[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Garcia, E G; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Bacquelaine Veloso, Alexandra ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie ; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Oliveira, M L; Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Allen, J R ; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Loontiens, S ; Cancer Research Institute Ghent, Ghent, Belgium
Brunson, D; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Do, D; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Yan, C ; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Morris, R; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA
Iyer, S; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Garcia, S P ; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Iftimia, N; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Van Loocke, W; Cancer Research Institute Ghent, Ghent, Belgium ; Department of Biomolecular Medicine and Center for Medical Genetics, Ghent University, Ghent, Belgium
Matthijssens, F; Cancer Research Institute Ghent, Ghent, Belgium ; Department of Biomolecular Medicine and Center for Medical Genetics, Ghent University, Ghent, Belgium
McCarthy, K; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Barata, J T ; Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Speleman, F ; Cancer Research Institute Ghent, Ghent, Belgium ; Department of Biomolecular Medicine and Center for Medical Genetics, Ghent University, Ghent, Belgium
Taghon, T ; Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
Gutierrez, A ; Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, USA
Van Vlierberghe, P ; Cancer Research Institute Ghent, Ghent, Belgium ; Department of Biomolecular Medicine and Center for Medical Genetics, Ghent University, Ghent, Belgium
Haas, W; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA ; Harvard Stem Cell Institute, Boston, MA, 02114, USA ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
Blackburn, J S; Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40536, USA
Langenau, D M ; Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA. dlangenau@mgh.harvard.edu ; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA. dlangenau@mgh.harvard.edu ; Harvard Stem Cell Institute, Boston, MA, 02114, USA. dlangenau@mgh.harvard.edu ; Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. dlangenau@mgh.harvard.edu
Acknowledgements We thank Christina Luo, Hiranmayi Ravichan-dran, 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\u2019s Hospital (AG), the Research Foundation Flanders (PVV, TT, SL), \u2018Kom op tegen Kanker\u2019 (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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