title: 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.
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: Behzad
authors.initials: B
authors.lastname: Kharabi Masouleh
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Sigal
authors.initials: S
authors.lastname: Gery
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Serhan
authors.initials: S
authors.lastname: Alkan
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Chie
authors.initials: C
authors.lastname: Akiba
authors.affiliation: Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Paquette
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Chien
authors.affiliation: Department of Hematology and Oncology, University Hospital Halle, Halle, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Muenster, Muenster, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Agelopoulos
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000818:Animals; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012260:Ribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D056811:Unfolded Protein Response; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D012260:Ribonucleases
keywords: ER stress; IRE1; XBP1; micro RNA; unfolded protein response