REGULATION OF BCL-2 GENE-EXPRESSION BY BCR-ABL IS MEDIATED BY RAS

BCR-ABL is a chimaeric oncogene generated by translocation of sequence s from the c-ABL protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210(BCR-AB L) and 190(BCR-ABL), are produced that are characteristic of chronic m yelogenous leukemia and acute lymphoblastic leukemia, respectively. Th eir role in the aetiology of human leukemia remains to be defined. We have previously shown that the tumorigenic effect of BCR-ABL oncogenes is mediated by Bcl-2. Ln addition to Bcl-2, is a protein essential fo r transformation by BCR-ABL. However, it is not known how Bcl-2 and Ra s fit together in cell transformation by BCR-ABL. The data presented h ere establish that Bcl-2 is a downstream target gene of the Ras signal ling pathway in cells transformed by BCR-ABL, and that constitutive Ra s activation results in constitutive expression of the gene. Conversel y, a truncated form of the BCR-ABL, which lacks a critical BCR region required for activation of the Ras signalling pathway, failed to induc e Bcl-2 expression. These results indicate that BCR-ABL prevents apopt osis by inducing Bcl-2 through a signalling pathway involving Ras and links constitutive Ras activation and Bcl-2 gene regulation. Hence, th ese results further imply that Ras is involved in both mitogenic signa ls and survival signals. (C) 1997 Academic Press Limited.