Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD–negative acute myeloid leukemia

Authors

  • Shuang Qu MD,

    1. Department of Hematology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
    2. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    3. Department of Hematology, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
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  • Bin Liu MD,

    1. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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  • Xiaoling Guo BS,

    1. Translational Medicine Centre, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Hongshun Shi MD,

    1. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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  • Meifeng Zhou MD,

    1. Department of Hematology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Li Li BS,

    1. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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  • Shulan Yang PhD,

    1. Translational Medicine Centre, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Xiuzhen Tong MD, PhD,

    Corresponding author
    1. Department of Hematology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
    • Corresponding authors: Xiuzhen Tong, MD, PhD, 58 Second Zhonshan Road, Guangzhou, CPZN 510080, People's Republic of China, Telephone: (011) 86-20-87755766-8831; tongxz05@163.com, or Haihe Wang, PhD, 74 Second Zhonshan Road, Guangzhou, CPZN 510080, People's Republic of China; Telephone: (011) 86-20-87335035; wanghaih@mail.sysu.edu.cn.

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  • Haihe Wang PhD

    Corresponding author
    1. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    2. Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
    • Corresponding authors: Xiuzhen Tong, MD, PhD, 58 Second Zhonshan Road, Guangzhou, CPZN 510080, People's Republic of China, Telephone: (011) 86-20-87755766-8831; tongxz05@163.com, or Haihe Wang, PhD, 74 Second Zhonshan Road, Guangzhou, CPZN 510080, People's Republic of China; Telephone: (011) 86-20-87335035; wanghaih@mail.sysu.edu.cn.

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Abstract

BACKGROUND

Internal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD–negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL-3 as a key mediator of FLT3-ITD–negative AML.

METHODS

A total of 112 FLT3-ITD–negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL-3 hyperexpression in FLT3-ITD–negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL-3 expression with the specific small interfering RNAs was performed to investigate the role of PRL-3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL-3.

RESULTS

Compared to healthy donors, PRL-3 is upregulated more than 3-fold in 40.2% of FLT3-ITD–negative AML patients. PRL-3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL-3. Mechanistically, aberrant PRL-3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL-3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis-related caspases. Xenograft assays further confirmed PRL-3's oncogenic role in leukemogenesis.

CONCLUSIONS

Our results demonstrated that PRL-3 is a novel independent crucial player in both FLT3-ITD–positive and FLT3-ITD–negative AML and could be a potential therapeutic target. Cancer 2014;120:2130–2141. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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