Constitutive Activation of the JAK/STAT and Toll-Like Receptor Signaling Pathways in Adult T-Cell Leukemia/Lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATLL) caused by the retrovirus human T-cell leukemia virus type 1 (HTLV-1) infection is one of aggressive mature CD4+ T-cell neoplasms with a marked expansion of leukemic cells during the acute phase. ATLL is endemic in several regions of the world, especially in southwest Japan, the Caribbean basin, and parts of Central Africa. ATLL is divided into four clinical subtypes: acute, chronic, smoldering, and lymphoma type, based on the number of leukemic cells in peripheral blood, serum lactic acid dehydrogenase level, tumor lesions in various organs, and clinical course. The acute and lymphoma types still have an extremely poor prognosis, despite the advance in chemotherapy. Chemotherapy for ATLL has limited efficacy with median survivals of approximate one year. The HTLV-1 genome encodes not only structural proteins, but also non-structural proteins such as Tax, Rex, p13, p12, p30, p21Rex and HTLV-1 bZIP factor (HBZ). The functional analysis of the viral proteins such as Tax has shed light on the pathogenesis of ATLL. Tax is a crucial viral protein encoded by the pX region, which can induce viral replication and a variety of cellular genes associated with cytokine production, inhibition of apoptosis and cell cycle dysregulation (Arima 1999, Azimi 1998, Geleziunas 1998, Kanno 1994, Mori 1996b). Tax-induced gene regulation, which is linked to malignant transformation of HTLV-1-infected T-cells, has been shown to be mediated by CREB/ATF, NF-B and SRF pathways. Constitutive activation of NF-B is one of common features of HTLV-1–transformed T-cells and ATLL leukemic cells, since inhibition of NF-B activity reduces cell growth and induces apoptosis of cells, suggesting a central role of NF-B in their proliferation and survival. Moreover, Tax binds to the upstream kinase, the mitogen-activated protein kinase/ERK kinase kinase-1 and enhance its kinase activity (Harhaj 1999, Huang 2002, Jin 1999). Nevertheless, ATLL develops in a period 40 to 60 years after initial infection, indicating that the development of ATLL requires a multistep oncogenic process including accumulation of genetic mutations. HTLV-1 infection alone is not sufficient to induce neoplastic transformation of infected cells. In fact, viral gene expression is at extremely low levels in primary ATLL cells (Franchini 1984). Thus, the mechanism which develops ATLL still remains unclear.