Regulation of Bcl-2 gene expression by BCR-ABL is mediated by Ras

BCR-ABL is a chimaeric oncogene generated by translocation of sequences from the c-ABL protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210BCR-ABL and p190BCR-ABL, are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their 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. In addition to Bcl-2, is a protein essential for transformation by BCR-ABL. However, it is not known how Bcl-2 and Ras fit together in cell transformation by BCR-ABL. The data presented here establish that Bcl-2 is a downstream target gene of the Ras signalling pathway in cells transformed by BCR-ABL, and that constitutive Ras activation results in constitutive expression of the gene. Conversely, a truncated form of the BCR-ABL, which lacks a critical BCR region required for activation of the Ras signalling pathway, failed to induce Bcl-2 expression. These results indicate that BCR-ABL prevents apoptosis by inducing Bcl-2 through a signalling pathway involving Ras and links constitutive Ras activation and Bcl-2 gene regulation. Hence, these results further imply that Ras is involved in both mitogenic signals and survival signals.This work was supported by grants from Fundación Internacional José Carreras (FIJC-94/INT)and from the Spanish Ministry of Science and Education( DGYCIT refs PM91-0005 and PB94-1104).Peer reviewe