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

The BCR/ABL hybrid gene plays a central role in the pathogenesis of the chr onic phase of chronic myeloid leukemia (CML). We used a very sensitive quan titative reverse transcriptase-polymerase chain reaction to investigate the levels of hybrid BCR/ABL mRNA in bone marrow cells of 20 patients with Phi ladelphia positive (Ph+) CML treated with interferon-alpha (IFN-alpha) as a single agent. Bone marrow samples were collected at diagnosis and at hemat ologic remission induced by IFN-alpha, or by hydroxyurea in case of resista nce to IFN-alpha. The mean levels of BCR/ABL transcripts in bone marrow mon onuclear cells of patients who showed a complete hematologic response to IF N-alpha were significantly reduced with respect to those at diagnosis (48 x 10(3) v 168 x 10(3); P < .001), whereas no difference was detected between the values at diagnosis and at hematologic remission in patients resistant to IFN-alpha. In cell culture experiments, IFN-alpha priming significantly reduced the levels of BCR/ABL hybrid transcripts in a dose-dependent manne r in Ph+ bone marrow precursors obtained at diagnosis from patients who sub sequently responded to IFN-alpha treatment (P < .005). No downmodulation wa s 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-alpha treatment. (C) 1999 by The American Society of He matology.