Converting an oncogenic protein into an apoptotic factor: targeting BCR-ABL to the mitochondria

The advent of rational drug design to target a single molecular event, as so aptly demonstrated with tyrosine kinase inhibitor (TKI) therapy and Bcr-Abl, has set a precedent for the ability to attack malignancy directly at the level of the oncogenic event. However, in the last decade it has become clear that new therapeutic strategies for chronic myelogenous leukemia (CML) must move beyond the mere inhibition of Bcr-Abl's tyrosine kinase activity if a cure is to be found. TKI resistance, persistent leukemic stem cells, and the acute blast phase crisis remain major problems to be solved. This work describes the efforts to use the central leukemogenic protein of CML, Bcr-Abl (oncogenic event itself), to selectively destroy the diseased cells that harbor it. The subcellular localization of Bcr-Abl determines its function. This is also true for Bcr-Abl's normal counterpart, c-Abl. When localized to the mitochondria, c-Abl is a potent inducer of cell death. However, c-Abl pro-death activity is disrupted in CML. The mitochondriolytic mechanism of ‘death-directed' c-Abl is unknown. Yet, under conditions of cell stress from a variety of sources (e.g., endoplasmic reticulum stress, genotoxic agents, and oxidative stress) active c-Abl migrates to the mitochondria causing dysfunction and cell death. Our direct targeting of c-Abl and Bcr-Abl to the mitochondria demonstrated the sufficiency of c-Abl alone to kill leukemia cells and of Bcr-Abl's ability to recapitulate this function. iv The central hypothesis of this study is that forcing Bcr-Abl to the mitochondria will selectively induce the death of leukemic cells by converting Bcr-Abl into an apoptotic factor. This approach restores a defunct apoptotic pathway (i.e., the mitochondrial ‘death-directed' c-Abl pathway) and does not rely on the indirect engagement of (often dysregulated) cell death mechanisms like many chemotherapeutics. c-Abl requires a mitochondrial chaperone (protein kinase Cδ). Therefore, we designed a protein chaperone, the intracellular cryptic escort (iCE), for Bcr-Abl that selectively functions in the pro-oxidative environment of CML cells. Though, the iCE did not move Bcr-Abl to the mitochondria, it did synergistically and selectively kill CML cells as a combination with imatinib or alone was as toxic as high dose imatinib.