Inducing apoptosis in chemotherapy‐resistant B‐lineage acute lymphoblastic leukaemia cells by targeting HSPA5, a master regulator of the anti‐apoptotic unfolded protein response signalling network

Summary We present previously unknown evidence that the immunoglobulin heavy chain binding protein BIP/HSPA5, also known as glucose regulated protein (GRP)78, serving as a pivotal component of the pro‐survival axis of the unfolded protein response (UPR) signalling network, is abundantly expressed in relapsed B‐lineage acute lymphoblastic leukaemia (ALL) and contributes to chemotherapy resistance of leukaemic B‐cell precursors. The resistance of B‐lineage ALL cells to the standard anti‐leukaemic drug vincristine was overcome by the HSPA5 inhibitor epigallocatechin gallate, which inhibits the anti‐apoptotic function of HSPA5 by targeting its ATP‐binding domain. Notably, chemotherapy‐resistant B‐lineage ALL cells underwent apoptosis within 48 h of exposure to a doxorubicin‐conjugated cell‐penetrating cyclic anti‐HSPA5 peptide targeting surface‐expressed HSPA5 molecules on leukaemia cells. The identification of the HSPA5 as a chemoresistance biomarker and molecular target for B‐lineage ALL may lead to new anti‐leukaemic treatment strategies that are much needed.