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

Haibo Sun,Xiao Guo,Wenwen Chien,Ronald Paquette,Takayuki Ikezoe,Sigal Gery,De-Chen Lin,Carsten Müller-Tidow,Markus Müschen,Serhan Alkan,Chie Akiba,Yang Jing,Behzad Kharabi Masouleh,Konstantin Agelopoulos,H Phillip Koeffler,Qi Cao

doi:10.18632/oncotarget.7702

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.

Highlights

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by a small population of self-renewing leukemic stem cells (LSCs) giving rise to a large population of immature leukemic blasts [1,2,3,4]
IRE1 signaling pathway through x-box binding protein 1 (XBP1) and XBP1s is strongly linked with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) [33]
To examine if XBP1 has a crucial role in acute myeloid leukemia (AML), we first analyzed the AML methylation database (27k Illumina methylation version) from The Cancer Genome Atlas (TCGA)

Summary

Introduction

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by a small population of self-renewing leukemic stem cells (LSCs) giving rise to a large population of immature leukemic blasts [1,2,3,4]. Hematopoietic cells, including LSCs, are exposed to low levels of oxygen in the bone marrow, which may cause accumulation of misfolded proteins in the endoplasmic reticulum (ER), thereby stimulating ER stress and activating the unfolded-protein-response (UPR) pathway [5, 6, 10,11,12]. Leukemic cells proliferating in a hostile environment of low oxygen and limited nutrients accumulate misfolded proteins in the ER, causing continuous ER stress with initiation of UPR [15, 16]. Sustained UPR initiates cellular defense mechanisms rescuing leukemic cells from extreme cellular stress by limiting de novo entry of proteins into the ER which in turn enhances both protein folding capacity and degradation activity [16]. The ability of leukemic cells to handle ER stress may allow them to escape apoptosis and continue their growth [16, 18]

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Results

Conclusion