Oncogenic Properties Of Tax Protein From Human T Cell Leukemia Virus Type 2

Abstract Human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are two closely related retroviruses with the former causing adult T cell leukemia. A causal role for HTLV-2 with leukemia is much less well-defined and based on a handful of case reports. Both retroviruses encode highly homologous transforming proteins, Tax. Tax1 plays an essential role in triggering transforming activity, acting as a potent transcriptional activator of both viral and cellular genes. Tax1 is known to alter cellular signaling pathways by interacting with a number of cellular transcription factors including activating transcription factor/c-AMP response element-binding protein (ATF/CREB) and NF-κB. Specifically Tax enhances transcription of the viral genome by interacting with CREB/ATF that increases its affinity for conserved binding sites within the LTR and cellular promoters. With respect to the NF-κB pathway, cytoplasmic Tax acts by binding the IKKγ that induces the phosphorylation and degradation of IkB-α, the inhibitor of NF-κB, thereby allowing the NF-κB complex to migrate to the nucleus and induce gene expression. But little is known about the oncogenic properties of Tax2. Using a lentivirus tool, we found that Tax2 has a higher efficiency in immortalizing CD4+ memory T lymphocytes with CD3/TCRαβ/CD4/CD25/CD45RO/CD69 immunophenotype. NF-κB plays a causative role in tumorigenesis and tumor resistance to cancer therapy. Previous studies showed that involvement of Tax2 in canonical NF-κB pathway. Tax2 is localized in cytoplasm and interacts with IKKγ and the related proteins NRP/Optineurin, contributing to the induction of persistent activation of NF-κB in immortalized cells. Our study showed that Tax2-immortalized T cells exhibited constitutive activation of PI3 kinase/Akt, mitogen-activated protein kinase and STAT3 as well as increased levels of of surviving factors such as Mcl-1. Disruption of these oncogenic pathways led to growth retardation and apoptotic cell death of the Tax2-established T cell lines. Autophagy is emerging as a central component of antimicrobial host defense against diverse infections in addition to its cellular homeostasis function. Evidences showed that many pathogens have evolved to evade, subvert, or exploit autophagy in order to counteract this mechanism. We provide the first evidence that Tax2 induces autophagy to promote T cell survival and proliferation by interacting with the autophagy molecule complex containing beclin1 and PI3 kinase class III to form LC3+ autophagosome. Tax2-mediated autophagy promoted survival and proliferation of the immortalized T cells. Here we validated the oncogenic properties of Tax2 in promoting aberrant proliferation of human T lymphocytes. Our study sheds a new light on the oncogenic properties of HTLV-2 tax protein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-66. doi:1538-7445.AM2012-LB-66