Inhibition of IRE1α RNase activity sensitizes patient‐derived acute myeloid leukaemia cells to proteasome inhibitors

• Published in: Journal of cellular and molecular medicine Vol. 26; no. 16; pp. 4629 - 4633
• Main Authors: Creedican, Stuart, Robinson, Claire M., Mnich, Katarzyna, Islam, Md Nahidul, Szegezdi, Eva, Clifford, Ruth, Krawczyk, Janusz, Patterson, John B., FitzGerald, Stephen P., Summers, Mark, Richardson, Ciaran, Martin, Kenneth, Gorman, Adrienne M., Samali, Afshin
• Format: Journal Article
• Language: English
• Published: Chichester John Wiley & Sons, Inc 01.08.2022; John Wiley and Sons Inc
• Subjects: Acute myeloid leukemia; Apoptosis; Bone marrow; Cell culture; Cell fate; Cell survival; Cellular stress response; Chemokines; Chemotherapy; Clinical trials; Cytokines; Cytotoxicity; Endoplasmic reticulum; Flow cytometry; Inositol; Letter to the Editor; Leukemia; Mesenchyme; Multiple myeloma; Patients; Phospholipids; Population; Proteasome inhibitors; Protein folding; Proteins; Ribonuclease; Signal transduction; Statistical analysis; Stromal cells
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.17479

Clinical trials suggest proteasome inhibitors may be beneficial, but further interrogation of the molecular consequences of proteasome inhibition in AML is warranted to identify novel approaches that enhance their efficacy. 1 In multiple myeloma (MM), resistance to proteasome inhibitors can occur upon activation of the unfolded protein response (UPR), a stress response pathway that can control cell fate. 2 Inositol-requiring enzyme 1 alpha (IRE1α) is one of three stress sensors that mediates UPR signalling. XBP1s enhances cell survival by increasing transcription of genes associated with protein folding, endoplasmic reticulum-associated degradation (ERAD) and phospholipid synthesis. Unpaired t-tests or one-way anova with post-hoc Tukey tests were used to determine statistical significance. ns = not significant, *p [less than] 0.05, **p [less than] 0.01, ***p [less than] 0.001, ***p [less than] 0.0001 Bone marrow mesenchymal stromal cells (BMSCs) protect AML cells from chemotherapy-mediated killing, which can be modelled in vitro by co-culture with HS-5 cells, an immortalized BMSC feeder cell line. 5 We hypothesized that BMSC would protect AML cells treated with proteasome inhibitor(s), and that IRE1α inhibitors may overcome this protection. Statistical analysis was performed using Wilcoxon test, one-way anova with post-hoc Tukey test or Spearman's coefficient. ns = not significant, *p [less than] 0.05, **p [less than] 0.01, ***p [less than] 0.001, ***p [less than] 0.0001 XBP1s levels in MM patients positively correlate with patient outcome when treated with BTZ. 8 No such correlative studies have been performed in AML.