It was recently suggested that the translocation of the c-abl gene (the human cellular homologue of the transforming sequence of Abelson murine leukaemia virus) from chromosome 9 to 22 in Philadelphia translocation, might have a role in the generation of chronic myeloid leukaemia (CML).
Activation of the abl gene and its involvement in human leukemia is one of the most thoroughly characterized examples of the structural alterations of chromosomes associated with the conversion of a normal cell into a cancer cell.
The Philadelphia translocation, t(9;22), fuses the BCR and ABL genes resulting in the expression of leukemia-specific, chimeric BCR-ABL messenger RNAs.
The present study suggests that formation of the chimeric bcr-abl gene and its genetic products may play an important role in the development of leukemia in either radiation-induced or de novo CML.
Some oncogene abnormalities are relatively specific for certain leukemias and occur in almost all cases; examples include ABL in chronic myelogenous leukemia or MYC in Burkitt leukemia/lymphoma.
We have successfully used this method to analyze 60 leukemia samples (34 from Ph1-negative acute leukemias; 6 from Ph1-positive acute leukemias; and 20 from CML) with complete correlation (of BCR-ABL positivity or negativity) with the results of karyotype or Southern Blot analysis of genomic DNA for bcr rearrangement.
Because the BCR-ABL fusion gene appears to be the result of cytogenetic rearrangement in all cases of these leukemias, the causes and mechanism of chromosome rearrangement will be relevant to the development of leukemia in man.
Interestingly, the leukaemia and the derived cell line each displayed different, clonal patterns of immunoglobulin gene rearrangements providing direct evidence that the t(9;22) translocation which results in the expression of the p190 bcr-abl protein must occur before immunoglobulin heavy chain gene rearrangement.
This was due to a corresponding unusual localization of the breakpoint in the c-abl gene and was seen in a patient with Philadelphia (Ph) chromosome positive chronic myelogeneous leukemia in chronic phase.
The present study indicates that herbimycin A is a beneficial agent for the investigation of the role of the bcr-abl gene in Ph1-positive leukemias and further suggests that the development of agents inhibiting the bcr-abl gene product may offer a new therapeutic potential for Ph1-positive leukemias.
BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive human leukemias.
Third, recent advances in understanding the functions of the normal ABL protein have given clues to the mechanism(s) of ABL-induced leukemias and approaches to blocking this process.
The human BCR-ABL oncogenes encoded by the Philadelphia chromosome (Ph) affect the pathogenesis of diverse types of leukemia and yet are rarely associated with T-lymphoid leukemia.
The significance of the finding that a part of the SH3 region of ABL protein is missing in some Philadelphia chromosome-positive leukemias is discussed in reference to the cases reported previously.