PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia

Author:

Kleppe Maria12,Soulier Jean3,Asnafi Vahid4,Mentens Nicole12,Hornakova Tekla56,Knoops Laurent567,Constantinescu Stefan567,Sigaux François3,Meijerink Jules P.8,Vandenberghe Peter2,Tartaglia Marco9,Foa Robin10,Macintyre Elizabeth4,Haferlach Torsten11,Cools Jan12

Affiliation:

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

2. Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium;

3. Inserm U944 and Hematology Laboratory, Hôpital Saint-Louis, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France;

4. National Center for Scientific Research (CNRS) Unité Mixte de Recherche (UMR) 8147 and Department of Hematology, Hôpital Necker-Enfants-Malades Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris-5 Descartes, Paris, France;

5. Ludwig Institute for Cancer Research, Brussels, Belgium;

6. de Duve Institute, Université Catholique de Louvain, Brussels, Belgium;

7. Division of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium;

8. Department of Pediatrics, Erasmus Medical Center-Sophia, Rotterdam, The Netherlands;

9. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy;

10. Division of Hematology, Department of Cellular Biotechnologies and Hematology, La Sapienza University of Rome, Rome, Italy; and

11. Munich Leukemia Laboratory, Munich, Germany

Abstract

We have recently reported inactivation of the tyrosine phosphatase PTPN2 (also known as TC-PTP) through deletion of the entire gene locus in ∼ 6% of T-cell acute lymphoblastic leukemia (T-ALL) cases. T-ALL is an aggressive disease of the thymocytes characterized by the stepwise accumulation of chromosomal abnormalities and gene mutations. In the present study, we confirmed the strong association of the PTPN2 deletion with TLX1 and NUP214-ABL1 expression. In addition, we found cooperation between PTPN2 deletion and activating JAK1 gene mutations. Activating mutations in JAK1 kinase occur in ∼ 10% of human T-ALL cases, and aberrant kinase activity has been shown to confer proliferation and survival advantages. Our results reveal that some JAK1 mutation–positive T-ALLs harbor deletions of the tyrosine phosphatase PTPN2, a known negative regulator of the JAK/STAT pathway. We provide evidence that down-regulation of Ptpn2 sensitizes lymphoid cells to JAK1-mediated transformation and reduces their sensitivity to JAK inhibition.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference26 articles.

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