Molecular Genetic Studies of Ph-positive Leukemias and the BCR and ABL Genes

Abstract: In the present thesis molecular genetic methods were used to address different biological and clinical aspects of Philadelphia (Ph) chromosome-positive leukemias and the BCR and ABL genes. In the first study, children with Ph-positive chronic myeloid leukemia (CML) were found to have essentially the same breakpoint locations in BCR as adults, a pattern which differs from the one seen in Ph-positive acute lymphoid leukemia (ALL). In the second study, the breakpoint position within the major breakpoint cluster region (M-bcr) of the BCR gene was determined in 133 Ph-positive CML patients. No correlation was found between the breakpoint site and different clinical and/or hematologic parameters, including duration of the chronic phase and survival time. In the third study, the CRK proto-oncogene was localized to chromosome band 17p13, a segment frequently deleted during disease progression in CML, offering a new candidate gene to be investigated for its possible involvement in the disease progression. In the fourth study, it was shown that both BCR genes are expressed in the peripheral blood of healthy individuals, making it unlikely that imprinting would account for the previously reported parental-specific involvement of chromosomes 9 and 22 in the t(9;22). The identification of the adaptor protein CRKL as the major phosphorylated protein in the CML cell line K562 in the fifth study, and the demonstration that BCR/ABL and ABL bind to and phosphorylate CRKL, indicate that CRKL is likely to play a biologically important role in the development of Ph-positive leukemias. In the sixth study, first steps were taken to evaluate the effects of interferon-alfa treatment on a transgenic mouse model for Ph-positive ALL. No prolonged survival or altered disease pattern was observed. In the final study, RNA in situ hybridization was used in an attempt to further elucidate the significance of the high expression of BCR in the brain. It was found that the expression of BCR was localized to highly specialized brain regions, reflecting a potentially interesting, yet presently poorly understood, function of BCR in the brain.