Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) drives migration and progression of T-cell acute lymphoblastic leukemia in vitro and in vivo

M. Wei, M. G. Haney, D. R. Rivas, J. S. Blackburn

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer. There are no immunotherapies and few molecularly targeted therapeutics available for treatment of this malignancy. The identification and characterization of genes and pathways that drive T-ALL progression are critical for the development of new therapies for T-ALL. Here, we determined that the protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) plays a critical role in T-ALL initiation and progression by promoting leukemia cell migration. PRL-3 is highly expressed in patient T-ALL samples at both the mRNA and protein levels compared to normal lymphocytes. Knock-down of PRL-3 expression using short-hairpin RNA (shRNA) in human T-ALL cell lines significantly impeded T-ALL cell migration capacity in vitro and reduced their ability to engraft and proliferate in vivo in xenograft mouse models. Additionally, PRL-3 overexpression in a Myc-induced zebrafish T-ALL model significantly accelerated disease onset and shortened the time needed for cells to enter blood circulation. Reverse-phase protein array (RPPA) and gene set enrichment analysis (GSEA) revealed that the SRC signaling pathway is affected by PRL-3. Immunoblot analyses validated that manipulation of PRL-3 expression in T-ALL cells affected the SRC signaling pathway, which is directly involved in cell migration, although Src was not a direct substrate of PRL-3. More importantly, T-ALL cell growth and migration were inhibited by small molecule inhibition of PRL-3, suggesting that PRL-3 has potential as a therapeutic target in T-ALL. Taken together, our study identifies PRL-3 as an oncogenic driver in T-ALL both in vitro and in vivo and provides a strong rationale for targeted therapies that interfere with PRL-3 function.

Original languageEnglish
Article number6
JournalOncogenesis
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2020

Bibliographical note

Funding Information:
The authors thank the UK Flow Cytometry & Immune Monitoring Core and the Biostatistics and Bioinformatics Shared Resource Facility (supported by the Markey Cancer Center and an NCI Center Core Support Grant P30CA177558) for assistance with FACS and data analysis, respectively, the MD Anderson RPPA Core facility for assistance with RPPA (funded by P30CA16672) and Hera Biolabs for assistance with mouse xenograft experiments. Donna Gilbreath of the Markey Cancer Center Research Communications Office provided invaluable assistance with graphical editing. We are grateful to John Lazo and Peter Wipf for providing JMS-053, Caroline Smith for synthesizing and providing PRL protein, and Kristin O’Leary for assistance with zebrafish experiments. This research was supported by a St. Baldrick’s Foundation Research Grant, and NIH grants DP2CA228043, R01CA227656 (to J.S.B.) and NIH Training Grant T32CA165990 (M.G.H.).

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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