Localization of p210 BCR-ABL to the Mitochondria Promotes Chronic Myeloid Leukemia Cell Proliferation Through cIAP...

The chimeric protein p210 BCR-ABL is a major causative factor of chronic myeloid leukemia (CML). Previously, we found that p210 BCR-ABL translocates from the cytosol to the mitochondria upon mitochondrial damage via the interaction of its pleckstrin homology domain (p210-PH) with cardiolipin (CL), a mitochondria-specific phospholipid. However, the precise pathological functions of this event are unknown. Here, using multivalent peptide library screens, we identified a tetravalent peptide, WDD-R4-tet, which binds to the CL-binding region of p210-PH and inhibits the translocation of p210 BCR-ABL to the mitochondria. Notably, WDD-R4-tet induced the apoptosis of CML cells by specifically suppressing the expression of cellular inhibitor of apoptosis 1 and 2 (cIAP1/2), ubiquitin ligases with anti-apoptotic functions, leading to the activation of caspases. Other compounds that inhibited cIAP1/2 also efficiently inhibited the proliferation of CML cells. Thus, WDD-R4-tet might be a novel therapeutic agent for CML, which functions by inhibiting novel cell-survival signaling pathways generated on the mitochondrial outer membrane of CML cells.