Arnold B. Rabson
	Professor Department of Molecular Genetics and Microbiology Department of Pathology UMDNJ-Robert Wood Johnson Medical School Associate Director for Basic Science Cancer Institute of New Jersey M.D., 1980, Brown University Tel:  [732]-235-5368 Fax: [732]-235-5289 rabson@cabm.rutgers.edu

HIV, HTLV-1, NF-kB, cancer, lymphomas, transcription, gene expression, oncogenesis.

Our laboratory is interested in the molecular basis of human disease pathogenesis. Our research focuses on gene regulation in human cancer and on the regulation and pathogenesis of human retroviral infections.

Several projects in the lab focus on the roles of the NF-kB family of transcription factors in human cancer. One project is directed at understanding the roles of NF-kB in the development of human lymphomas. NF-kB plays an important role in the control of normal immune activation and T-cell proliferation. Previous studies from our laboratory identified alterations of the NF-kB transcription factor in a subset of T-cell lymphomas. We demonstrated that the NF-kB-2 protein is truncated in patients with cutaneous T cell lymphoma (CTCL), a malignant disease of T lymphocytes involving the skin, lymph nodes, and blood. Alterations of this gene result in constitutive activation of the NF-kB transcription factor, which may lead to unrestrained T-cell proliferation and the eventual development of malignancy. Studies in the laboratory are aimed at understanding the mechanisms by which alterations of the NF-kB-2 gene leads to uncontrolled T cell proliferation and cancer. We have shown that NF-kB-2 alterations result in both loss of an "IkB-like" inhibitory function associated with the full-length NF-kB-2 molecule as well as a gain of function of the truncated, tumor-associated molecules in enhancing T-cell viability and proliferation. Further experiments are also examining the functions of the Bcl-3 protein, an IkB-like protein that cooperates with NF-kB-2 proteins to increase the expression of NF-kB target genes. Bcl-3 is a protooncogene whose expression is deregulated in a subset of chronic lymphocytic leukemias. We have shown that Bcl-3 mediated transcription is regulated by immune activation stimuli, thus Bcl-3 overexpression may activate genes involved in immune cell survival and proliferation, thus contributing to lymphomagenesis.

A second series of studies is focused on the regulation of gene expression in human prostate cancer. Prostate cancer is an important clinical problem in the United States. Although early detection and aggressive local therapy can be curative, progressive prostate cancer is generally incurable. The molecular basis for both the initiation and the progression of prostate cancer is only poorly understood. Our laboratory has demonstrated that constitutive and inappropriate activation of the NF-kB transcription factor in a series of androgen-independent prostate cancer cell lines. In collaboration with Dr. Amenta (Dept. of Pathology) we have also observed NF-kB activation in prostate tumor samples. We hypothesize that NF-kB activation plays a role in the progression of prostate cancer.

In collaboration with Dr. Roger Strair at the Cancer Institute of New Jersey and Dr. Eileen White at CABM, new strategies for specific killing of human leukemia cells have been developed, based on expression of transcriptional regulators and regulators of cell proliferation in malignant cells. We have demonstrated the ability of mutated adenoviruses to specifically replicate in, and kill cells derived from malignant human lymphoid neoplasms. Certain highly attenuated mutants of human adenoviruses retain the ability to replicate in and kill malignant B lymphocytes from a subset of patients with chronic lymphocytic leukemia (CLL), and thus, may have therapeutic potential. We are also collaborating with Drs. Strair and Conney and Chang (Rutgers University) to study the effects of differentiating agents in human leukemia.

Our laboratory also studies the molecular biology and pathogenesis of the human retroviruses, HTLV-1 and HIV. HTLV-1 infects human T cells. HTLV-1 infected individuals either remain asymptomatic, or develop either aggressive T-cell leukemias and lymphomas (ATL) or a central nervous system disease, HTLV-associated myelopathy (HAM/TSP). The variable outcome of HTLV-1 infection suggests that host factors such as the host immune response or intracellular factors that control HTLV-1 gene expression may contribute to the pathogenesis of HTLV-1 infection. Our laboratory identified models of HTLV-1 latent infection of human T cells, and showed that HTLV-1 gene expression can be induced by treatment of the cells with immune activation stimuli. This suggests that immune system activation may directly regulate the replication of HTLV-1and expression of viral transforming proteins, possibly contributing to the pathogenesis of HTLV-1-associated disease. The cellular mechanisms responsible for HTLV-1 activation as well as implications for viral pathogenesis are currently under study.

The roles of cellular transcription factors in the regulation of HIV gene expression are also under study. We identified the critical role of NF-kB in activating latent HIV and demonstrated the effects of Sp1 on viral replication. Studies of the replication of HIV LTR promoter mutants are on-going.

Immunohistochemical localization of RelA NF-kB in human prostate adenocarcinoma specimens. Many tumor cells exhibit nuclear staining for RelA (arrowheads), indicative of NF-kB activation.

Selected Publications1