The role of the Philadelphia translocation in chronic myeloid leukemia

During the last two decades evidence for a close association between the presence of specific chromosomal abnormalities and the occurrence of several types of cancers and leukemias has accumulated. The Philadelphia (Ph 1) translocation, present in about 90% of the patients with chronic myeloid leukemia (CML), is one of the most typical and best documented examples of such an aberration. Usually this translocation involves chromosome 9 and 22: t(9;22)(q34;q11). The translocation products are designated 9q+ and 22q-. Variant translocations involving an array of translocation sites different from 9 have been described as well, but chromosome 22 is always involved. So far, no clear indications were found for the possible role played by this highly specific chromosomal aberration in the etiology of CML. Moreover, results concerning the exact nature of the Ph1 translocation, obtained by different investigators using different techniques, appeared to be contradictory. In this thesis the application of somatic cell hybridization and gene segregation analyses to these questions has been described. Rodent cells (fibroblasts) were fused with human Ph1 positive leucocytes and, subsequently, hybrid cell 1 ines were isolated. These hybrids appeared to segregate human chromosomes, including the Ph1 translocation products. The segregation of genes, previously assigned to the regions of the chromosomal breakpoints, was studied together with the segregation of the relevant human (translocation) chromosomes. Several genes on chromosome 22 were found to be translocated to the 9q+ chromosome which confirmed, on a molecular level, the translocation of chromosome 22 materia] to chromosome 9. Another gene on chromosome 22 (immunoglobulin A 1 ight chain) stayed on the Ph1 chromosome (22q-). One gene on chromosome 9 (c-abl) appeared to be translocated to 22q-. This latter result provided unequivocal evidence for reciprocity of the Ph 1 translocation. No apparent differences in chromosomal breakpoints could be revealed in the different CML patients used for analysis and no evidence was found for loss of chromosomal material {genes) as a result of the Ph 1 translocation. The clonal origin of the Ph 1 translocation in CML was confirmed using a chromosome 9 encoded polymorphic enzyme (AKI).