Recent investigations have shown a therapeutic and cytogenetic response in chronic myelogenous leukemia (CML) patients treated with recombinant alpha 2-interferon (IFN alpha 2). Philadelphia chromosome-positive (and many Ph1-negative) chronic myelogenous leukemia cells transcribe a novel bcr-abl fusion mRNA which may confer a growth advantage upon these cells. We investigated the effect of IFN alpha 2 on the levels of bcr-abl transcript expression in three Ph1-positive CML cell lines, EM2, KCL22, and K562. Although IFN alpha 2 inhibited cell proliferation in all three CML cell lines, IFN alpha 2 had no effect on the level of bcr-abl mRNA expression in any of the CML cell lines. In contrast, IFN alpha 2 increased the expression of class I HLA gene products. We conclude that while the bcr-abl fusion gene and its transcript undoubtedly play key roles in the pathogenesis of CML, the antiproliferative effect of IFN alpha 2 in CML cell lines relies upon genetic mechanisms other than modulation of bcr-abl expression.