CCR4, HTLV-1 infection, and ATL oncogenesis

Abstract

Adult T-cell leukemia (ATL) is a malignancy of mature CD4⁺ T cells that is etiologically associated with the infection of human T-cell leukemia virus type 1 (HTLV-1), an exogenous human retrovirus. Previously, we have shown that leukemic cells of most ATL patients express CCR4, a chemokine receptor known to be selectively expressed by T cell subsets such as Th2 cells, skin-homing memory/effector T cells, and regulatory T cells. Therefore, the expression of CCR4 suggests that ATL cells are mostly derived from one of these T cell subsets. We have also shown that Tax, the HTLV-1-encoded potent transcriptional activator, strongly induces the expression of CCL22, a CCR4 ligand, which promotes the cell-dependent transmission of HTLV-1 from HTLV-1-infected T cells to CCR4⁺ target T cells by inducing close cell-to-cell interactions. We have also shown that ATL cells aberrantly express the AP-1 family member Fra-2 which, by forming the heterodimer with JunD, potently induces the expression of not only CCR4 but also the genes such as c-Myb, MDM2 and Bcl-6, the well-known proto-oncogenes. Thus, Fra-2 is a novel oncogene of ATL, and CCR4 may be regarded as a useful tumor marker of ATL.