title: BEX1 acts as a tumor suppressor in acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is a heterogeneous disease of the myeloid lineage. About 35% of AML patients carry an oncogenic FLT3 mutant making FLT3 an attractive target for treatment of AML. Major problems in the development of FLT3 inhibitors include lack of specificity, poor response and development of a resistant phenotype upon treatment. Further understanding of FLT3 signaling and discovery of novel regulators will therefore help to determine additional pharmacological targets in FLT3-driven AML. In this report, we identified BEX1 as a novel regulator of oncogenic FLT3-ITD-driven AML. We showed that BEX1 expression was down-regulated in a group of AML patients carrying FLT3-ITD. Loss of BEX1 expression resulted in poor overall survival (hazard ratio, HR = 2.242, p = 0.0011). Overexpression of BEX1 in mouse pro-B and myeloid cells resulted in decreased FLT3-ITD-dependent cell proliferation, colony and tumor formation, and in increased apoptosis in vitro and in vivo. BEX1 localized to the cytosolic compartment of cells and significantly decreased FLT3-ITD-induced AKT phosphorylation without affecting ERK1/2 or STAT5 phosphorylation. Our data suggest that the loss of BEX1 expression in FLT3-ITD driven AML potentiates oncogenic signaling and leads to decreased overall survival of the patients.
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Lindblad
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.|Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Xianwei
authors.initials: X
authors.lastname: Su
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh.
authors.forename: Nuzhat N
authors.initials: NN
authors.lastname: Kabir
authors.affiliation: Bioinformatics Infrastructure for Life Sciences (BILS), Department of Immunotechnology, Lund University, Lund, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Levander
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.|Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh.
authors.forename: Julhash U
authors.initials: JU
authors.lastname: Kazi
mesh_terms: D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D016016:Proportional Hazards Models; D015398:Signal Transduction; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: C469586:BEX1 protein, human; D009419:Nerve Tissue Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: AKT; AML; FLT3; FLT3-ITD; apoptosis