Thursday, June 8, 2023
6/8/2023
The retrovirus human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm that occurs in ~5% of infected individuals after a long latent period. HTLV-1 infection is also associated with a host of inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax is a multifunctional trans-activating protein and key player in pathogenesis. Tax is required for viral gene expression by coordinating the recruitment of the CREB transcription factor and CBP/p300 co-activators to the 5’ viral long terminal repeat (LTR). Tax is also a potent oncogene and induces the persistent activation of the NF- kB pathway to drive the survival, expansion and persistence of HTLV-1-infected T cell clones. Emerging studies have revealed that the expression of HTLV-1 genes is highly dynamic, with prolonged periods of latency to evade antiviral immune responses. However, little is known about host proteins that regulate Tax expression or protein stability which may impact on viral gene expression, host antiviral immunity and the survival of HTLV-1-infected T cells. Furthermore, there is an urgent and unmet clinical need for novel therapeutic approaches for ATLL, a highly aggressive and lethal disease. We have conducted a kinome-wide shRNA screen to identify host factors important for the survival of an HTLV-1- transformed T cell line. The top hit in the screen was the tyrosine kinase receptor KDR/VEGFR2, which we have validated as a critical survival factor in a subset of HTLV-1-transformed T cell lines. Inhibition of KDR with shRNA or a small molecule inhibitor induced cell death selectively in KDR+ HTLV-1-transformed T cells. Furthermore, inhibition of KDR blunted the chronic activation of NF-kB and triggered the degradation of the Tax protein. In this exploratory application, we will investigate the mechanisms by which KDR signaling regulates Tax stability, as well as the role of KDR in the activation of oncogenic signaling pathways, cell survival and migration of HTLV-1- transformed T cells. The central hypothesis driving these investigations is that KDR activates oncogenic signaling pathways in HTLV-1-infected T cells that promote cell survival and the stability of the Tax protein. We will test this hypothesis experimentally with the following Specific Aims: (1) determine the oncogenic role of VEGFR2/KDR in HTLV-1-transformed T cells, and (2) determine how KDR signaling regulates Tax protein stability and viral gene expression. Completion of the proposed studies will provide new insight into the complex regulation of the HTLV-1 Tax oncoprotein and viral gene expression and may lead to new strategies to curtail the proviral load in HTLV-1-infected individuals.
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