Adult T cell Leukemia/Lymphoma (ATL) is a rare blood malignancy carrying a dismal prognosis (1), which is secondary to chronic infection with the human T cell leukemia virus type 1 (HTLV-1) (2). HTLV-1 infects 10 to 20 million individuals worldwide (3), of which around 5% develop ATL after a long latency period exceeding several decades (3).
ATL development is preceded by oligoclonal expansion of some HTLV-1 infected cells, driven by expression of the viral oncoprotein Tax (4). Tax is a multifaceted oncoprotein playing pleiotropic functions in ATL leukemogenesis (5–7). Tax is a transcriptional activator initiating transcription of HTLV-1 mRNAs from the 5’LTR promoter (8). Tax also alters several cellular genes and interacts with essential signaling pathways imperative for cellular transformation (5, 7–12). At early stages of HTLV-1 infection, Tax-mediates the constitutive activation of NF-κB, paramount for the proliferation and survival of infected T cells (5, 9). Tax connects to the IKK kinase complex, resulting in IκBα phosphorylation ubiquitination, and proteasomal degradation, ultimately activating NF-κB, a key regulator of T lymphocytes growth (8–10, 13–16).
Tax oncogenic capacity is well documented, as its sole expression transforms T cells in vitro, and induces leukemia in transgenic mice or flies (17–23). While the role of Tax in initiating ATL development is well established, its role in maintaining the leukemic phenotype is contentious. Indeed, Tax protein is not detected in most ATL cells (24–26). This was attributed to (1) multiple DNA methylations identified at Tax 5’LTR promoter or even deletion of the 5’LTR (9), (2) the strong immunogenicity of Tax protein ultimately leading to the rapid elimination of Tax-expressing cells by the immune system (27–29), (3) Tax-induced NF-κB activation which may result in cellular senescence (30–32). Nonetheless, primary ATL cells exhibit many properties of Tax-expressing cells, particularly constitutive NF-κB activation (33), proposed to result from mutations targeting the T-cell receptor and the NF-κB pathways (34, 35).
Nevertheless, some indications suggest a role of Tax in the maintenance of the leukemic phenotype in vivo. Transient bursts of Tax expression occur in small fractions of the ATL-derived cell line MT-1 (36, 37). Anti-Tax antibodies and Tax-specific cytotoxic T lymphocytes were reported in ATL patients (38, 39). Injection of ATL cells in animals led to the development of Tax specific CTL (40, 41), while a Tax peptide-pulsed dendritic cell vaccine showed some efficacy in treating Tax-positive ATL patients (42). Finally, treatment with arsenic trioxide (ATO) and interferon-alpha (IFN), which induces Tax proteasomal degradation, resulted in selective cell death of ATL cells and ensured long-lasting responses in ATL patients (17, 43–48).
HBZ, encoded by the complementary strand of HTLV-1 (49), is constantly expressed in asymptomatic carriers or ATL patients (50). HBZ decreases Tax expression (51) and inhibits NF-κB activity (52) to counterbalance its Tax-induced activation and preclude senescence (31, 32). Accordingly, HBZ overexpression in tax-transgenic flies rescues Tax-induced cellular transformation (53) providing a direct in vivo evidence for antagonistic roles between Tax and HBZ.
High levels of interleukin-10 (IL-10), an immunosuppressive cytokine modulated by both Tax and HBZ, were reported in ATL patients (44, 54, 55). IL-10 is an immuno-suppressive NF-κB target which enhances the proliferation of HTLV-1-infected cells (56). Anti-viral therapies of ATL decrease IL-10 levels in mice and patients (44, 48), restoring innate immunity (48).
Here, we demonstrate that the survival of primary ATL cells from patients is dependent on Tax expression and identify IL-10 as a key downstream target. These results strengthen the concept of ATL as Tax-dependent malignancy highlighting its role as a key therapeutic target.