Although human T cell leukemia virus type 1 and 2 (HTLV-1 and HTLV-2) share similar genetic organization, they have major differences in their pathogenesis and disease manifestation. HTLV-1 is capable of transforming T lymphocytes in infected patients resulting in adult T cell leukemia/lymphoma whereas HTLV-2 is not clearly associated with lymphoproliferative diseases. Numerous studies have provided accumulating evidence on the involvement of the viral transactivators Tax-1 versus Tax-2 in T cell transformation. Tax-1 is a potent transcriptional activator of both viral and cellular genes. Tax-1 post-translational modifications and specifically ubiquitylation and SUMOylation have been implicated in nuclear factor-kappaB (NF-κB) activation and may contribute to its transformation capacity. Although Tax-2 has similar protein structure compared to Tax-1, the two proteins display differences both in their protein–protein interaction and activation of signal transduction pathways. Recent studies on Tax-2 have suggested ubiquitylation and SUMOylation independent mechanisms of NF-κB activation. In this present review, structural and functional differences between Tax-1 and Tax-2 will be summarized. Specifically, we will address their subcellular localization, nuclear trafficking and their effect on cellular regulatory proteins. A special attention will be given to Tax-1/Tax-2 post-translational modification such as ubiquitylation, SUMOylation, phosphorylation, acetylation, NF-κB activation, and protein–protein interactions involved in oncogenecity both in vivo and in vitro.

Imiquimod is an immune response modifier currently used as a topical treatment of genital warts, basal cell carcinoma, cutaneous metastasis of malignant melanoma, and vascular tumors. We developed more efficient killers from the same family of compounds that can induce apoptosis without the prominent proinflammatory response associated with imiquimod. Among these new products, tk;4EAPB0203, a member of the imidazo IntroductionImiquimod, the first member of the imidazoquinolone family, is an immune response modifier with potent antiviral and antitumor activity in vivo. This product is currently approved as a topical treatment of external genital warts caused by human papilloma virus. [1][2][3] Recent evidence suggests that imiquimod is also efficacious as a topical therapy for basal cell carcinoma, intraepidermal keratinocyte neoplasias, cutaneous metastasis of malignant melanoma, and vascular tumors. 4,5 Moreover, imiquimod applied systemically in animal experiments has proven efficacy in a variety of transplantable tumors, including colon carcinomas, melanomas, lung sarcomas, mammary carcinomas, and bladder carcinomas. [6][7][8] It has been shown that imiquimod exerts its antiviral and antitumor effects in vivo, primarily by stimulating both the innate and adaptive immune responses. Imiquimod effects are mediated by the secretion of proinflammatory cytokines, including interferon-␣, interferon gamma, interleukin 6, interleukin 12, and tumor necrosis factor-␣. 9 However, recent in vitro studies showed that imiquimod, at clinically achievable concentrations, directly induces apoptosis in malignant keratinocytes and malignant melanoma cells, in the absence of immune cells. Furthermore, melanoma cell lines derived from imiquimod-resistant cutaneous metastasis, were also resistant to imiquimod in vitro. Interestingly, normal primary human melanocytes are resistant to imiquimod. 10 However, because imiquimod induces a significant proinflammatory response and stimulates the production of proinflammatory cytokines that can exert deleterious effects, more efficient killers from the same family of compounds, which can induce apoptosis without a prominent proinflammatory response, are needed. In a previous study, we designed and analyzed a series of imidazo[1,2-a]quinoxalines, as possible imiquimod analogues. We found that, contrary to imiquimod, these imidazo[1,2-a]quinoxalines inhibit both the production and the effects of tumor necrosis factor-␣; hence, these imiquimod antagonists can be considered as potential anti-inflammatory drugs. 11 Among these new products, EAPB0203 exhibits an important cytotoxic activity in vitro and is 50 times more potent than imiquimod against a human melanoma cell line (G.M. et al, unpublished data, 2007).The retrovirus HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL), an aggressive malignancy of CD4 ϩ T lymphocytes. 12 ATL is preceded by oligoclonal expansions of HTLV-I-infected activated T cells 13 as a result of the viral transactivator protein Tax expression, whic...

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In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34+ bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML.