Abstract
Of the millions of HTLV-1 infected carriers worldwide, 3–5% will develop an aggressive T-cell neoplasm that is highly refractory to conventional therapy. The virus carries the Tax oncogene which constitutively activates the NFκB pathway. This co-option of signaling through NFκB provides for the HTLV-1 infected cell an escape from cell cycle arrest and apoptosis, a steady source of growth factors, and a mechanism by which the virus can activate its own target cell. Therapies that target the NFκB pathway sensitize adult T-cell leukemia/lymphoma (ATLL) cells to apoptosis. A focus on translational interrogation of NFκB inhibitors in animal models and ATLL patients is needed to advance NFκB-targeted ATLL therapies to the bedside.
Highlights
Of the 15–20 million HTLV-1 infected carriers worldwide, more than 500,000 will develop an aggressive T-cell neoplasm that is highly refractory to conventional therapy
Lymphoma is commonly associated with constitutive NFκB activity and oncogenic human viruses, including Epstein-Barr virus (EBV), Human papillomavirus (HPV), Hepatitis B virus (HBV), and Hepatitis C virus (HCV) all carry viral factors that directly target and co-opt the NFκB pathway during oncogenesis
HTLV-1 Tax targets the pathway at several points. (a) Tax leads to the activation of receptor-associated kinases that signal through the NFκB pathway [16,17]. (b) Tax directly binds to IKKγ (NEMO) which leads to constitutive phosphorylation and degradation of the
Summary
Of the 15–20 million HTLV-1 infected carriers worldwide, more than 500,000 will develop an aggressive T-cell neoplasm that is highly refractory to conventional therapy. Despite intensive efforts to improve the overall survival, adult T-cell leukemia/lymphoma (ATLL) remains one of the hematologic malignancies with the poorest prognosis. ATLL is typically preceded by decades of clinical latency during which infected cells accumulate selectable traits leading to malignant transformation. Host pathways commandeered by the virus can be used as therapeutic targets and a Viruses 2011, 3 constitutively activated NFκB pathway has emerged as an essential hit in the development of ATLL. Mouse models of ATLL have been created to recapitulate the virus induced, NFκB-dependent leukemias and lymphomas. Translational investigations of NFκB inhibitors in mouse models and ATLL patients are necessary to bring this work from bench to bedside
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