NF ‐κB signaling mechanisms in HTLV ‐1‐induced adult T‐cell leukemia/lymphoma

Abstract

<p class="first" id="P1">The human T-cell leukemia virus type 1 (HTLV-1) is a complex deltaretrovirus linked to adult T-cell leukemia/lymphoma (ATLL), a fatal CD4+ malignancy in 3–5% of infected individuals. The HTLV-1 Tax regulatory protein plays indispensable roles in regulating viral gene expression and activating cellular signaling pathways that drive the proliferation and clonal expansion of T cells bearing HTLV-1 proviral integrations. Tax is a potent activator of NF-κB, a key signaling pathway that is essential for the survival and proliferation of HTLV-1 infected T cells. However, constitutive NF-κB activation by Tax also triggers a senescence response, suggesting the possibility that only T cells capable of overcoming NF-κB-induced senescence can selectively undergo clonal expansion after HTLV-1 infection. Tax expression is often silenced in the majority of ATLL due to genetic alterations in the <i>tax</i> gene or DNA hypermethylation of the 5′-LTR. Despite the loss of Tax, NF-κB activation remains persistently activated in ATLL due to somatic mutations in genes in the T/B-cell receptor (T/BCR) and NF-κB signaling pathways. In this review, we focus on the key events driving Tax-dependent and independent mechanisms of NF-κB activation during the multi-step process leading to ATLL. </p><p id="P2">Chronic activation of the NF-κB pathway is a key event in HTLV-1-induced leukemia. HTLV-1 Tax directs RNF8 and LUBAC to assemble hybrid polyubiquitin chains to promote TAK1, IKK and NF-κB activation, and clonal expansion. Tax expression frequently becomes silenced by genetic/epigenetic mechanisms. Somatic mutations in B/T cell receptor signaling pathways then develop to drive Tax-independent NF-κB activation in ATLL cells. </p><p id="P3"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/207dd604-51cb-43fb-b04c-77516660cde7/PubMedCentral/image/nihms963993u1.jpg"/> </div> </p>