Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2.

TLDR

BCR‑ABL, a chimeric tyrosine‑kinase formed by translocation of c‑abl into BCR, produces p210 and p190 variants linked to chronic myelogenous and acute lymphoblastic leukemia, yet its precise role in leukemia development remains unclear. The authors employed murine hematopoietic cells transformed by BCR‑ABL as a model, demonstrating that the oncogene renders these cells growth‑factor independent and tumorigenic. They showed that BCR‑ABL blocks apoptosis by upregulating Bcl‑2, and that silencing Bcl‑2 restores growth‑factor dependence and non‑tumorigenicity, thereby explaining BCR‑ABL’s synergy with c‑myc in cellular transformation.

Abstract

BCR-ABL is a chimeric 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 etiology of human leukemia remains to be defined. Transformed murine hematopoietic cells can be used as a model of BCR-ABL function since these cells can be made growth factor independent and tumorigenic by the action of the BCR-ABL oncogene. We show that the BCR-ABL oncogenes prevent apoptotic death in these cells by inducing a Bcl-2 expression pathway. Furthermore, BCR-ABL-expressing cells revert to factor dependence and nontumorigenicity after Bcl-2 expression is suppressed. These results help to explain the ability of BCR-ABL oncogenes to synergize with c-myc in cell transformation.