Persistence of Chronic Myelocytic Leukemia

Chronic myelocytic leukemia (CML)' is a clonal pluripotent stem cell disease, clinically divided into a chronic phase of a median duration of ^-4 yr, followed by an acute phase (blast crisis) lasting for few months (1) . Cytogenetic hallmark of most (95%) CML cases is the presence of the Philadelphia (Ph) chromosome, resulting from a reciprocal translocation between chromosomes 9 and 22 (2, 3) . Molecular analyses established that, in leukemic cells of all Ph' CML patients, the c-abl oncogene is transferred from chromosome 9 into the breakpoint cluster region (bcr) on chromosome 22 (4, 5) ; this area is part of a gene of as-yetunknown function, the bcr gene, of which the coding regions are spread over at least 70 kb, including the bcr and exons 5' and 3' to it (6-8). This genomic rearrangement on the Ph-chromosome results in the transcription of a chimeric 8.5 kb bcr/c-abl RNA species, which represents mRNA for an altered c-abl protein that differs from its normal counterpart in a higher associated tyrosine kinase activity (8-12) . Herein, we report on a Ph' CML patient cytogenetically characterized by the appearance of asecond Ph chromosome during blast crisis . Southern blot analyses and in situ hybridization studies suggested a deletion of rearranged 5' bcr and cabl sequences in acute phase of this case . Northern blots of blastic cells detect normal bcr and abl RNA species instead of the fused 8.5 kb transcript usually observed in Ph' CML. These data may indicate that the altered abl protein is of subordinate importance for the maintenance of the leukemic state once Ph' CML has entered blast crisis .