title: Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD-negative acute myeloid leukemia.
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.
authors.affiliation: Department of Hematology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Hematology, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qu
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Guo
authors.forename: Hongshun
authors.initials: H
authors.lastname: Shi
authors.forename: Meifeng
authors.initials: M
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Shulan
authors.initials: S
authors.lastname: Yang
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Tong
authors.forename: Haihe
authors.initials: H
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000009:adverse effects* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000009:adverse effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis*
chemical_list: C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; D050799:STAT5 Transcription Factor; D019938:Cyclin D1; D051941:fms-Like Tyrosine Kinase 3; D051057:Proto-Oncogene Proteins c-akt; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: FLT3-ITD-negative; PRL-3; acute myeloid leukemia; apoptosis; cell proliferation; drug resistance
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