Volume 12 Supplement 1
The HTLV-1 latency-maintenance factor p30II activates p53-dependent metabolic effectors to promote oncogene-activation and aberrant lymphoproliferation
© Harrod et al. 2015
Published: 28 August 2015
The human T-cell leukemia retrovirus type-1 (HTLV-1) transforms CD4+ T-lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive hematological malignancy that is refractive to most anticancer treatments. The highly-conserved pX sequence of HTLV-1 encodes three latency-maintenance factors: p30II, p13II and Hbz, which suppress proviral gene expression and help HTLV-1-infected cells evade detection by host immune responses as a prelude to neoplastic disease. We have previously demonstrated that p30II enhances the transcriptional and oncogenic functions of the c-Myc oncoprotein and induces aberrant lymphoproliferation through molecular interactions with the TIP60 acetyltransferase. Our recent studies have demonstrated the cooperation between p30II and c-Myc is dependent upon the induction of p53-dependent pro-survival signals. The p30II protein activates p53 and induces expression of p53-dependent metabolic effectors, including the Tp53-induced glycolysis and apoptosis regulator (TIGAR). Acute and lymphoma-stage ATLL clinical isolates frequently over express c-Myc and contain wildtype p53. We therefore hypothesize the induction of p53-dependent pro-survival signals by p30II could promote c-myc oncogene-activation during retroviral carcinogenesis by preventing c-Myc-induced cytotoxicity and apoptosis. Indeed, we have found that lentiviral-p30II induces mitochondrial expression of TIGAR and prevents the intracellular accumulation of c-Myc-induced reactive oxygen species (ROS) and inhibits oncogene-induced cellular senescence. Knockdown of TIGAR expression, using a small-interfering RNA (siRNA-tigar), inhibited the ability of p30II to suppress c-Myc-induced cytotoxicity. A panel of primary ATLL patient tumor lymphocytes exhibited over expression of TIGAR which correlated with c-Myc deregulation, compared to donor hu-PBMCs. Furthermore, we have shown that siRNA-knockdown of TIGAR expression sensitizes HTLV-1-transformed SLB1 lymphoma cells to oncogene-induced ROS and causes cellular senescence, suggesting siRNA-inhibition of TIGAR may be a plausible approach to sensitize ATLL tumor lymphocytes to anticancer chemotherapy drugs that induce oxidative damage. Our studies reveal a paradoxical role for p53-dependent metabolic effectors in promoting oncogene-activation by HTLV-1 p30II, which could promote proviral replication and leukemic disease progression.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.