Structural alterations in the carboxyl-terminal domain of the BCRABL gene product activate its fibroblastic transforming potential.

Abstract

Activation of the c-abl protooncogene occurs in Abelson murine leukemia virus, Hardy-Zuckerman-2 feline sarcoma virus, and during the chromosomal translocation that generates the BCRABL fusion gene. The three genes exhibit varying degrees of transforming activity; the two viral genes transform NIH-3T3 cells in vitro, whereas the BCRABL gene is incapable of transforming these cells. To determine whether genetic alterations can enhance the transforming potential of the BCRABL gene, we employed genetic selection techniques which led to the isolation of a mutant form of the BCRABL gene with high levels of fibroblastic transforming activity. Molecular analysis of this clone shows that it suffered a deletion of 3' ABL sequences and their replacement with a cellular sequence of unknown origin, termed X. This tripartite gene is capable of inducing 35 foci/10 ng of DNA. Deletion of 3' ABL sequences analogous to that seen in the activated BCRABL protein without the addition of X yields 5 foci/100 ng of DNA. These results suggest that carboxyl-terminal truncations unmask the fibroblastic transforming activity of the BCRABL gene product and the addition of X sequences dramatically enhances this transforming potential, indicating a dominant contribution by the X reading frame.