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

Despite improvements in prognostic stratification and optimization of therapeutic intervention in acute myeloid leukaemia (AML) patients, long-term survival is low. 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. IRE1α activity occurs via its RNase domain resulting in cleavage of a 26-nucleotide intron from X-Box Binding Protein 1 (XBP1) mRNA leading to formation of a transcription factor, XBP1s. XBP1s enhances cell survival by increasing transcription of genes associated with protein folding, endoplasmic reticulum-associated degradation (ERAD) and phospholipid synthesis. We demonstrate that an IRE1 RNase inhibitor (MKC8866), in combination with proteasome inhibitors, significantly decreases XBP1s levels and increases cell death in AML cell lines and patient-derived AML cells. In addition, this combination treatment can successfully target the CD34+CD38− population and reduce clonogenic ability.