Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation leading to the Philadelphia chromosome. Two fusion genes are created by this translocation: bcr/abl and abl/bcr. The fusion regions of both translocation products are unique and strictly limited to leukemia cells, giving rise to potential tumor-specific antigens. Although several studies on the immunogenicity of peptides spanning the bcr/abl fusion region have been reported, little is known about the corresponding reciprocal translocation product abl/bcr. Here we report that synthetic peptides representing the fusion region of the abl/bcr forms a1bb3 and a1bb4 can be specifically recognized by HLA-A2-restricted cytotoxic T lymphocytes from healthy donors. Furthermore, HLA-matched a1bb3-expressing CML cells can be recognized by a1bb3-specific HLA-A2-restricted T cells, indicating natural processing and presentation of abl/bcr protein by leukemia cells. Moreover, a 19-mer peptide encompassing this class I-binding sequence also elicited a1bb3-specific class II-restricted T-cell responses. Thus, both class I- and class II-restricted T-cell responses can be stimulated in healthy donors by abl/bcr peptides in vitro. Because abl/bcr is expressed in the majority of CML patients, it may represent a highly leukemia-specific antigen with potential use in immunotherapy.