Human T cell leukemia virus type 1 encodes an “accessory” protein named p13 ^II that is targeted to mitochondria and triggers a rapid flux of K ⁺ and Ca ²⁺ across the inner membrane. In this study, we investigated the effects of p13 ^II on tumorigenicity in vivo and on cell growth in vitro . Results showed that p13 ^II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13 ^II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro . Mixed culture assays revealed that the phenotype of the p13 ^II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13 ^II cell lines exhibited an enhanced response to Ca ²⁺ -mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine. p13 ^II -expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13 ^II as a negative regulator of cell growth and underscore a link between mitochondria, Ca ²⁺ signaling, and tumorigenicity.

Temozolomide (TMZ) administered daily with radiation therapy (RT) for 6 weeks, followed by adjuvant TMZ for 6 cycles, is the standard therapy for newly diagnosed glioblastoma (GBM) patients. Although TMZ is considered to be a safe drug, it has been demonstrated to cause severe myelotoxicity; in particular, some case reports and small series studies have reported severe myelotoxicity developing during TMZ and concomitant RT. We performed a prospective study to analyze the incidence of early severe myelotoxicity and its possible clinical and genetic factors. From November 2010 to July 2012, newly diagnosed GBM patients were enrolled. They were eligible for the study if they met the following criteria: pathologically proven GBM, age 18 years and older, an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate renal and hepatic function, and adequate blood cell counts before starting TMZ plus RT. Grading of hematologic toxicity developing during radiation and TMZ was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Clinical factors from all patients were recorded. The methylation status and polymorphic variants of O-methylguanine-DNAmethyl-transferase gene in peripheral blood mononuclear cells, and polymorphic genetic variants of genes involved in the pharmacokinetics and pharmacodynamics of TMZ, were analyzed. For genetic analyses, patients with toxicity were matched (1:2) for age, performance status, anticonvulsants, and proton pump inhibitors with patients without myelotoxicity. We enrolled 87 consecutive GBM patients: 32 women and 55 men; the average age was 60 years. During TMZ and RT, 4 patients (5%) showed grade 3-4 myelotoxicity, and its median duration was 255 days. Predictor factors of severe myelotoxicity were female sex, pretreatment platelet count of ≤3,00,000/mm, methylated O-methylguanine-DNA methyltransferase promoter in the hematopoietic cell system, and specific polymorphic variants of the cytochrome P450 oxidoreductase and methionine adenosyltransferase 1A genes. Although we studied a small population, we suggest that both clinical and genetic factors might simultaneously be associated with severe myelosuppression developed during TMZ plus RT. However, our results deserve validation in larger prospective studies and, if the factors associated with severe myelotoxicity are validated, dose adjustments of TMZ for those patients may reduce the risk of severe myelotoxicity during the concomitant treatment.

The present study investigated the function of p13, a mitochondrial protein of human T-cell leukemia virus type 1 (HTLV-1). Although necessary for viral propagation in vivo, the mechanism of function of p13 is incompletely understood. Drawing from studies in isolated mitochondria, we analyzed the effects of p13 on mitochondrial reactive oxygen species (ROS) in transformed and primary T cells. In transformed cells (Jurkat, HeLa), p13 did not affect ROS unless the cells were subjected to glucose deprivation, which led to a p13-dependent increase in ROS and cell death. Using RNA interference we confirmed that expression of p13 also influences glucose starvation-induced cell death in the context of HTLV-1–infected cells. ROS measurements showed an increasing gradient from resting to mitogen-activated primary T cells to transformed T cells (Jurkat). Expression of p13 in primary T cells resulted in their activation, an effect that was abrogated by ROS scavengers. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels; in the context of the HTLV-1 propagation strategy, p13 could increase the pool of “normal” infected cells while culling cells acquiring a transformed phenotype, thus favoring lifelong persistence of the virus in the host.

Individuals infected with HTLV-1 harbor the virus mainly in CD4+ memory T-cells as a lifelong infection that remains subclinical in the majority of cases. However, about 3-5% of HTLV-1-infected individuals develop an aggressive T-cell neoplasia (ATLL) or a neurodegenerative disease (TSP/HAM) after a latency period ranging from years to decades. This review summarizes the current knowledge of the effects of the HTLV-1 proteins Tax, p13 and p12 on cell death and survival pathways. Tax, the major oncogenic determinant of HTLV-1, enhances cell survival through its effects on the NF-kappaB, CREB and AKT pathways and on the tumor suppressors p53 and Rb. p13 is targeted to the inner mitochondrial membrane and sensitizes cells to the Fas/ceramide apoptotic pathway and reactive oxygen species-mediated cell death. p12 enhances release of calcium from the endoplasmic reticulum and therefore may influence calcium-dependent apoptotic signals, including opening of the mitochondrial permeability transition pore. The long-term fate of HTLV-1-infected cells (apoptosis, survival, transformation) may therefore depend on the balance of the effects of Tax, p13 and p12 on cell death pathways.