Chronic myeloid leukemia (CML) is a malignant disease of pluripotent hematopoietic stem cells and is characterized by excessive accumulation of the myeloid lineage. The causative event in the initiation of CML is the translocation of the abl gene in continuity with the bcr gene resulting in a fusion gene encoding for a Bcr-Abl tyrosine kinase. The expression of Bcr-Abl protects hematopoietic cells against apoptosis. We investigated the survival pathways triggered by Bcr-Abl. Apoptosis was measured in two cell lines expressing the Bcr-Abl protein either constitutively (K562) or ectopically (BaF/Bcr-Abl). Imatinib mesylate, an inhibitor of the tyrosine kinase activity of Bcr-Abl, induced apoptosis and caspase activation in K562 and BaF/Bcr-Abl and this effect was almost completely inhibited by cycloheximide (CHX) indicating that imatinib needs de novo protein synthesis to induce apoptosis in Bcr-Abl cell lines. MG132, a proteasome inhibitor, was also found to induce apoptosis in both cell lines, an effect also inhibited by CHX. By measuring mitochondrial membrane potential we found that CHX affected the apoptotic process induced by both inhibitors upstream of the mitochondrial step. Co-treatment with imatinib and MG132 failed to show any additive effect and imatinib did not inhibit proteasome activity by itself. These results are in agreement with Bcr-Abl tyrosine kinase exerting its anti-apoptotic effect by driving the degradation of a pro-apoptotic protein with a high turnover which, after phosphorylation, became a substrate for the proteasome. When protein kinase C was activated by PMA, Bim-EL, a pro-apoptotic, BH3-only member of the Bcl-2 family, was converted in its phosphorylated form and its cell content was decreased by 60%. The phosphorylated form of Bim-EL was preserved when proteasome was inhibited by MG132 inducing a two times increase in Bim-EL protein content. Similarly, the content in Bim-EL was increased (three times in K562 and five times in BaF/Bcr-Abl) after 18h imatinib treatment. In this case, Bim-EL accumulated in an un-phosphorylated form and this accumulation was inhibited by CHX. Thus, Bcr-Abl kinase could indirectly drive the phosphorylation of Bim-EL, maintaining its degradation by the proteasome and, consequently, a low apoptotic potential for the cell. Conversely, Bim-EL accumulation could play a crucial role in the apoptotic response of Bcr-Abl expressing cells treated by either imatinib or proteasome inhibitors.