Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

Jung Eun Park, Hiu Fung Yuen, Jian Biao Zhou, Abdul Qader O Al-Aidaroos, Ke Guo, Peter J. Valk, Shu Dong Zhang, Wee Joo Chng, Cheng William Hong, Ken Mills, Qi Zeng

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Abstract

FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients.
Original languageEnglish
Pages (from-to)1351-1366
JournalEMBO Molecular Medicine
Volume5
Issue number9
Early online date08 Aug 2013
DOIs
Publication statusPublished - 03 Sep 2013

Bibliographical note

© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

ASJC Scopus subject areas

  • Molecular Medicine

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  • Cite this

    Park, J. E., Yuen, H. F., Zhou, J. B., Al-Aidaroos, A. Q. O., Guo, K., Valk, P. J., Zhang, S. D., Chng, W. J., Hong, C. W., Mills, K., & Zeng, Q. (2013). Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia. EMBO Molecular Medicine, 5(9), 1351-1366. https://doi.org/10.1002/emmm.201202183