New-targeted therapy for leukemia based on Endoplasmic Reticulum Stress

The unfolded protein response (UPR) is an evolutionarily conserved adaptive pathway, which is activated by the stress of the endoplasmic reticulum (ER). ER stress often occurs due to the high protein demand in cells and protein folding errors in several diseases, such as different cancers and autoimmune diseases. UPR is mediated by three primary arms called inositol-requiring enzyme-1α (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6α (ATF6α). Given that homeostasis in protein synthesis is frequently deregulated in cancers, UPR plays a critical role in controlling survival and cell death. In addition,, resistance to apoptosis is mediated by the pro-survival mechanism of ER stress in cancer cells. Recent evidence highlighted the deregulation of UPR signaling in hematopoietic stem cells (HSCs) and leukemic cells, so that targeting UPR-driven pro-survival pathways may present new therapeutic benefits in leukemia. In this review article, we aim to provide an updated knowledge on the role of UPR as a novel therapeutic target in leukemia. We first define the different types of leukemia and their challenges with current treatments, and then explore the contribution of UPR to leukemia pathogenesis and treatment. Finally, UPR targeting strategies in pre-clinical and clinical trials of patients with leukemia will be presented.