Insight into the Regulation of TIGAR's Pro-Oncogenic Functions and Roles in Metastatic Disease and Immune Evasion Through Studies of HTLV-1-Induced Adult T-cell Lymphoma

It is estimated that 15-20% of human cancers are etiologically linked to persistent viral infections, yet the mechanisms by which transforming viruses cooperate with host cellular oncogenes are myriad and not completely understood. The human T-cell lymphotropic virus type-1 (HTLV-1) infects CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL) --an aggressive hematological malignancy that is highly resistant to anti-cancer therapies and often correlates with poor clinical prognoses. Importantly, the HTLV1-1 pX-encoded tax-open reading frame II (tof-II) products, p30II and p13II, which are co-expressed through alternative mRNA splicing, are essential for the survival and persistence of HTLV-1-infected cells in vivo. My laboratory's research focuses on advancing our understanding of how the HTLV-1 latency-maintenance factors, p30II and p13II, cooperate with cellular and other viral oncoproteins (Tax, HBZ) to promote HTLV-1 carcinogenesis and ATLL disease progression. Our preliminary studies have demonstrated that p30II induces the expression of the TP53-induced glycolysis and apoptosis regulator (TIGAR), a 2,6-bis-fructose phosphatase that prevents the accumulation of damaging oncogene-induced ROS by increasing the available levels of NADPH and reduced glutathione. We have further shown that p30II activates cellular kinases, PI3K and Akt, and induces the serine-phosphorylation and mitochondrial targeting of the TIGAR protein; however, the mechanism(s) by which p30II induces the phosphorylation of TIGAR remains to be fully elucidated. Intriguingly, the p13II protein has been shown to interact with farnesyl pyrophosphate synthetase (FPPS) and induces the farnesylation, membrane localization, and activation of the p21-Ras GTPase which could activate the downstream effector PI3K. Based upon these findings, we hypothesize that p30II and p13II could functionally cooperate to induce the phosphorylation and mitochondrial targeting of TIGAR to enhance the survival and persistence of HTLV-1-infected cells. The following specific aims are proposed: 1) To determine if p30II and p13II work together to activate cellular kinases and induce the Ser-phosphorylation and mitochondrial targeting of TIGAR, 2) To determine how the modulation of TIGAR's antioxidant and metabolic functions by p30II promotes the oncogenic dysregulation of HTLV-1-infected T-lymphocytes, and 3) To determine if the p30II-induced phosphorylation and mitochondrial localization of TIGAR contribute to metastatic disease progression and immune evasion by HTLV-1+ lymphoblasts in an established NOD/scid xenograft model of HTLV-1-induced lymphomagenesis. The use of an in vivo murine xenograft model of HTLV-1-induced lymphomagenesis is justified as alternative in vitro cell-culture/organoid-based models cannot fully reproduce the complex heterotypic signaling interactions involved in viral carcinogenesis. The findings from in vivo studies will be validated using human HTLV-1+ ATLL tumor cell-lines and de-identified primary ATLL clinical samples. These studies will provide new mechanistic insight into the regulation of TIGAR's pro-oncogenic functions in HTLV-1+ lymphoid malignancies with broad translational implications for other cancers.