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Biology of Human Tumors

Jab1/Csn5–Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress

Fuling Zhou, Yunbao Pan, Yongchang Wei, Ronghua Zhang, Gaigai Bai, Qiuju Shen, Shan Meng, Xiao-Feng Le, Michael Andreeff and Francois X. Claret
Fuling Zhou
Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China.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.
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  • For correspondence: zhoufuling@163.companyunbao@outlook.comfxclaret@mdanderson.org
Yunbao Pan
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
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  • For correspondence: zhoufuling@163.companyunbao@outlook.comfxclaret@mdanderson.org
Yongchang Wei
Department of Clinical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
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Ronghua Zhang
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Gaigai Bai
Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.
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Qiuju Shen
Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.
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Shan Meng
Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University, School of Medicine, Xi'an, China.
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Xiao-Feng Le
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Michael Andreeff
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Francois X. Claret
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Experimental Therapeutic Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
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  • For correspondence: zhoufuling@163.companyunbao@outlook.comfxclaret@mdanderson.org
DOI: 10.1158/1078-0432.CCR-16-2426 Published August 2017
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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 of TRX and JAB1/COPS5 were 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 both in vitro and in vivo.

Conclusions: 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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received October 4, 2016.
  • Revision received November 1, 2016.
  • Accepted March 1, 2017.
  • ©2017 American Association for Cancer Research.
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Clinical Cancer Research: 23 (15)
August 2017
Volume 23, Issue 15
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Jab1/Csn5–Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress
Fuling Zhou, Yunbao Pan, Yongchang Wei, Ronghua Zhang, Gaigai Bai, Qiuju Shen, Shan Meng, Xiao-Feng Le, Michael Andreeff and Francois X. Claret
Clin Cancer Res August 1 2017 (23) (15) 4450-4461; DOI: 10.1158/1078-0432.CCR-16-2426

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Jab1/Csn5–Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress
Fuling Zhou, Yunbao Pan, Yongchang Wei, Ronghua Zhang, Gaigai Bai, Qiuju Shen, Shan Meng, Xiao-Feng Le, Michael Andreeff and Francois X. Claret
Clin Cancer Res August 1 2017 (23) (15) 4450-4461; DOI: 10.1158/1078-0432.CCR-16-2426
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