Methylation of p15 and p16 genes in acute promyelocytic leukemia:: Potential diagnostic and prognostic significance

Purpose: To investigate the frequency of p15 and p 16 gene promoter methylation in acute promyelocytic leukemia (APL), and to define its value in the detection of minimal residual disease (MRD) and treatment prognostication. Patients and Methods: Bone marrow DNA obtained from 26 patients with APL at diagnosis and during follow-up was studied with the methylation-specific polymerase chain reaction (MS-PCR), Serial marrow DNA wets studied by MS-PCR for MRD, and disease-free and overall survival were correlated with p15 methylation status at diagnosis. Results: MS-PCR for p16 and p15 gene methylation has a maximum sensitivity of 10(-4) and 10(-5). At diagnosis, 19 patients (73.1%) exhibited p15 methylation, whereas only three patients (11.5%) exhibited p16 methylation, all of whom had concomitant p15 methylation. During follow-vp, p16 methylation was acquired in two patients, one during the third hematologic relapse, and the other during transformation into therapy-related myelodysplastic syndrome. Six patients were evaluated serially with MS-PCR for p15 methylation at diagnosis and at follow-up examinations. Persistent p15 methylation preceded subsequent hematologic relapses in two patients, and conversion to negative MS-PCR for p15 methylation correlated with prolonged survival in another four patients. The 5-year disease-free survival of patients with p15 methylation was significantly inferior to that of patients without p15 methylation (15% v 62.5% P = .02), and this remained significant in multivariate analysis. Conclusion: In APL, p15 but not p16 gene methylation is frequent. It is possible that p16 methylation is acquired during clonal evolution. p15 methylation is a potential marker of MRD and might be of prognostic significance. (C) 2001 by American Society of Clinical Oncology.