The specific enhancement of interferon alpha induced growth inhibition by BCR/ABL only occurs in multipotent cells

Introduction: The causative oncogene in CML is the BCR/ABL protein tyrosine kinase. This stem cell disease is often treated with interferon alpha (IFN-α) which can initiate haematological and cytological remission which is associated with increased survival. There is however no clear indication of why CML cells are more responsive to IFN-α. Materials and methods: To establish if BCR/ABL increases the sensitivity of multipotent cells to IFN-α a temperature sensitive mutant of BCR/ABL was expressed in the multipotent haemopoietic stem cell line FDCP-Mix. The effect of IFN-α in terms of proliferation, induction of apoptosis, changes in cell cycle inhibitor proteins, and differentiation was assessed by [3H]thymidine incorporation, Annexin V and Western blot analysis. Results: When the BCR/ABL tyrosine kinase was activated, the IFN-α-induced inhibition on the growth rate of the FDCP-Mix cell population was more marked than in control populations. The BCR/ABL-mediated effect was due to decreased rates of DNA synthesis. There was no IFN-α-mediated induction of apoptosis. This enhanced BCR/ABL mediated growth inhibition occurred over a range of growth factor concentrations and was independent of changes in p21Cipl and p27Kip levels. When FDCP-Mix cells were induced to differentiate into mature macrophages and neutrophils in the presence of IFN-α, there was increased sensitivity to IFN-α that was independent of BCR/ABL activity. Conclusion: BCR/ABL PTK expression in this primitive multipotent haematopoietic cell line results in an enhanced response to IFN-α. In contrast, the more mature myeloid progenitor cells are equally responsive to this growth inhibitor. This data may explain some of the clinical effects of IFN-α.