Oncogenic activation of the proto-oncogene c-abl in human leukemias occurs as a result of the addition of exons from the gene bcr and truncation of the first abl exon. Analysis of tyrosine kinase activity and quantitative measurement of transformation potency in a single-step assay indicate that variation in bcr exon contribution results in a functional difference between p210bcr-abl and p185bcr-abl proteins. Thus, foreign upstream sequences are important in the deregulation of the kinase activity of the abl product, and the extent of deregulation correlates with the pathological effects of the bcr-abl proteins.

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The Abelson (ABL) family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration, and invasion. ABL1 was first identified as an oncogene required for the development of leukemias initiated by retroviruses or chromosome translocations. The demonstration that small molecule ABL kinase inhibitors effectively treat chronic myeloid leukemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumors. Enhanced ABL expression and activation in some solid tumors, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may have utility in treating selected solid tumors.

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The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCRIABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.The BCRIABL oncogene is a product of the Philadelphia chromosome (Ph'). The reciprocal translocation between chromosomes 9 and 22 which generates this cytogenetic abnormality defines Ph' leukemias (for a review, see reference 4). BCR sequences constitute a gene of unknown function (14), portions of which are fused upstream of the second exon of c-ABL by mRNA splicing (47). The Ph' breakpoints in chromosome 22 are clustered within two regions, giving rise to two distinct forms of BCRIABL. The breakpoints for the gene encoding P210 fall within the introns of a 5.8-kb region spanning a cluster of five small BCR exons (14). The breakpoints for the gene encoding P185 predominantly fall within a 20-kb region at the 3' end of the 70-kb first intron of BCR (3, 8). The two chimeric BCR/ABL proteins induce transformation of lymphoid cells in vitro (33, 34) and produce lymphoid and myeloid leukemias in mice (7,10,18,23).We have previously demonstrated that the P185 form of BCRIABL has approximately a fivefold-higher level of tyrosine kinase activity than the P210 form when the proteins are assayed for both in vitro autophosphorylation following synthesis in rabbit reticulocyte lysate and total in vivo tyrosine phosphorylation following acute infection of Rat 1 cells (29). This correlates with the greater transforming potency of P185 relative to P210 in both primary bone marrow cultures (34) and Rat 1 fibroblasts (29) chronic form of leukemia (for a review, see reference 4). These data indicate that the specific contents of BCR sequences can influence both the enzymatic activity and the transforming potency of BCRIABL.The c-abl proto-oncogene shares homology with src in its tyrosine kinase domain (17) and in the upstream kinase regu...

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BCR-ABL is a deregulated tyrosine kinase expressed in