The Role Of Unfolded Protein Response In Sensitivity Of MLL Leukemia Cells To Proteasome Inhibitors

MLL leukemia is a class of acute leukemia caused by 11q23 chromosome translocation.This type of leukemia have very poor prognosis.Currently,there is no effective treatment for MLL leukemia.The treatment of proteasome inhibitor is the first clinically validated targeted therapy strategy for such leukemia.Our group’s previous work found that proteasome inhibitor can specifically triggers apoptosis of pro-B ALL MLL leukemia cells.Previously studies have shown that proteasome inhibitor can only trigger apoptosis of plasma cells,which are at the end of B cell differentiation and do not affect early stages B cells differentiation.The mechanisms for proteasome inhibitors specifically induce apoptosis of pro-B MLL leukemia cells remain unknown.In this study,we sought to define mechanisms of proteasome inhibitor specifically induce apoptosis of pro-B MLL leukemia cells.Our results reveal that proteasome inhibitor can induce endoplasmic reticulum stress and activate unfolded protein responses in pro-B MLL leukemia cells.Then we investigate how three branches of unfolded protein response change after proteasome inhibitor treatment.In pro-B MLL leukemia cells,PERK pathway was atypical activated,while anti-apoptotic IRE1 pathway cannot be activated.Furthermore,we explore the mechanism why IRE1 pathway cannot be activated in pro-B MLL leukemia cells.We found that mi R-210 is highly expressed in pro-B MLL leukemia cells,resulting in low expression of its target gene Raptor.Raptor is one of the m TORC1 complex compositions.The activity of m TORC1 decreased,resulting in IRE1 protein synthesis disorder.IRE1 protein level low expression.So IRE1 pathway cannot be activated by proteasome inhibitor in pro-B ALL MLL leukemia cells.However,unlike proteasome inhibitors,classical endoplasmic reticulum stress inducers can’t selectively kill pro-B MLL leukemia cells.We further explored the mechanism.First,we examined changes in unfolded protein pathways and found that the classical endoplasmic reticulum stress inducer did not activate the PERK pathway,and IRE1 pathway was activated in MLL leukemia cells.Second,proteasome inhibitors disrupt the ubiquitin homeostasis of MLL leukemia cells,whereas classical endoplasmic reticulum stress inducers do not alter the ubiquitin homeostasis of MLL leukemia cells.When ubiquitin homeostasis was reconstructed,the cytotoxic effect of proteasome inhibitor on MLL leukemia cells was significantly reduced.In summary,this study clarified the mechanism underlying the extreme sensitivity of pro-B MLL leukemia cells to proteasome inhibitors,especially the role of UPR.Furthermore,this study also indicated the mechanism classical endoplasmic reticulum stress inducer cannot induce apoptosis of pro-B MLL leukemia cells.Our findings may open an avenue for proteasome inhibitors in the treatment of pro-B MLL leukemia.