ARNOLD B. RABSON, M.D.
Child Health Institute of New Jersey
Department of Molecular Genetics and Microbiology
RBHS, Robert Wood Johnson Medical School
Department of Biochemistry and Molecular Biology
RBHS, Robert Wood Johnson Medical School
M.D., 1980, Brown University
Telephone: (732) 235-9523
Fax: (732) 235-8612
Pathogenesis of human retroviral infections; role of transcriptional regulators in cancer and development
Our laboratory studies the molecular basis of human disease pathogenesis. We are particularly focused on human retroviral infections and on the role that altered gene regulation plays in human cancers and in development.
It is estimated that over 5-15 million people are infected by the human T-cell leukemia virus (HTLV-1), the first identified human retrovirus, and 2-5% of them are likely to develop a serious HTLV-1-associated disease. Our laboratory is interested in the pathogenesis of HTLV-1 infection, in particular, the differential mechanisms by which HTLV-1 causes an aggressive and fatal T cell leukemia/lymphoma (Adult T-Cell Leukemia, ATL) in some infected individuals and a series of immunological disorders including a neurological disease of the spinal cord in other infected people. These disorders occur in only a minority of patients, years after initial infection. This suggests that there are important interactions between the virus and the host that determine its pathogenicity. We have identified and characterized the mechanisms by which the expression of HTLV-1 can be activated in infected human T-lymphocytes leading ultimately to disease pathogenesis. Immune activation of HTLV-1-infected T-cells, by stimulation through the T-cell receptor, can potently induce HTLV-1 gene expression, including the expression of the HTLV-1 Tax protein, a transcriptional activator capable of immortalizing T-cells. We have recently shown that induction of Tax is mediated through increased stability of the tax/rex mRNA and are currently further investigating these mechanisms.
We hypothesized that stimulation of infected T-cells through their T-cell receptor leading to enhanced HTLV-1 gene expression, would result in increased T-cell proliferation. This could explain the polyclonal to oligoclonal proliferation to ultimately monoclonal proliferation of infected T-cells that characterizes HTLV-1-associated diseases. Using a transgenic mouse model in which the HTLV-1 LTR promoter region directs the expression of the oncogenic viral Tax protein, responsible for transformation of infected T-cells, we have shown that T-cell activation of CD4 T cells from these mice will induce HTLV-1 LTR expression, resulting in induction of Tax oncogene expression and long-term survival and proliferation of these cells. The stimulated LTR-Tax CD4 T cells have the phenotype of HTLV-1 leukemia cells and can grow upon transplantation into immunocompromised animals, thus providing a model of HTLV-1 leukemia.
Our laboratory also studies the roles of transcriptional regulation in the pathogenesis of human cancers. We have identified mutations in the “non-canonical” NF-κB pathway in a number of human leukemias and lymphomas. We have identified target genes through which mutated NF-κB2 may act to induce increased T-cell proliferation, survival and oncogenesis and are now characterizing how these targets may function in the development of lymphomas. In collaboration with Dr. Strair at CINJ, we are also working to develop novel therapies for human leukemias aimed at blocking NF-κB, and have participated in a clinical trial examining the effects of NF-κB inhibition by choline-magnesium trisalicylate in acute myeloid leukemia therapy. Results from this trial have shown that sets of NF-kB and Wnt/-catenin targets genes are modulated in patients receiving CMT, proving effective targeting of these pathways by the drug.
Recently, we have also begun to examine the effects of novel cell regulatory genes that are expressed in cancer, stems cells and development and have focused on a highly conserved gene, PDCD2. We have shown that the PDCD2 gene is essential for cancer cell growth and for stem cell function, as well as for early embryonic development. PDCD32 knockout results in p53 activation and cell cycle arrest. These studies are elucidating new pathways essential for normal development and for cancer.
Medina D, David K, Lin Y, Schaar D, Patel V, Gharibo M, Bannerji R, Walton K, Aisner J, Rabson AB, Strair R. (2017) Choline-magnesium trisalicylate modulates acute myelogenous leukemia gene expression during induction chemotherapy. Leuk Lymphoma 58:1227-30
Shou P, Chen Q, Jiang J, Xu C, Zhang J, Zheng C, Jiang M, Velletri T, Cao W, Huang Y, Yang Q, Han X, Zhang L, Wei L, Rabson AB, Chin YE, Wang Y, Shi Y. (2016) Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells. Oncogene 35:5953-62
Cao K, Wang G, Li W, Zhang L, Wang R, Huang Y, Du L, Jiang J, Wu C, He X, Roberts AI, Li F, Rabson AB, Wang Y, Shi Y. (2015) Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. Oncogene 34:5960-70
Granier CJ, Wang W, Tsang T, Steward R, Sabaawy HE, Bhaumik M, Rabson AB. (2014) Conditional inactivation of PDCD2 induces p53 activation and cell cycle arrest. Biol Open 3:821-31
Kramer J, Granier CJ, Davis S, Piso K, Hand J, Rabson AB, Sabaawy HE. (2013) PDCD2 controls hematopoietic stem cell differentiation during development. Stem Cells Dev 22:58-72
Barboza N, Minakhina S, Medina DJ, Balsara B, Greenwood S, Huzzy L, Rabson AB, Steward R, Schaar DG. (2013) PDCD2 functions in cancer cell proliferation and predicts relapsed leukemia. Cancer Biol Ther 14:546-55
Medina DJ, Goodell L, Glod J, Gelinas C, Rabson AB, Strair RK. (2012) Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor kB pathways. Haematologica 97:1255-63
Fu J, Qu Z, Yan P, Ishikawa C, Aqeilan RI, Rabson AB, Xiao G. (2011) The tumor suppressor gene WWOX links the canonical and noncanonical NF- κB pathways in HTLV-I Tax-mediated tumorigenesis. Blood 117:1652-61
De Lorenzo MS, Baljinnyam E, Vatner DE, Abarzua P, Vatner SF, Rabson AB. (2011) Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 32:1381-7
Swaims AY, Khani F, Zhang Y, Roberts AI, Devadas S, Shi Y, Rabson AB. (2010) Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells. Blood 116:2994-3003
Strair RK, Gharibo M, Schaar D, Rubin A, Harrison J, Aisner J, Lin HC, Lin Y, Goodell L, Anand M, Balsara B, Dudek L, Rabson A, Medina DJ. (2008) Nuclear factor-κB modulation in patients undergoing induction chemotherapy for acute myelogenous leukemia. Clin Cancer Res 14:7564-8