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Prolonged unfolded protein reaction is involved in the induction of CML cell death upon oprozomib treatment.

To select the most efficient chemical to induce apoptosis in leukemia cells, a multidrug screen was applied on BM-MNCs from CML patients. Oprozomib (Cpd 21) was chose for the subsequent experiments. The iTRAQ was then performed to identify the responsible pathway relative to apoptosis and results showed that ER chaperons were upregulated. Apoptosis was arrtributed to a joint effect of calcium leakage, PERK and IRE1α phosphorylation. PERK branch was responsible for the first wave of cell death that occurred within 24 hours. The later wave of apoptosis was mediated by IRE1α, which transmit apoptotic signals through ASK-JNK-BIM axis. Release of Ca2+ from ER into cytosol resulted in activation of calpain, which, in turn, cleaved Caspase-12. Our data also explained the selective killing effects of oprozomib on CML cell, for they relied more on proteasome activity. Conclusively, this study demonstrated that prolonged inhibition of proteasome to trigger UPR could be an alternative strategy for treating CML in the light of TKIs resistance.