HTLV-I is the causative agent of adult T-cell leukemia (ATL). However, the precise mechanism underlying the neoplastic cell growth of ATL remains unclear. In this study, we established a leukemic cell line, termed SYK-11L(+), from tumor cells (S-YU) in an in vivo cell proliferation model of ATL using severe combined immunodeficiency (SCID) mice. Unexpectedly, SYK-11L(+) was found to have no tumorigenicity in SCID mice. Flow cytometric analysis showed that S-YU expressed cell adhesion molecules including CD44, ICAM-1 and OX40, whereas SYK-11L(+) had lost the expression of these molecules. The administration of anti-OX40 monoclonal antibody inhibited the engraftment of S-YU cells into SCID mice, suggesting that OX40 is a potential target for immunotherapy. Significant differences in responsiveness to IL-2 and IL-15 were observed between the two cell types. To better understand the molecular basis of tumorigenicity, cDNA microarray analysis was performed using tumorigenic S-YU and non-tumorigenic SYK-11L(+) cells. We obtained several candidate genes differentially overexpressed in S-YU compared with SYK-11L(+). Interestingly, one such gene, regulator of G protein signaling 1 (RGS1), was shown to be overexpressed in most ATL patients. Further characterization of the differentially expressed molecules, such as OX40 and RGS1, would provide useful information not only to elucidate the mechanism of ATL cell growth in vivo, but also to develop novel molecularly targeted therapies.