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Acute lymphoblastic leukemia

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

Leukemia volume 35, pages 679–690 (2021)Cite this article

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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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References

  1. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354:166–78.

    Article  CAS  PubMed  Google Scholar 

  3. Belver L, Ferrando A. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer. 2016;16:494–507.

    Article  CAS  PubMed  Google Scholar 

  4. Gianni F, Belver L, Ferrando A. The genetics and mechanisms of T-cell acute lymphoblastic leukemia. Cold Spring Harb Perspect Med. 2020;10:a035246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 2006;20:2096–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L, Wendorff AA, et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med. 2014;20:1130–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ortega M, Bhatnagar H, Lin AP, Wang L, Aster JC, Sill H, et al. A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies. Leukemia. 2015;29:968–76.

    Article  CAS  PubMed  Google Scholar 

  8. Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, Dewald G, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALLXII/ECOG 2993). Blood. 2009;114:5136–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Petit A, Trinquand A, Chevret S, Ballerini P, Cayuela JM, Grardel N, et al. Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia. Blood. 2018;131:289–300.

    Article  CAS  PubMed  Google Scholar 

  10. Ko RH, Ji L, Barnette P, Bostrom B, Hutchinson R, Raetz E, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia consortium study. J Clin Oncol. 2010;28:648–54.

    Article  PubMed  Google Scholar 

  11. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366:1371–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Trinquand A, Dos Santos NR, Quang CT, Rocchetti F, Zaniboni B, Belhocine M, et al. Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia. Cancer Discov. 2016;6:973–85.

    Article  CAS  Google Scholar 

  13. Bollu LR, Mazumdar A, Savage MI, Brown PH. Molecular pathways: targeting protein tyrosine phosphatases in cancer. Clin Cancer Res. 2017;23:2136–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Saha S, Bardelli A, Buckhaults P, Velculescu VE, Rago C, St. Croix B, et al. A phosphatase associated with metastasis of colorectal cancer. Science. 2001;294:1343–6.

    Article  CAS  PubMed  Google Scholar 

  15. Li ZR, Wang Z, Zhu BH, He YL, Peng JS, Cai SR, et al. Association of tyrosine PRL-3 phosphatase protein expression with peritoneal metastasis of gastric carcinoma and prognosis. Surg Today. 2007;37:646–51.

    Article  CAS  PubMed  Google Scholar 

  16. Zhao WB, Li Y, Liu X, Zhang LY, Wang X. Evaluation of PRL-3 expression, and its correlation with angiogenesis and invasion in hepatocellular carcinoma. Int J Mol Med. 2008;22:187–92.

    CAS  PubMed  Google Scholar 

  17. Radke I, Götte M, Kersting C, Mattsson B, Kiesel L, Wülfing P. Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer. Br J Cancer. 2006;95:347–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fiordalisi JJ, Keller PJ, Cox AD. PRL tyrosine phosphatases regulate Rho family GTPases to promote invasion and motility. Cancer Res. 2006;66:3153–61.

    Article  CAS  PubMed  Google Scholar 

  19. Liang F, Liang J, Wang WQ, Sun JP, Udho E, Zhang ZY. PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. J Biol Chem. 2007;282:5413–9.

    Article  CAS  PubMed  Google Scholar 

  20. Kozlov G, Cheng J, Ziomek E, Banville D, Gehring K, Ekiel I. Structural insights into molecular function of the metastasis-associated phosphatase PRL-3. J Biol Chem. 2004;279:11882–9.

    Article  CAS  PubMed  Google Scholar 

  21. Rios P, Li X, Köhn M. Molecular mechanisms of the PRL phosphatases. FEBS J. 2013;280:505–24.

    Article  CAS  PubMed  Google Scholar 

  22. Ariës IM, Bodaar K, Karim SA, Chonghaile TN, Hinze L, Burns MA, et al. PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia. J Exp Med. 2018;215:3094–114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Burns MA, Liao ZW, Yamagata N, Pouliot GP, Stevenson KE, Neuberg DS, et al. Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia. Leukemia. 2018;32:2126–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Blackburn JS, Liu S, Raiser DM, Martinez SA, Feng H, Meeker ND, et al. Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency. Leukemia. 2012;26:2069–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Garcia EG, Iyer S, Garcia SP, Loontiens S, Sadreyev RI, Speleman F, et al. Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia. Leukemia. 2018;32:1860–5.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wilsbacher JL, Moores SL, Brugge JS. An active form of Vav1 induces migration of mammary epithelial cells by stimulating secretion of an epidermal growth factor receptor ligand. Cell Commun Signal. 2006;4:1–13.

    Article  CAS  Google Scholar 

  27. Borga C, Park G, Foster C, Burroughs-Garcia J, Marchesin M, Shah R, et al. Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC: implications for oncogenesis and lymphopoiesis. Leukemia. 2019;33:333–47.

    Article  CAS  PubMed  Google Scholar 

  28. Borga C, Foster CA, Iyer S, Garcia SP, Langenau DM, Frazer JK. Molecularly distinct models of zebrafish Myc-induced B cell leukemia. Leukemia 2018;33:559–62.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hara J, Benedict SH, Champagne E, Mak TW, Minden M, Gelfand EW. Comparison of T cell receptor α, β, and γ gene rearrangement and expression in T cell acute lymphoblastic leukemia. J Clin Investig. 1988;81:989–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bajnok A, Ivanova M, Rigó J, Toldi G. The distribution of activation markers and selectins on peripheral T lymphocytes in preeclampsia. Mediators Inflamm. 2017;8045161.

  31. Haubert D, Li J, Saveliev A, Calzascia T, Sutter E, Metzler B, et al. Vav1 GEF activity is required for T cell mediated allograft rejection. Transpl Immunol. 2012;26:212–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu J, Katzav S, Weiss A. A functional T-cell receptor signaling pathway is required for p95vav activity. Mol Cell Biol. 1995;15:4337–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gulbins E, Coggeshall KM, Baier G. Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation. Science. 1993;260:822–5.

    Article  CAS  PubMed  Google Scholar 

  34. Lazer G, Pe’er L, Farago M, Machida K, Mayer BJ, Katzav S. Tyrosine residues at the carboxyl terminus of Vav1 play an important role in regulation of its biological activity. J Biol Chem. 2010;285:23075–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wardenburg JB, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, et al. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem. 1996;271:19641–4.

    Article  CAS  Google Scholar 

  36. Bustelo XR. Vav proteins, adaptors and cell signaling. Oncogene. 2001;20:6372–81.

    Article  CAS  PubMed  Google Scholar 

  37. Gulbins E, Coggeshall KM, Baier G, Telford D, Langlet C, Baier-Bitterlich G, et al. Direct stimulation of Vav guanine nucleotide exchange activity for Ras by phorbol esters and diglycerides. Mol Cell Biol. 1994;14:4749–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Helou YA, Petrashen AP, Salomon AR. Vav1 regulates T cell activation through a feedback mechanism and crosstalk between the T cell receptor and CD28. J Proteome Res. 2015;176:2963–75.

    Article  CAS  Google Scholar 

  39. Aghazadeh B, Lowry WE, Huang XY, Rosen MK. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell. 2000;102:625–33.

    Article  CAS  PubMed  Google Scholar 

  40. Kobayashi M, Chen S, Gao R, Bai Y, Zhang ZY, Liu Y. Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies. Cell Cycle. 2014;13:2827–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zimmerman MW, Homanics GE, Lazo JS. Targeted Deletion of the metastasis-associated phosphatase Ptp4a3 (PRL-3) suppresses murine colon cancer. PLoS ONE. 2013;8:e58300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wei M, Haney MG, Rivas DR, Blackburn JS. Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) drives migration and progression of T-cell acute lymphoblastic leukemia in vitro and in vivo. Oncogenesis. 2020;9:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nicholson JM, Cimini D. Cancer karyotypes: survival of the fittest. Front Oncol. 2013;3:148.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Peterson EJ, Maltzman JS, Koretzky GA. T-cell activation and tolerance. In: Robert R. Rich editor. Clinical Immunology: Principles and Practice, 4th ed. USA: Elsevier Inc; 2013;160–71.

  45. Nagasawa K, Howatson A, Mak TW. Induction of human malignant T‐lymphoblastic cell lines MOLT‐3 and jurkat by 12‐O‐tetradecanoylphorbol‐13‐acetate: biochemical, physical, and morphological characterization. J Cell Physiol. 1981;109:181–92.

    Article  CAS  PubMed  Google Scholar 

  46. Wang B, Kishihara K, Zhang D, Sakamoto T, Nomoto K. Transcriptional regulation of a receptor protein tyrosine phosphatase gene hPTP-J by PKC-mediated signaling pathways in Jurkat and Molt-4 T lymphoma cells. Biochim Biophys Acta—Mol Cell Res. 1999;1450:331–40.

    Article  CAS  Google Scholar 

  47. Abate F, Da Silva-Almeida AC, Zairis S, Robles-Valero J, Couronne L, Khiabanian H, et al. Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc Natl Acad Sci USA. 2017;114:764–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Robles-Valero J, Lorenzo-Martín LF, Menacho-Márquez M, Fernández-Pisonero I, Abad A, Camós M, et al. A paradoxical tumor-suppressor role for the Rac1 exchange factor Vav1 in T cell acute lymphoblastic leukemia. Cancer Cell. 2017;32:608–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA

    E. G. Garcia, A. Veloso, J. R. Allen, D. Brunson, D. Do, C. Yan, S. Iyer, S. P. Garcia, N. Iftimia, K. McCarthy, W. Haas & D. M. Langenau

  2. Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA

    E. G. Garcia, A. Veloso, J. R. Allen, D. Brunson, D. Do, C. Yan, R. Morris, S. Iyer, S. P. Garcia, N. Iftimia, K. McCarthy, W. Haas & D. M. Langenau

  3. Harvard Stem Cell Institute, Boston, MA, 02114, USA

    E. G. Garcia, A. Veloso, J. R. Allen, D. Brunson, D. Do, C. Yan, S. Iyer, S. P. Garcia, N. Iftimia, K. McCarthy, W. Haas & D. M. Langenau

  4. Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA

    E. G. Garcia, A. Veloso, J. R. Allen, D. Brunson, D. Do, C. Yan, S. Iyer, S. P. Garcia, N. Iftimia, K. McCarthy, W. Haas & D. M. Langenau

  5. Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    M. L. Oliveira & J. T. Barata

  6. Cancer Research Institute Ghent, Ghent, Belgium

    S. Loontiens, W. Van Loocke, F. Matthijssens, F. Speleman & P. Van Vlierberghe

  7. Department of Biomolecular Medicine and Center for Medical Genetics, Ghent University, Ghent, Belgium

    W. Van Loocke, F. Matthijssens, F. Speleman & P. Van Vlierberghe

  8. Department of Diagnostic Sciences, Ghent University, Ghent, Belgium

    T. Taghon

  9. Division of Hematology/Oncology, Boston Children’s Hospital and Dana-Farber Cancer Institute, Boston, USA

    A. Gutierrez

  10. Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40536, USA

    J. S. Blackburn

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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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