymphomagenesis. Further experiments have demonstrated that CK2alpha lymphomas constitutively up-regulate a panel of lymphocyte transcription factor families including AP-1, NFkappaB, CREB, NFAT, and TCF/LEF. Normally, these factors appear to be involved in physiological activation responses of lymphocytes rather than in malignant growth control. In the proposed experiments, the role of CK2alpha in the direct or indirect regulation of these transcriptional factors to lymphocyte transformation in vitro and in vivo. To answer the question of how essential CK2alpha is to normal lymphocyte growth using a genetic approach, we will develop a CDK2alpha "knockout" mouse model. We will also assess the impact of the other CK2 subunits, CK2alpha' and CK2beta, upon lymphocyte growth and development in a combination of transgenic and knockout experiments. These studies will fully elucidate the role of the CK2 subunits in lymphocyte development and transformation, and will also provide important new insights into the pathogenic contribution that constitutively expressed transcriptional activators may make to lymphomagenesis. In addition to expanding our understanding of growth control pathways in lymphocytes, it is hoped that these studies will contribute to the development of new anti-tumor therapies in the future, directed against proven kinase CDK2 itself or collaborating oncogenic transcription factors.