ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

• Published in: Biomolecules (Basel, Switzerland) Vol. 11; no. 2; p. 199
• Main Authors: Féral, Kelly, Jaud, Manon, Philippe, Céline, Di Bella, Doriana, Pyronnet, Stéphane, Rouault-Pierre, Kevin, Mazzolini, Laurent, Touriol, Christian
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.01.2021; MDPI
• Subjects: Activating transcription factor 6; ALL; AML; Apoptosis; Biosynthesis; Cancer; Cell activation; Cell death; Cell proliferation; Cell survival; Chemotherapy; CLL; Endoplasmic reticulum; endoplasmic reticulum stress; Homeostasis; Inositol; Kinases; Leukemia; Life Sciences; Mammals; Metabolism; Microenvironments; Phosphorylation; Protein folding; Protein kinase; Protein synthesis; Proteins; Quality control; Review; Ribonucleic acid; RNA; Sensors; Signal transduction; Transcription factors; Tumor cells; unfolded protein response (UPR); AML; ALL; leukemia; CLL; CML; unfolded protein response (UPR); endoplasmic reticulum stress
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom11020199

The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)—allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases.