Interaction of HTLV-1 Tax & Hbz in Transformation Abstract Human T-cell leukemia virus type 1 (HTLV-1) is the cause of a refractory T cell lymphoproliferative disorder, designated adult T-cell leukemia lymphoma (ATLL). HTLV-1 encodes two oncogenes, Tax and Hbz, each of which induces T cell lymphoma in transgenic mice. Tax is a potent transcriptional trans activator protein that also induces genetic instability. However, Tax is immunogenic and its expression is down-regulated after ATLL develops. Hbz RNA and protein have separable activities that promote T cell activation and proliferation. Hbz is continuously expressed throughout infection. We hypothesize that the predominant role of Tax is T cell lymphoma initiation, and the predominant role of Hbz is a T cell lymphoma promoter. We developed three animal models to test this hypothesis and elucidate the underlying molecular mechanisms for the roles of these oncogenes and their interactions. In our Tax+Hbz- transgenic mice, Tax is under the regulation of a doxycycline inducible promoter. T cell lymphomas develop in the presence of doxycycline, and regress in its absence. In our Tax-Hbz+ transgenic mice, full length Hbz RNA and functional epitope tagged Hbz protein are expressed in activated T cells and induce T cell lymphomas. Double transgenic Tax+Hbz+ mice develop tumors more rapidly than either single transgenic model. These animals have imaging markers to monitor doxycycline induction and Tax activity. In Aim 1, we will compare full exon genomics and transcriptomics by RNAseq of Tax+Hbz-, Tax-Hbz+, and Tax+Hbz+ mice all maintained on doxycycline in order to determine if Tax induces genetic instability in our mouse model and whether mutations occur in genes that are frequently mutated in ATLL. We will use RNAseq to identify genes responsible for the unique features of each transgene, and if there are distinct alterations in double transgenic animals compared to single transgenic animals. In Aim 2, we will withdraw doxycycline in order to determine if tumors continue to proliferate in Tax+Hbz+ animals, but regress in Tax+Hbz- animals, and to determine, by RNAseq, the genes responsible for the different biological results. We will compare our transcriptomic alterations to those in ATLL. In Aim 3, we will use shRNAs or lentivirus expression of key genes identified in the transgenic models, to test high priority candidates from our murine model in short-term cultured ATLL cell lines. These studies will provide new insights into how Tax and Hbz mediate transformation, which could lead to new therapies for ATLL and identification of novel biomarkers for this disease.