Jung Eun Park1, Hiu Fung Yuen1, Jian Biao Zhou2, Abdul Qader O. Al-aidaroos1, Ke Guo1, Peter J Valk3, Shu Dong Zhang4, Wee Joo Chng2,5,6, Cheng William Hong7, Ken Mills4 and Zeng Qi1,8, *
1 - Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore
2 - Cancer Science Institute of Singapore, National University of Singapore, Singapore
3 - Department of Hematology, Erasmus University Medical Center Rotterdam, Netherlands
4 - Centre for Cancer Research and Cell Biology, Queen's University Belfast, United Kingdom
5 - Department of Haematology-Oncology, National University Cancer Institute, Singapore
6 - Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
7 - Cleveland Clinic Lerner College of Medicine, USA.
8 - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
* Corresponding author: Zeng Qi: email@example.com
Published in EMBO Molecular Medicine on 8 August 2013.
FLT3-ITDmutations are prevalent mutations in acute myeloid leukemia (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 leukemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 overexpression is mediated by the FLT3-STAT5 signalling pathway in leukemia cells, leading to 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 4 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.
Figure Legend: PRL-3 mRNA levels are elevated inFLT3-ITD-positive AML samples
A. RT-PCR analysis of PRL-3 mRNA expression levels in 19 bone marrow samples from AML patients either negative (ITD NEG; n = 12) or positive (ITD POS; n = 7) for FLT3-ITD mutation. MOLM-14 and MV4-11 AML cell lines were used as FLT3-ITD positive controls. β-actin, loading control.
B. (a-d) Microarray data analysis of PRL-3 mRNA levels in FLT-ITD-positive (POS) or FLT3-ITD-negative (NEG) patients in four independent patient cohorts (total n = 1158). a. Cohort 1 AML patient with normal karyotype (n = 101, p = 0.001). b. GSE1159 AML patient cohort (n = 285, p < 0.001). c. GSE6891 AML patient cohort (n = 521, p < 0.001). d. GSE15434 AML patient cohort (n = 251, p < 0.001). Statistical differences between ITD-POS and ITD-NEG patients were determined using Chi-square test. PRL-3 expression level is divided into 4 groups; Very high, High, Intermediate, Low
C. Western blot analysis of PRL-3 protein levels in four AML cell lines.
D. Western blot analysis of PRL-3 in MOLM-14 and MV4-11 cells upon siRNA-mediated knock-down of FLT3 expression. NS, control non-silencing siRNA. GAPDH, loading control.
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