Breakpoint Analysis in CML: Potentials for Detection of Minimal Residual Disease

Abstract

Chronic myelocytic leukemia (CML) is a pluripotent stem cell disease characterized by the presence of the Philadelphia (Ph) chromosome in the leukemic cells of 96% of all CML patients. The Ph chromosome is the result of a translocation between chromosomes 22 and 9. The human c-abl oncogene (1) has been mapped to the long (q) arm of chromosome 9 (2). By analysis of somatic cell hybrids, we have shown that this oncogene is translocated to the Ph (22q-) chromosome in Ph positive CML, demonstrating that c-abl is involved in the (9;22) translocation (3). The location of the c-abl oncogene adjacent to the translocation breakpoint in CML was shown by the isolation of a DNA fragment from the 9q+ chromosome of a CML patient: this fragment contained sequences of both chromosome 9 and 22. The breakpoint had occurred 14 kb immediately 5′ of the v-abl homologous sequences and resulted in a 9q+ chromosome in which the tip of chromosome 9, including the v-abl homologous sequences, were replaced by sequences of chromosome 22 (4). The isolated chromosome 22 sequences of this chimeric DNA fragment enabled us to study their role in the Ph translocation in greater detail. A breakpoint cluster region (bcr) was identified on chromosome 22; the DNAs of all (over 30) Ph positive CML patients examined to date have breakpoints in this region of up to 5.8 kb.