1. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia
- Author
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Park, JE, Yuen, HF, Zhou, JB, Al-aidaroos, AQO, Guo, K, Valk, Peter, Zhang, SD, Chng, WJ, Hong, CW, Mills, K, Zeng, Q, Park, JE, Yuen, HF, Zhou, JB, Al-aidaroos, AQO, Guo, K, Valk, Peter, Zhang, SD, Chng, WJ, Hong, CW, Mills, K, and Zeng, Q
- 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.
- Published
- 2013