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

// Haibo Sun 1, 2, * , De-Chen Lin 1, * , Xiao Guo 1, * , Behzad Kharabi Masouleh 3 , Sigal Gery 1 , Qi Cao 1 , Serhan Alkan 1 , Takayuki Ikezoe 4 , Chie Akiba 1 , Ronald Paquette 5 , Wenwen Chien 6 , Carsten Müller-Tidow 7 , Yang Jing 4 , Konstantin Agelopoulos 8 , Markus Müschen 9 , H. Phillip Koeffler 1, 6 1 Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA 2 Department of Surgery, University of California San Francisco, San Francisco, CA, USA 3 Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany 4 Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan 5 Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA 6 Cancer Science Institute of Singapore, National University of Singapore, Singapore 7 Department of Hematology and Oncology, University Hospital Halle, Halle, Germany 8 Department of Medicine, Hematology and Oncology, University of Muenster, Muenster, Germany 9 Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA * These authors have contributed equally to this work Correspondence to: Haibo Sun, e-mail: Haibo.Sun@ucsf.edu De-chen Lin, e-mail: De-chen.Lin@cshs.org Keywords: IRE1, ER stress, XBP1, unfolded protein response, micro RNA Received: July 13, 2015 Accepted: January 29, 2016 Published: February 25, 2016 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 (p21 cip1 , p27 kip1 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 AS 2 O 3 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.