Molecular Dissection of the Leukaemia Promoting Properties of the HTLV-1 Tax Oncoprotein

Human T-cell leukaemia virus (HTLV-1) is the aetiological agent of an aggressive adult T-cell leukaemia/lymphoma (ATLL). The events that promote transformation and immortalisation of CD4+ T cells by HTLV-1 are incompletely understood but the burden of evidence incriminates the viral tax product in this process. Tax is a multifunctional oncoprotein and pleiotropic regulator of viral and cellular gene expression, and a potent inducer of cell proliferation and transformation. Tax-transgenic mice develop thymically derived large-cell lymphomas and leukaemia with clinical, pathological and immunological characteristics typical of ATLL. In this study, we will use lentiviral gene transfer to transduce epitope-tagged Tax into primary haematopoietic progenitor cells. We will examine the effects of Tax and genotoxic stress on haematopoiesis and leukaemogenesis and will use mass-spectrometry and immuno-fluorescence imaging to identify and characterise host-cell proteins that support the Tax-mediated immortalisation of T cells. Understanding the process by which HTLV-1 causes leukaemia will provide new opportunities to develop clinically relevant therapies for ATLL and for chemotherapy-resistant leukaemias in general.