We have established a human IL-5 (hIL-5) dependent cell line, JYTF-1, derived from TF-1 parental human erythroleukemic cells by long-term cultivation in the presence of hIL-5. The ED50 values of hIL-5 for both TF-1 and JYTF-1 cell lines remained similar. However, when cells were grown in an optimal concentration of IL-5, some TF-1 cells but not JYTF-1 cells died via apoptosis. Although the rates of DNA synthesis were similar for TF-1 and JYTF-1 cells grown in IL-5, [3-H]thymidine releasing of pulse-labeled DNA analysis indicated that the viable TF-1 cells in IL-5 were more apoptosis-prone than were JYTF-1 cells. Therefore, in the JYTF-1 variant, the ability to suppress apoptosis has apparently been restored. The following findings suggest that overexpression of the hIL-5 receptor alpha-chain may be responsible for restoring the apoptosis suppression ability of IL-5: 1) the growth of JYTF-1 cells remained cytokine-dependent; 2) the proliferation of JYTF-1 cells in IL-5 was not mediated by autocrine secretion; 3) JYTF-1 and TF-1 cells responded similarly to other cytokines such as human erythropoietin; 4) Northern blot analysis revealed that JYTF-1 cells expressed approximately eightfold more IL-5 receptor alpha-chain mRNA than did TF-1. To our knowledge, JYTF-1 represents the first example in which coupling of mitogenesis stimulation and apoptosis suppression from otherwise uncoupled parental cells confers a phenotype of IL-5-dependent growth.