Oncotarget

Research Papers:

BEX1 acts as a tumor suppressor in acute myeloid leukemia

Oscar Lindblad _, Tianfeng Li, Xianwei Su, Jianmin Sun, Nuzhat N. Kabir, Fredrik Levander, Hui Zhao, Gang Lu, Lars Rönnstrand, Julhash U. Kazi

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Oncotarget. 2015; 6:21395-21405. https://doi.org/10.18632/oncotarget.4095

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Abstract

Oscar Lindblad1,2,3, Tianfeng Li4, Xianwei Su4,5, Jianmin Sun1,2, Nuzhat N. Kabir6, Fredrik Levander7, Hui Zhao4, Gang Lu4,5, Lars Rönnstrand1,2, Julhash U. Kazi1,2,6

1Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden

2Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden

3Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden

4School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

5Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

6Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh

7Bioinformatics Infrastructure for Life Sciences (BILS), Department of Immunotechnology, Lund University, Lund, Sweden

Correspondence to:

Julhash U. Kazi, e-mail: kazi.uddin@med.lu.se

Keywords: FLT3, FLT3-ITD, AML, apoptosis, AKT

Received: April 16, 2015     Accepted: May 12, 2015     Published: May 26, 2015

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.


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