Clonal nature of Philadelphia chromosome-positive and -negative chronic myelogenous leukemia by DNA hybridization analyses.

Evidence for the clonal nature of chronic myelogenous leukemia (CML) has been obtained primarily from studies of black females expressing polymorphic glucose-6-phosphate dehydrogenase (G6PD) isoenzymes where, instead of the heterozygous pattern normally found as a result of random X chromosome inactivation, exclusive expression of only one G6PD allele has been demonstrated in leukemic cell populations. We report here the use of two other molecular approaches to examine clonality of peripheral blood cells in patients with CML. The first of these is based on the analysis of consistent differential methylation patterns associated with active and inactive X chromosomes within the region spanned by a BamHI restriction fragment length polymorphism (RFLP) at the hypoxanthine phosphoribosyltransferase (HPRT) locus. By this method, three heterozygous females gave results consistent with monoclonal origin of the disease, including one patient lacking the Philadelphia chromosome (Ph1) normally associated with CML. In the other two patients, both of whom had Ph1-positive CML, clonality was confirmed by the demonstration of simple gene rearrangements by Southern hybridization with a breakpoint cluster region (bcr) probe from chromosome 22.