CELLULAR PATHWAY DEREGULATION AND POTENTIAL TARGETED THERAPY FOR ADULT T-CELL LEUKEMIA

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T-cell Leukemia (ATL), a lymphoproliferative disorder with a very poor prognosis. While approximatively 5% of individuals infected with HTLV-1 develop ATL within twenty years of first infection, the molecular mechanism that the virus uses to induce ATL is not entirely understood. microRNAs are posttranscriptional regulators involved in a wide range of biological processes. Based on biological functions, alteration of their expression can potentially contribute to tumor initiation and progression. The purpose of this thesis is to study changes in miRNA expression and their role in the deregulation of cellular pathways essential in HTLV-1-transformed and ATL cells. Moreover, the absence of an effective treatment for patients led to investigation of potential therapeutic strategies for ATL. Since previous findings show that DNA repair is impaired in HTLV-1-transformed cells, this thesis is focused on targeting DNA repair as a new therapeutic option in ATL. More specifically, the aim is the study of antiproliferative effects and cytotoxicity of PARP and helicase inhibitors in HTLV-1-transformed and ATL cells.