Available apoptosis pathways in 32D myeloid hematopoietic cells. In this model we propose that 32D cells have at least 2 pathways by which death can be initiated. Pathway 1 is often referred to as “classical” and involves BH3 protein activation leading to cytochrome c release and caspase activation. Calcium release from damaged organelles is a late event and is prevented by caspase inhibitors. Pathway 2 is initiated by calcium release, leading to activation of calcium-dependent cytosolic enzymes and ER/mitochondrial Ca²⁺ coupling. This has been proposed to generate reactive oxygen species (ROS) and lead to irreversible mitochondria damage. This process is likely to release apoptogenic factors including cytochrome c and, therefore, caspase activation, but also apoptosis-inducing factor (AIF) and endonuclease G (EndoG), which will subsequently lead to caspase-independent DNA fragmentation. Although late caspase activation will occur, inhibition cannot prevent the calcium accumulation or rescue the cells from apoptosis as other pathways contribute to cell death (activation of calcium-dependent cytosolic proteases, endonucleases, ER/mitochondrial coupling leading to mitochondrial dysfunction and release of apoptogenic factors). Evidence from our study suggests that Bcr-Abl–expressing cells are deficient in the calcium-dependent pathway. Cells expressing high levels of Bcr-Abl (C4 cells) are also resistant to the classical/BH3 pathway. This dual resistance may make a major contribution to treatment failure in BC CML, where elevated expression of Bcr-Abl is a common feature.