Protein Tyrosine Phosphatase 4A3 (PTP4A3/PRL-3) Drives Migration and Progression of T-Cell Acute Lymphoblastic Leukemia in Vitro and in Vivo

Authors

Min Wei, University of KentuckyFollow
Meghan G. Haney, University of KentuckyFollow
Dylan R. Rivas, University of KentuckyFollow
Jessica S. Blackburn, University of KentuckyFollow

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.

Document Type

Article

Publication Date

1-30-2020

Notes/Citation Information

Published in Oncogenesis, v. 9, issue 1, article no. 6.

© The Author(s) 2020

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Digital Object Identifier (DOI)

https://doi.org/10.1038/s41389-020-0192-5

Funding Information

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.).

Repository Citation

Wei, Min; Haney, Meghan G.; Rivas, Dylan R.; and Blackburn, Jessica S., "Protein Tyrosine Phosphatase 4A3 (PTP4A3/PRL-3) Drives Migration and Progression of T-Cell Acute Lymphoblastic Leukemia in Vitro and in Vivo" (2020). Molecular and Cellular Biochemistry Faculty Publications. 175.
https://uknowledge.uky.edu/biochem_facpub/175