title: Jab1/Csn5-Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress.
abstract: Purpose:High levels of ROS and ineffective antioxidant systems contribute to oxidative stress, which affects the function of hematopoietic cells in acute myeloid leukemia (AML); however, the mechanisms by which ROS lead to malignant transformation in relapsed AML-M5 are not completely understood. We hypothesized that alterations in intracellular ROS would trigger AML-M5 relapse by activating the intrinsic pathway.Experimental Design:We studied ROS levels and conducted c-Jun activation domain-binding protein-1 (JAB1/COPS5) and thioredoxin (TRX) gene expression analyses with blood samples obtained from 60 matched AML-M5 patients at diagnosis and relapse and conducted mechanism studies of Jab1's regulation of Trx in leukemia cell lines.Results:Our data showed that increased production of ROS and a low capacity of antioxidant enzymes were characteristics of AML-M5, both at diagnosis and at relapse. Consistently, increased gene expression levels ofTRXandJAB1/COPS5were associated with low overall survival rates in patients with AML-M5. In addition, stimulating AML-M5 cells with low concentrations of hydrogen peroxide led to increased Jab1 and Trx expression. Consistently, transfection of ectopic Jab1 into leukemia cells increased Trx expression, whereas silencing of Jab1 in leukemia cells reduced Trx expression. Mechanistically, Jab1 interacted with Trx and stabilized Trx protein. Moreover, Jab1 transcriptionally regulated Trx. Furthermore, depletion of Jab1 inhibited leukemia cell growth bothin vitroandin vivoConclusions:We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of AML-M5. Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5.Clin Cancer Res; 23(15); 4450-61. ©2017 AACR.
authors.affiliation: Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China. zhoufuling@163.com panyunbao@outlook.com fxclaret@mdanderson.org.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.
authors.forename: Fuling
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. zhoufuling@163.com panyunbao@outlook.com fxclaret@mdanderson.org.|Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Yunbao
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Clinical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.
authors.forename: Gaigai
authors.initials: G
authors.lastname: Bai
authors.affiliation: Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Meng
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Le
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. zhoufuling@163.com panyunbao@outlook.com fxclaret@mdanderson.org.|Experimental Therapeutic Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: Francois X
authors.initials: FX
authors.lastname: Claret
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000075686:COP9 Signalosome Complex / Q000097:blood* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics; D007948:Leukemia, Monocytic, Acute / Q000097:blood*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D010447:Peptide Hydrolases / Q000097:blood* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics; D013879:Thioredoxins / Q000097:blood* / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013879:Thioredoxins; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex