Treatment of HL-60 cells with drugs induces granulocytic differentiation and c-MYC down-regulation that is irreversible and associated with loss of DNase I-hypersensitive sites in c-MYC promoter. The expression of these phenotypes requires a slow process that appears to accompany a loss of c-MYC copies in double minutes via micronuclei. However, the drug treatment induced c-MYC down-regulation very early, though only reversibly. Here we show that we can resolve this paradox by assuming a gene(s) in other extrachromosomal, acentromeric DNA. Treatment with drugs might induce no down-regulation of this gene, but its complete elimination via micronuclei might be necessary and sufficient for the expression of the above phenotypes. Loss of c-MYC copies is unavoidable because the exclusion of extrachromosomal DNAs via micronuclei is at random. This conclusion is based on the observation of a substantial number of c-MYC copies in certain differentiated cells, irrespective of whether the differentiation was induced with drugs or without.