Five monoclonal antibodies detected a surface antigen expressed exclusively on T-cell acute lymphoblastic leukemia (T-ALL) in a panel of 45 human hematopoietic cell lines, including T-cell lines derived from adult T-cell leukemia and those established by immortalization with human T-cell leukemia virus type 1 or Herpesvirus saimiri. Peripheral blood mononuclear cells, including fresh and activated T cells, were also completely devoid of this antigen. We designated this antigen as TALLA-1 (from T-ALL-associated antigen 1). By expression cloning, a cDNA clone encoding TALLA-1 was isolated from T-ALL cell line Molt-4. TALLA-1 was found to be a member of the transmembrane 4 superfamily (TM4SF). The cDNA was also essentially identical to A15, which was isolated from another T-ALL cell line, HPB-ALL, by differential hybridization with normal peripheral blood lymphocytes, and to CCG-B7, which was isolated from a brain cDNA library using CCG repeat as a probe. The gene product was now characterized in detail at the protein level. Northern blot analysis showed that the gene was expressed most strongly in brain, skeletal muscle and spleen. In a panel of 52 non-hematopoietic human cell lines, the majority of neuroblastoma cell lines were found to be positive for TALLA-1. Like ME491, CO-029 and L6, TALLA-1 may be another TM4SF member behaving as a potential tumor-associated antigen.