Molecular genetics of the pathogenesis and classification of chronic myelocytic leukemia

The Philadelphia (Ph) translocation in CML is molecular-genetically characterized by a rearrangement of the c-abl oncogene with sequences of the bcr gene on the Ph chromosome. In leukemic cells this recombination results in the transcription of a 8.5 kb bcr/c-abl hybrid RNA which is translated into a p210 abl protein. The p210 abl protein contains, in contrast to its normal 145 abl counterpart, associated tyrosine kinase activity which is not physiologically controlled. Both genes do not participate in the acceleration of CML from chronic state into blast crisis. The majority of CML patients without cytogenetically detectable Ph chromosome also lack a bcr/abl rearrangement. However, some cases of Ph-negative CML could be reclassified into the group of Ph-positive CML by demonstration of a bcr gene rearrangement. One patient exhibited a bcr gene recombination without translocation of c-abl sequences. A similar heterogenous pattern is observed in Ph-positive acute leukemias. About 50% of cases are characterized by a bcr/abl rearrangement, as is likewise observed in Ph-positive CML. It is tempting to speculate that these patients represent Ph-positive CML cases that initially presented themselves for treatment with CML blast crisis. Particularly in pediatric Ph-positive ALL, the majority of cases show a c-abl oncogene translocation without bcr rearrangement. Precise molecular-genetic analyses of those cases are still pending. Molecular-genetic analyses have already been proven to be of clinical value 1) in the diagnosis of Ph-positive CML in the absence of cytogenetic methods, 2) in the subclassification of Ph-negative CML or Ph-positive acute leukemias.(ABSTRACT TRUNCATED AT 250 WORDS)