ABSTRACT 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.
Ikegami et al. (Sat,) studied this question.