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A transgenic Drosophila melanogaster model to study HTLV-I oncoprotein Tax-driven leukemogenesis in vivo

Adult T-cell Leukemia/Lymphoma is an aggressive malignancy caused by HTLV-1 infection. HTLV-2 is genetically related to HTLV-1, but does not cause a malignant disease. The HTLV-1 Tax (Tax-1) viral transactivator is required for HTLV-1 expression and modulates the classical and non-canonical NF-κB pathways. Interaction of Tax-1 with IKKγ/NEMO results in constitutive activation of NF-κB in HTLV-1 infected cells, and contributes to HTLV-1-driven leukemogenesis. Tax-1 transgenic mice develop leukemia, lymphomas or spontaneous osteolytic bone metastases demonstrating Tax-1 oncogenic properties in vivo. However, the cellular pathways and the partners involved in vivo have not been described. HTLV-2 Tax (Tax-2) has properties different from Tax-1, including different post-translational modifications and different intracellular localization. Thanks to the availability of collection of mutants and RNAi lines, Drosophila melanogaster allows simple and exhaustive genetic screens. We generated transgenic Drosophila models expressing either Tax-1 or Tax-2 in the compound eye and plasmatocytes (leukocyte-like cell). We demonstrate that Tax-1 but not Tax-2 induces a perturbation of the crystalline array of the ommatidia and increase in plasmatocyte proliferation indicating that Tax-1 but not Tax-2 has transforming potential in Drosophila. We further show that induction of the eye phenotype is primarily dependent on Kenny, the Drosophila homolog of IKKγ/NEMO, upstream of Relish (NF-κB) activation. Using this model we were able to identify a novel post-translational modification which Tax-1 undergoes in addition to the well-known ubiquitylation and SUMOylation. This novel Tax post-translational modification was confirmed in HTLV-I transformed cell lines. Altogether, these results show that the Drosophila system is useful for dissecting the molecular mechanisms of HTLV-1-induced cell transformation in vivo.

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Correspondence to Ali Bazarbachi.

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Zakaria Kambris, Lama Hamadeh contributed equally to this work.

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Shirinian, M., Kambris, Z., Hamadeh, L. et al. A transgenic Drosophila melanogaster model to study HTLV-I oncoprotein Tax-driven leukemogenesis in vivo. Retrovirology 12 (Suppl 1), O40 (2015).

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