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Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia

Nature Genetics volume 42, pages 530–535 (2010)Cite this article

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Abstract

PTPN2 (protein tyrosine phosphatase non-receptor type 2, also known as TC-PTP) is a cytosolic tyrosine phosphatase that functions as a negative regulator of a variety of tyrosine kinases and other signaling proteins1,2,3. In agreement with its role in the regulation of the immune system, PTPN2 was identified as a susceptibility locus for autoimmune diseases4,5. In this work, we describe the identification of focal deletions of PTPN2 in human T-cell acute lymphoblastic leukemia (T-ALL). Deletion of PTPN2 was specifically found in T-ALLs with aberrant expression of the TLX1 transcription factor oncogene6, including four cases also expressing the NUP214-ABL1 tyrosine kinase7. Knockdown of PTPN2 increased the proliferation and cytokine sensitivity of T-ALL cells. In addition, PTPN2 was identified as a negative regulator of NUP214-ABL1 kinase activity. Our study provides genetic and functional evidence for a tumor suppressor role of PTPN2 and suggests that expression of PTPN2 may modulate response to treatment.

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Figure 1: Comprehensive analysis of T-ALL individuals featuring PTPN2 deletion.
Figure 2: Knockdown of PTPN2 causes higher sensitivity of T-cell lines to cytokine stimulation.
Figure 3: Mouse T-ALL cells display altered cytokine receptor signaling in correlation with Ptpn2 expression.
Figure 4: Identification of NUP214-ABL1 oncogene as a new substrate of PTPN2.
Figure 5: Reduction of PTPN2 expression affects treatment response of NUP214-ABL1–dependent cells to the kinase inhibitor imatinib.

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Acknowledgements

We thank S. Aerts for assistance with data analysis. This work was supported by grants from the K.U. Leuven (concerted action grant to J.C., I.W. and P.V.), the FWO-Vlaanderen (G.0287.07, J.C.), the Foundation against Cancer (SCIE2006-34, J.C.), a European Research Council starting grant (J.C.), a José-Carreras Fellowship grant from the European Hematology Association (J.C.), the Interuniversity Attraction Poles granted by the Federal Office for Scientific, Technical and Cultural Affairs, Belgium (J.C. and P.V.), a grant from the French program Carte d'Identite des Tumeurs (CIT, Ligue Contre le Cancer) and from Canceropole d'Ile de France (F.S. and J.S.); a Blood Disease Research Project research grant from The New York Community Trust (A.A.F.) and the National Institutes of Health (grants CA120196 and CA129382 to A.A.F.). A.A.F. is a Leukemia and Lymphoma Society Scholar. K.D.K. is a postdoctoral researcher, and P.V. is a senior clinical investigator of FWO-Vlaanderen.

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Authors and Affiliations

  1. Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium

    Maria Kleppe, Idoya Lahortiga, Kim De Keersmaecker, Nicole Mentens, Katrien Van Roosbroeck & Jan Cools

  2. Center for Human Genetics, K.U. Leuven, Leuven, Belgium

    Maria Kleppe, Idoya Lahortiga, Kim De Keersmaecker, Nicole Mentens, Katrien Van Roosbroeck, Iwona Wlodarska, Peter Vandenberghe & Jan Cools

  3. INSERM U944 and Hematology Laboratory, Hôpital Saint-Louis, Institut Universitaire d′Hématologie, Paris, France

    Tiama El Chaar, François Sigaux & Jean Soulier

  4. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA

    Kim De Keersmaecker & Adolfo A Ferrando

  5. Cliniques universitaires de Mont-Godinne, Yvoir, Belgium

    Carlos Graux

  6. Department of Pathology, Columbia University Medical Center, New York, New York, USA

    Adolfo A Ferrando

  7. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA

    Adolfo A Ferrando

  8. Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands

    Anton W Langerak

  9. Department of Pediatrics, Erasmus Medical Center–Sophia, Rotterdam, The Netherlands

    Jules P P Meijerink

  10. Munich Leukemia Laboratory, Munich, Germany

    Torsten Haferlach

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  1. Maria Kleppe
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Contributions

All authors contributed to the text; M.K. designed and carried out experiments and analyzed data; I.L., T.E.C., K.D.K., N.M., C.G., K.V.R. and I.W. carried out experiments and analyzed data; A.A.F., A.W.L., J.P.P.M., F.S., T.H. and P.V. collected samples, carried out experiments and analyzed data; J.S. and J.C. supervised the project and analyzed data.

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Correspondence to Jean Soulier or Jan Cools.

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The authors declare no competing financial interests.

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Kleppe, M., Lahortiga, I., El Chaar, T. et al. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet 42, 530–535 (2010). https://doi.org/10.1038/ng.587

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