HTLV-1-Mediated Epigenetic Pathway to Adult T-Cell Leukemia-Lymphoma

Abstract

Human T-cell leukemia virus type 1 (HTLV-1), the first reported human oncogenic retrovirus, is the etiologic agent of highly aggressive, currently incurable diseases such as adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 proteins, including Tax and HBZ, have been shown to have critical roles in HTLV-1 pathogenicity, yet the underlying mechanisms of HTLV-1-driven leukemogenesis are unclear. The frequent disruption of genetic and epigenetic gene regulation in various types of malignancy, including ATL, is evident. In this review, we illustrate a focused range of topics about the establishment of HTLV-1 memory: (1) genetic lesion in the Tax interactome pathway, (2) gene regulatory loop/switch, (3) disordered chromatin regulation, (4) epigenetic lock by the modulation of epigenetic factors, (5) the loss of gene fine-tuner microRNA, and (6) the alteration of chromatin regulation by HTLV-1 integration. We discuss the persistent influence of Tax-dependent epigenetic changes even after the disappearance of HTLV-1 gene expression due to the viral escape from the immune system, which is a remaining challenge in HTLV-1 research. The summarized evidence and conceptualized description may provide a better understanding of HTLV-1-mediated cellular transformation and the potential therapeutic strategies to combat HTLV-1-associated diseases.

Keywords: ATLL; EZH2; HTLV-1; epigenetics; gene expression; gene mutations.

FIGURE 1

Transition of the molecular characteristics during latent period. The acquired cellular characteristics such as promoting cell proliferation and apoptotic resistance are conferred by viral genes in early-phase infected cells and by genetic/epigenetic abnormalities in late-phase ATL cells. The aberrant characteristics are acquired and imprinted, nevertheless Tax disappears. The consequent genotype and epigenotype support the differential phenotypes and the disease entities.

FIGURE 2

A hypothetical model of developmental pathway in HTLV-1-associated diseases [adapted from Waddington (1957)]. The height of the walls between the valleys (or canals) is determined by several molecular events. The first HTLV-1 infection and the accompanied epigenetic alterations change the cell fate. The permissive state induced by HTLV-1-infection allows following stochastic perturbations such as genetic mutations and dysregulation of the signaling pathways and clonal selection, paralleled by a decrease in transcriptional noise, and the stabilization of cell states (deepening of the valleys).

FIGURE 3

The mechanism-based medicines such as epigenetic drugs and inhibitors of signaling pathways could reprogram the fate of HTLV-1-infected cells (conceptualized as a reduction or elevation of the walls (blue arrows), which promote crossing or bypassing within the epigenetic landscape (black curved arrows) into the normal state).