BCR/ABL mRNA and the P210(BCR/ABL) protein are downmodulated by interferon-α in chronic myeloid leukemia patients

The BCR/ABL hybrid gene plays a central role in the pathogenesis of the chronic phase of chronic myeloid leukemia (CML). We used a very sensitive quantitative reverse transcriptase-polymerase chain reaction to investigate the levels of hybrid BCR/ABL mRNA in bone marrow cells of 20 patients with Philadelphia positive (Ph⁺) CML treated with interferon-α (IFN-α) as a single agent. Bone marrow samples were collected at diagnosis and at hematologic remission induced by IFN-α, or by hydroxyurea in case of resistance to IFN-α. The mean levels of BCR/ABL transcripts in bone marrow mononuclear cells of patients who showed a complete hematologic response to IFN-α were significantly reduced with respect to those at diagnosis (48 x 10³ v 168 x 10³; P <.001), whereas no difference was detected between the values at diagnosis and at hematologic remission in patients resistant to IFN-α. In cell culture experiments, IFN-α priming significantly reduced the levels of BCR/ABL hybrid transcripts in a dose-dependent manner in Ph+ bone marrow precursors obtained at diagnosis from patients who subsequently responded to IFN-α treatment (P <.005). No downmodulation was observed in bone marrow precursors from patients who subsequently proved to be IFN- resistant. These results indicate that downmodulation of BCR/ABL gene expression could be one of the mechanisms involved in the response of CML patients to IFN-α treatment.