High Bcr-Abl expression prevents the translocation of Bax and Bad to the mitochondrion

Bcr-Abl is a constitutively active tyrosine kinase involved in the development and progression of chronic myeloid leukaemia (CML). It has been demonstrated that Bcr-Abl-positive cells can be uniquely resistant to apoptosis induced by different types of stimuli, but the mechanism by which this is achieved is not defined. In this study we have investigated how cells expressing high expression levels of Bcr-Abl may gain resistance to cytotoxic drugs. We have established cell lines expressing low and high expression levels of Bcr-Abl. Cells expressing elevated Bcr-Abl are resistant to cytotoxic drugs. In drug-sensitive 32D-parental and low Bcr-Abl expressing cells, pro-apoptotic Bcl-2 family members, Bax and Bad translocate from the cytosol to the mitochondrion following a cytotoxic insult. In contrast, high Bcr-Abl expression prevents the early translocation of these pro-apoptotic proteins to the mitochondrion, mitochondrial membrane potential is retained and caspases are inactive. We also demonstrate that IL-3 can contribute to drug resistance in low Bcr-Abl expressing cells, however, independent inhibition of IL-3 activated pathways (PI3K/AKT and Jak/STAT) does not sensitise cells to apoptosis. This study demonstrates that the subcellular translocation of Bax and Bad can be regulated by elevated Bcr-Abl expression and this may be a key event in the abrogation of an apoptotic response following a cytotoxic insult.LR: 20061115; PUBM: Print; JID: 8704895; 0 (Antineoplastic Agents, Phytogenic); 0 (BAD protein, human); 0 (BAX protein, human); 0 (BCL2L1 protein, human); 0 (Carrier Proteins); 0 (Enzyme Inhibitors); 0 (Fusion Proteins, bcr-abl); 0 (Interleukin-3); 0 (Proto-Oncogene Proteins); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (bcl-2-Associated X Protein); 0 (bcl-Associated Death Protein); 0 (bcl-X Protein); 33419-42-0 (Etoposide); 55520-40-6 (Tyrosine); EC 2.7.1.112 (JAK2 protein, human); EC 2.7.1.112 (Janus Kinase 2); EC 2.7.1.112 (Protein-Tyrosine Kinases); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspases); 2001/10/29 [received]; 2002/03/20 [accepted]; ppublishSource type: Electronic(1