Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase

The frequency and mechanism of p16INK4A and p14ARF gene alterations were studied in cell samples from 30 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML), both at diagnosis and at the onset of the accelerated phase (AP) of the disease. No alterations in the p16INK4A or p14ARF genes were found in any of the chronic phase (CP) samples. DNA sequencing analyses detected p16INK4A or p14ARF mutations in 17 AP samples. All mutations were heterozygous without loss of the other allele. Aberrant methylation of the p16INK4A or p14ARF promoters was found in 14 of 30 AP samples. The most common situation was the simultaneous methylation of both promoters. Our data indicate that p16INK4A and p14ARF are primary targets for inactivation by promoter methylation in the acceleration of CML. Transcriptional silencing of the p16INK4A and p14ARF genes may be important in the conversion of CML from the CP to the AP. [Copyright &y& Elsevier]