Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia.
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.
Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.
Jung Eun
JE
Park
Hiu Fung
HF
Yuen
Jian Biao
JB
Zhou
Abdul Qader O
AQ
Al-Aidaroos
Ke
K
Guo
Peter J
PJ
Valk
Shu Dong
SD
Zhang
Wee Joo
WJ
Chng
Cheng William
CW
Hong
Ken
K
Mills
Qi
Q
Zeng
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D009363:Neoplasm Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases
FLT3-ITD mutation; PRL-3; acute myeloid leukaemia; antibody therapy; prognostic marker