MOLECULAR FOLLOW-UP OF DISEASE PROGRESSION AND INTERFERON THERAPY IN CHRONIC MYELOCYTIC-LEUKEMIA

We previously reported that the abl promoter (Pa) undergoes de novo DN A methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present s tudy in which samples of CML patients, including a group treated with interferon alpha (IFN alpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) ampl ification of the Pa region after digestion with several site-methylati on sensitive restriction enzymes. Some 74% of the DNA samples from blo od and marrow drawn in the chronic phase were nonmethylated, similar t o control samples from non-CML patients. The remaining 26% were partia lly methylated in the ablPa region. The latter samples were derived fr om patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from pa tients known to have a disease of longer duration (26 months v 7.5 mon ths, P = .01). Samples of 30 IFN alpha-treated patients were sequentia lly analyzed in the course of treatment. Fifteen patients with no evid ence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFN alpha t herapy, as the Pa methylation status was not reversed in any of the pa tients treated with hydroxyurea. Methylation of the abl promoter indic ates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFN alpha therapy far better than the cytogenetic respo nse. (C) 1997 by The American Society of Hematology.