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.
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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.).
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.
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Supplemental Table 1 GSEA Analysis
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Supplemental Table 2 RPPA Knockdown
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Supplemental Table 3 RPPA Overexpression
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Supplemental Table 4 Antibodies
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Supplemental Table 5 shRNA sequences
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Supplemental Table 6 RT PCR primers
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Supplemental Video 1 PRL3+ circulating T-ALL
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Supplemental Video 2 Myc non-circulating T-ALL