Bcr-abl fusion peptide-specific CD4+ T-lymphocyte clones have recently been shown to augment colony formation by chronic myelogenous leukemia (CML) cells in a bcr-abl type-specific and HLA class II-restricted manner without addition of exogenous antigen. These findings suggest that CML cells can naturally process and present endogenous bcr-abl fusion protein to CD4+ T lymphocytes in the context of HLA class II molecules. To verify this possibility, the ability of CML-derived dendritic cells (DCs) to present endogenous bcr-abl fusion protein to bcr-abl fusion peptide-specific CD4+ T-lymphocyte clones was investigated. The bcr-abl b3a2 peptide-specific and HLA-DRB1*0901-restricted CD4+ T-lymphocyte clones produced interferon-gamma in response to stimulation with monocyte-derived DCs from HLA-DRB1*0901+ patients with b3a2 type CML. In contrast, DCs from patients with HLA-DRB1*0901- or b2a2 type CML and those from healthy individuals did not exert stimulatory activity on bcr-abl-specific CD4+ T-lymphocyte clones. The response of CD4+ T-lymphocyte clones to CML-derived mature DCs was higher than that to immature DCs and was inhibited by anti-HLA-DR monoclonal antibody. These data suggest that CML-derived DCs can process and present endogenous bcr-abl fusion protein to CD4+ T lymphocytes.