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Acute lymphoblastic leukemia

PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

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Fig. 1: PRL3 is co-amplified with MYC and highly expressed in subset of human T-ALL.
Fig. 2: Prl3 collaborates with Myc to accelerate T-ALL onset and suppresses apoptosis in transgenic zebrafish.
Fig. 3: PRL3 is required for human T-ALL viability and suppresses apoptosis.
Fig. 4: PRL3 is required for human T-ALL growth and maintenance in mouse xenograft studies.
Fig. 5: Quantitative mass-spectrophotometry analysis identifies that PRL3 suppresses classically defined T-cell receptor phosphorylation signaling pathways.
Fig. 6: PRL3 inhibition leads to downstream T-cell receptor pathway activation and subsequent induction of apoptosis in human T-ALL cells.
Fig. 7: Constitutively active VAV1 induces T-cell signaling pathways and subsequently induces apoptosis in both Jurkat and KE37 T-ALL cells.

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Acknowledgements

We thank Christina Luo, Hiranmayi Ravichandran, Rachel Servis, and Ravi Mylvaganam for technical assistance. We thank Drs. Finola Moore and Riadh Lobbardi for helpful discussion and thoughtful review of this manuscript. This work is supported by NIH grant R01CA211734 (DML), R37CA227656 (JSB), CA193651 (AG), the MGH Research Scholar Award (DML), Alex Lemonade Stand Foundation (JSB), the V Foundation for Cancer Research (AG), an Investigatorship from Boston Children’s Hospital (AG), the Research Foundation Flanders (PVV, TT, SL), ‘Kom op tegen Kanker’ (Stand up to Cancer; SL), and the Ghent University Special Research Fund (PVV and TT). Flow cytometry services were supported by MGH Pathology CNY Flow Cytometry Core shared instrumentation grant 1S10RR023440-01A1.

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Garcia, E.G., Veloso, A., Oliveira, M.L. et al. PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis. Leukemia 35, 679–690 (2021). https://doi.org/10.1038/s41375-020-0937-3

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