Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia

Abstract

Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1α-XBP1 pathway, a key branch of the UPR, is activated in many cancers. Here, we show that the expression of both mature and spliced forms of XBP1 (XBP1s) is up-regulated in acute myeloid leukemia (AML) cell lines and AML patient samples. IRE1α RNase inhibitors [MKC-3946, 2-hydroxy-1-naphthaldehyde (HNA), STF-083010 and toyocamycin] blocked XBP1 mRNA splicing and exhibited cytotoxicity against AML cells. IRE1α inhibition induced caspase-dependent apoptosis and G1 cell cycle arrest at least partially by regulation of Bcl-2 family proteins, G1 phase controlling proteins (p21cip1, p27kip1 and cyclin D1), as well as chaperone proteins. Xbp1 deleted murine bone marrow cells were resistant to growth inhibition by IRE1α inhibitors. Combination of HNA with either bortezomib or AS2O3 was synergistic in AML cytotoxicity associated with induction of p-JNK and reduction of p-PI3K and p-MAPK. Inhibition of IRE1α RNase activity increased expression of many miRs in AML cells including miR-34a. Inhibition of miR-34a conferred cellular resistance to HNA. Our results strongly suggest that targeting IRE1α driven pro-survival pathways represent an exciting therapeutic approach for the treatment of AML.

GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells

“…6G). However, viability of these mutants, especially the highly TKI-resistant FLT3-ITD-D835Y/F mutants 41 , 16 was significantly reduced by both PU-WS13 and ganetespib (Fig. 6G).…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…Accumulating evidence links IRE1 signaling with various aspects of cancer biology. For instance, combination of an IRE1 RNase inhibitor with either bortezomib (a proteasome inhibitor) or arsenic trioxide (AS 2 O 3 ) precluded XBP1 mRNA splicing and alleviated acute myeloid leukemia cell growth (48). The IRE1/XBP1 axis has been also implicated in decreased sensitivity of transformed cells to hypoxia-induced death (49).…”

JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia

“…11,30,31 In AML, the mean expression of XBP1 is significantly higher in AML patients compared to normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) and this increased expression is associated with hypomethylation of the XBP1 promoter. 32 Several studies have also observed that markers of activated UPR signaling, such as the presence of the XBP1s splice variant and increased expression of UPR-activated genes GRP78 (encoded by HSPA5) , PDI and CALR, are detectable in a significant number of AML patient samples. 33–35 However, the regulators of the UPR and the functional consequences of altered UPR signaling in AML have not been defined.…”