P210 BCR-ABL TYROSINE KINASE INHIBITS APOPTOTIC CELL DEATH THROUGH MULTIPLE PATHWAYS PREVENTING EARLY MITOCHONDRIAL ACTIVATION

The resistance to apoptotic death has a key role in the illegitimate enlargement of chronic myeloid leukemia (CML) hematopoiesis over its normal counterpart and in the genetic instability that drives clonal evolution of bcr-abl-rearranged myeloid progenitors towards the fully transformed phenotype of blast crisis. It results from multiple events preventing proapoptotic pathways (Trail-DR4, Fas-ligand and Bax induction, Bax and Bad translocation to the membranes of subcellular organelles such as mitochondria or endoplasmic reticulum, cytochrome-c release and caspase-3 activation) and/or enhancing pro-survival signals such as Bcl-2, Bcl-xL and survivin, and is mostly conditional upon the tyrosine kinase of p210 bcr-abl fusion protein. Our study addressed the matter of p210 bcr-abl tyrosine kinase effects on expression levels and subcellular locations of proteins that trigger apoptotic death in response to extrinsic or intrinsic signals by antagonizing anti-apoptotic Bcl- 2 and Bcl-xL at the mitochondrial membranes. To the purpose, in individuai cell clones generated from the murine myeloid 32D cell line transduced with a temperature-sensitive (ts) p210 bcr-abl construct (lacking the abl constitutive tyrosine kinase activity at the non-permissive temperature of 39°C) we investigated transcriptional induction and post-transcriptional modifications of pro-apoptotic signals in response to growth factor withdrawal, starvation, TNF-a and tyrosine kinase inhibitor STI571. Trail-DR4, Fas, Bax and Bim transcriptional induction, initiator caspase 8, 9 and 12 activation, Bad dephosphorylation, Bid cleavage and Bax and Bak aggregation at the mitochondrial membranes preceding citochrome-c release and executioner caspase activation are prevented by p210 bcr-abl tyrosine kinase through interactions with multiple trascription factors including Stat5, PI3K/Akt, Foxo3A and c-Myc. Our results may be helpful to design novel therapeutic strategies intended for targeting gene products relevant for CML progression in addition to p210 bcr-abl tyrosine kinase.