LEO1 Is Regulated by PRL-3 and Mediates Its Oncogenic Properties in Acute Myelogenous Leukemia

Abstract

PRL-3, an oncogenic dual-specificity phosphatase, is overexpressed in 50% of acute myelogenous leukemia (AML) and associated with poor survival. We found that stable expression of PRL-3 confers cytokine independence and growth advantage of AML cells. However, how PRL-3 mediates these functions in AML is not known. To comprehensively screen for PRL3-regulated proteins in AML, we performed SILAC-based quantitative proteomics analysis and discovered 398 significantly perturbed proteins after PRL-3 overexpression. We show that Leo1, a component of RNA polymerase II-associated factor (PAF) complex, is a novel and important mediator of PRL-3 oncogenic activities in AML. We described a novel mechanism where elevated PRL-3 protein increases JMJD2C histone demethylase occupancy on Leo1 promoter, thereby reducing the H3K9me3 repressive signals and promoting Leo1 gene expression. Furthermore, PRL-3 and Leo1 levels were positively associated in AML patient samples (N ¼ 24; P < 0.01). On the other hand, inhibition of Leo1 reverses PRL-3 oncogenic phenotypes in AML. Loss of Leo1 leads to destabilization of the PAF complex and downregulation of SOX2 and SOX4, potent oncogenes in myeloid transformation. In conclusion, we identify an important and novel mechanism by which PRL-3 mediates its oncogenic function in AML. Cancer Res; 74(11); 3043-53. Ó2014 AACR.

Global Cell Proteome Profiling, Phospho-signaling and Quantitative Proteomics for Identification of New Biomarkers in Acute Myeloid Leukemia Patients

“…Another type of proteomic screening or profiling where MS-based proteomics can reveal new biological insight and markers is over-expression or knock-down of oncogenes in cell lines followed by protein quantification of the induced biological activities, as demonstrated in a study of protein tyrosine phosphatase type IVA 3 (TP4A3) by Chong et al [107]. By screening the quantified proteins in the downstream signaling pathway of TP4A3, 398 proteins were significantly altered and RNA polymerase-associated protein Leo1 was identified as a novel mediator of the oncogenic functions of TP4A3 in leukemia.…”

PRL-3 promotes telomere deprotection and chromosomal instability

“…PRL-3 also modulates gene transcription through the functional and/or physical associations with key transcriptional factors (10,15–17). Moreover, the role of PRL-3 in epigenetic regulation was proposed, but the mechanism is unclear (18,19). In Xenopus laevis , lose-of-function and gain-of-function studies showed that PRL-3 is required for migration of cephalic neural crest cells during embryonic development (20).…”

LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell–like Transcriptional Program in AML

“…As reported in previous studies (15,18), we established a pair of stable, isogenic cell lines, TF1-pEGFP and TF1-hPRL3, by transfecting pEGFP (vector control) and pEGFP-hPRL-3 vectors into TF-1 cells, respectively, and showed that PRL-3 promoted cytokine-independent growth of AML cells. Here, we further determined the in vivo function of PRL-3 on leukemogenesis by using this pair of TF1 cells in a bone marrow transplantation xenograft assay.…”

“…Importantly, several studies have independently confirmed that the high expression of PRL-3 is associated with poor survival in AML (15)(16)(17). We previously demonstrated that LEO1, a component of RNA polymerase IIassociated factor (PAF) complex, was induced by PRL-3 in AML (18). PAF complex plays an essential role in MLL-rearranged leukemia (19).…”