Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin’s lymphoma and T-cell non-Hodgkin’s lymphoma

We recently reported deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Functional analyses confirmed that PTPN2 acts as classical tumor suppressor repressing the proliferation of T cells, in part through inhibition of JAK/STAT signaling. We investigated the expression of PTPN2 in leukemia as well as lymphoma cell lines. We identified bi-allelic inactivation of PTPN2 in the Hodgkin’s lymphoma cell line SUP-HD1 which was associated with activation of the JAK/STAT pathway. Subsequent sequence analysis of Hodgkin’s lymphoma and T-cell non-Hodgkin’s lymphoma identified bi-allelic inactivation of PTPN2 in 2 out of 39 cases of peripheral T-cell lymphoma not otherwise specified, but not in Hodgkin’s lymphoma. These results, together with our own data on T-cell acute lymphoblastic leukemia, demonstrate that PTPN2 is a tumor suppressor gene in T-cell malignancies.

[1]  J. Cools,et al.  MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context , 2011, Haematologica.

[2]  Michael R. Green,et al.  Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. , 2010, Blood.

[3]  A. Ferrando,et al.  Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia , 2009, Nature Genetics.

[4]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[5]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[6]  M. Tremblay,et al.  T‐cell protein tyrosine phosphatase is a key regulator in immune cell signaling: lessons from the knockout mouse model and implications in human disease , 2009, Immunological reviews.

[7]  I. Lossos,et al.  T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6 , 2007, Molecular and Cellular Biology.

[8]  T. Mattfeldt,et al.  Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation , 2006, Oncogene.

[9]  B. Gelb,et al.  Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. , 2004, Blood.

[10]  Toshiyuki Fukada,et al.  A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  V. Diehl,et al.  Hodgkin's disease: Establishment and characterization of four in vitro cell lines , 2004, Journal of Cancer Research and Clinical Oncology.

[12]  J. Licht,et al.  Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia , 2003, Nature Genetics.

[13]  M. Tremblay,et al.  The T Cell Protein Tyrosine Phosphatase Is a Negative Regulator of Janus Family Kinases 1 and 3 , 2002, Current Biology.

[14]  P. Marynen,et al.  Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. , 2000, Cancer research.

[15]  B. Kemp,et al.  The Protein-tyrosine Phosphatase TCPTP Regulates Epidermal Growth Factor Receptor-mediated and Phosphatidylinositol 3-Kinase-dependent Signaling* , 1999, The Journal of Biological Chemistry.

[16]  M. Tremblay,et al.  Cloning and characterization of a mouse cDNA encoding a cytoplasmic protein-tyrosine-phosphatase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  E. Krebs,et al.  cDNA isolated from a human T-cell library encodes a member of the protein-tyrosine-phosphatase family. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[18]  V. Diehl,et al.  Hodgkin's disease: establishment and characterization of four in vitro cell lies. , 1981, Journal of cancer research and clinical oncology.