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New therapies are needed for patients with T-cell lymphoblastic leukemia (T-ALL) who do not respond to standard chemotherapy. Our previous studies showed that the mTORC1 inhibitor everolimus increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis in T-ALL cells. Studies in T-ALL-xenografted NOD/SCID mice demonstrated that everolimus improved their response to the glucocorticoid (GC) dexamethasone. Here we show that verapamil, a calcium antagonist used in the treatment of supraventricular tachyarrhythmias, enhanced the effects of everolimus on ROS and cell death in T-ALL cell lines. The death-enhancing effect was synergistic and was confirmed in assays on a panel of therapy-resistant patient-derived xenografts (PDX) and primary samples from T-ALL patients. The verapamil-everolimus combination produced a dramatic reduction in the levels of G6PD and induction of p38 MAPK phosphorylation. Studies of NOD/SCID mice inoculated with refractory T-ALL PDX cells demonstrated that the addition of verapamil to everolimus plus dexamethasone significantly reduced tumor growth in vivo. Taken together, our results provide a rationale for repurposing verapamil in association with mTORC inhibitors and GC to treat refractory T-ALL. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus-1 (HTLV-1) is a retrovirus that persistently infects CD4+ T-cells, and is the causative agent of adult T-cell leukemia/lymphoma (ATLL), tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and several inflammatory diseases. T-cell transformation by HTLV-1 is driven by multiple interactions between viral regulatory proteins and host cell pathways that govern cell proliferation and survival. Studies performed over the last decade have revealed alterations in the expression of many microRNAs in HTLV-1-infected cells and ATLL cells, and have identified several microRNA targets with roles in the viral life cycle and host cell turnover. This review centers on miR-150-5p, a microRNA whose expression is temporally regulated during lymphocyte development and altered in several hematological malignancies. The levels of miR-150-5p are reduced in many HTLV-1-transformed- and ATLL-derived cell lines. Experiments in these cell lines showed that downregulation of miR-150-5p results in activation of the transcription factor STAT1, which is a direct target of the miRNA. However, data on miR-150-5p levels in freshly isolated ATLL samples are suggestive of its upregulation compared to controls. These apparently puzzling findings highlight the need for more in-depth studies of the role of miR-150-5p in HTLV-1 infection and pathogenesis based on knowledge of miR-150-5p-target mRNA interactions and mechanisms regulating its function in normal leukocytes and hematologic neoplasms. [ABSTRACT FROM AUTHOR]

The discovery of human retroviruses in the early 1980s revealed the existence of viral-encoded non-structural genes that were not evident in previously described animal retroviruses. Based on the absence or presence of these additional genes retroviruses were classified as 'simple' and 'complex', respectively. Expression of most of these extra genes is achieved through the generation of alternatively spliced mRNAs. The present review summarizes the genetic organization and expression strategies of human complex retroviruses and highlights the converging mechanisms controlling their life cycles. [ABSTRACT FROM AUTHOR]

Abstract: Human T-cell leukemia virus type-1 (HTLV-1) encodes a mitochondrial protein named p13. p13 mediates an inward K+ current in isolated mitochondria that leads to mitochondrial swelling, depolarization, increased respiratory chain activity and reactive oxygen species (ROS) production. These effects trigger the opening of the permeability transition pore and are dependent on the presence of K+ and on the amphipathic alpha helical domain of p13. In the context of cells, p13 acts as a sensitizer to selected apoptotic stimuli. Although it is not known whether p13 influences the activity of endogenous K+ channels or forms a channel itself, it shares some structural and functional analogies with viroporins, a class of small integral membrane proteins that form pores and alter membrane permeability. [Copyright &y& Elsevier]

Human T cell leukemia virus type 1 encodes an "accessory" protein named p13II that is targeted to mitochondria and triggers a rapid flux of K+ and Ca2+ across the inner membrane. In this study, we investigated the effects of p13II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13II 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 p13II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13II cell tines exhibited an enhanced response to Ca2+-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, p13II-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 p13II as a negative regulator of cell growth and underscore a link between mitochondria, Ca2+ signaling, and tumorigenicity. [ABSTRACT FROM AUTHOR]

Abstract: Human T-cell leukemia virus type 1 (HTLV-1) infection is characterized by life-long persistence of the virus in the host. While most infected individuals remain asymptomatic, 3–5% will eventually develop adult T-cell leukemia/lymphoma (ATLL) or tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM) after a clinical latency that can span years (TSP/HAM) to decades (ATLL). The major oncogenic determinant among HTLV-1 proteins is the Tax transactivator, which influences the expression and function of a great number of cellular proteins, drives cell proliferation, reduces cell death, and induces genetic instability. The present review is focused on the current knowledge of p13, an HTLV-1 accessory protein targeted to the inner mitochondrial membrane and, under certain conditions, to the nucleus. In mitochondria, p13 produces an inward K+current that results in an increased production of ROS by mitochondria. These effects are linked to the protein’s effects on cell turnover which include activation of primary T-cells and reduced proliferation/sensitization to death of tumor cells. Recent findings suggest that in the presence of Tax, p13 is subjected to ubiquitylation and partly targeted to the nucleus. Nuclear p13 binds Tax and inhibits its transcriptional activity. These findings suggest that the protein might exert distinct functions depending on its intracellular localization and influence both the turnover of infected cells and the balance between viral latency and productive infection. [ABSTRACT FROM AUTHOR]

Abstract: Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus that infects more than 20 million people worldwide, is the etiological agent of ATLL (adult T-cell leukemia/lymphoma), an aggressive leukemia of CD4+ T lymphocytes which arises in a small percentage of infected individuals after a long clinical latency. Tumor emergence is attributed primarily to the oncogenic activity of the viral protein Tax, which drives the expression of viral transcripts and controls the expression and function of a broad variety of host-cell genes involved in proliferation, genetic stability and apoptosis. Nevertheless, many aspects of HTLV-1 replication, persistence and pathogenesis remain to be understood. The emerging role of microRNAs in tumor development and viral infection has prompted investigations on the interactions between HTLV-1 and the microRNA regulatory network. In the present review we discuss recent data demonstrating changes in cellular microRNA expression in HTLV-1-infected cell lines and ATLL cells, and the functional impact of a subset microRNAs deregulated by HTLV-1 on cellular gene expression and signal transduction pathways. Mechanisms through which the viral proteins may influence microRNA expression are discussed. Results of searches for potential cellular microRNAs that target viral transcripts and for microRNAs produced by HTLV-1 are described. Observations along with regarding the expression of tRNA-derived small regulatory RNAs in HTLV-1-infected cells are presented. [ABSTRACT FROM AUTHOR]