BCR/ABL mRNA and the P210BCR/ABL Protein Are Downmodulated by Interferon- in Chronic Myeloid Leukemia Patients

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Abstract
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- (IFN-) as a single agent. Bone marrow samples were collected at diagnosis and at hematologic remission induced by IFN-, or by hydroxyurea in case of resistance to IFN-. The mean levels of BCR/ABL transcripts in bone marrow mononuclear cells of patients who showed a complete hematologic response to IFN- were significantly reduced with respect to those at diagnosis (48 × 103v168 × 103; P < .001), whereas no difference was detected between the values at diagnosis and at hematologic remission in patients resistant to IFN-. In cell culture experiments, IFN- 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- 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- treatment.