Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins.

Human T cell leukemia/lymphotropic virus type I (HTLV-I) induces adult T cell leukemia/lymphoma (ATLL). The mechanism of HTLV-I oncogenesis in T cells remains partly elusive. In vitro, HTLV-I induces ligand-independent transformation of human CD4+ T cells, an event that correlates with acquisition of constitutive phosphorylation of Janus kinases (JAK) and signal transducers and activators of transcription (STAT) proteins. However, it is unclear whether the in vitro model of HTLV-I transformation has relevance to viral leukemogenesis in vivo. Here we tested the status of JAK/STAT phosphorylation and DNA-binding activity of STAT proteins in cell extracts of uncultured leukemic cells from 12 patients with ATLL by either DNA-binding assays, using DNA oligonucleotides specific for STAT-1 and STAT-3, STAT-5 and STAT-6 or, more directly, by immunoprecipitation and immunoblotting with anti-phosphotyrosine antibody for JAK and STAT proteins. Leukemic cells from 8 of 12 patients studied displayed constitutive DNA-binding activity of one or more STAT proteins, and the constitutive activation of the JAK/STAT pathway was found to persist over time in the 2 patients followed longitudinally. Furthermore, an association between JAK3 and STAT-1, STAT-3, and STAT-5 activation and cell-cycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four patients tested. These results imply that JAK/STAT activation is associated with replication of leukemic cells and that therapeutic approaches aimed at JAK/STAT inhibition may be considered to halt neoplastic growth.

[1]  S. Wain-Hobson,et al.  Adult T-cell leukemia/lymphoma on a background of clonally expanding human T-cell leukemia virus type-1-positive cells. , 1996, Blood.

[2]  J. Johnston,et al.  Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways. , 1996, Immunity.

[3]  J. O’Shea,et al.  Signal Transduction by Interleukin‐12 and Interleukin‐2 , 1996, Annals of the New York Academy of Sciences.

[4]  Ling-mei Wang,et al.  Stat6 and Jak1 Are Common Elements in Platelet-derived Growth Factor and Interleukin-4 Signal Transduction Pathways in NIH 3T3 Fibroblasts* , 1996, The Journal of Biological Chemistry.

[5]  W. Leonard.  STATs and cytokine specificity , 1996, Nature Network Boston.

[6]  P. Nowell,et al.  Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[7]  L. Notarangelo.  Immunodeficiencies caused by genetic defects in protein kinases. , 1996, Current opinion in immunology.

[8]  V. Gouilleux-Gruart,et al.  Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. , 1996, Blood.

[9]  J. Darnell,et al.  Reflections on STAT3, STAT5, and STAT6 as fat STATs. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Lammers,et al.  STAT3β, a Splice Variant of Transcription Factor STAT3, Is a Dominant Negative Regulator of Transcription* , 1996, The Journal of Biological Chemistry.

[11]  T. Waldmann,et al.  IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. , 1996, Immunity.

[12]  H. Fujiwara,et al.  Relation of autonomous and interleukin-2-responsive growth of leukemic cells to survival in adult T-cell leukemia. , 1996, Blood.

[13]  B. Groner,et al.  STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients , 1996 .

[14]  A. Levitzki,et al.  Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor , 1996, Nature.

[15]  H. Nakauchi,et al.  Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. , 1995, Immunity.

[16]  W. Leonard,et al.  Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development , 1995, Science.

[17]  P. Doherty,et al.  Defective Lymphoid Development in Mice Lacking Jak3 , 1995, Science.

[18]  A. Sharpe,et al.  Defects in B Lymphocyte Maturation and T Lymphocyte Activation in Mice Lacking Jak3 , 1995, Science.

[19]  N. Danial,et al.  Jak-STAT signaling induced by the v-abl oncogene. , 1995, Science.

[20]  M. Nerenberg,et al.  Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells. , 1995, The Journal of clinical investigation.

[21]  W. Leonard,et al.  Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. , 1995, Science.

[22]  S. Wain-Hobson,et al.  Clonal expansion of human T-cell leukemia virus type I-infected cells in asymptomatic and symptomatic carriers without malignancy , 1995, Journal of virology.

[23]  S. Ruscetti,et al.  Induction of sequence-specific DNA-binding factors by erythropoietin and the spleen focus-forming virus. , 1995, Blood.

[24]  J. Darnell,et al.  Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. , 1995, Annual review of biochemistry.

[25]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[26]  J. Darnell,et al.  Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. , 1994, Science.

[27]  W. Leonard,et al.  The Molecular Basis of X‐Linked Severe Combined Immunodeficiency: The Role of the Interleukin‐2 Receptor γ Chain as a Common γ Chain, γc , 1994, Immunological reviews.

[28]  M. Shimoyama,et al.  Diagnostic criteria and classification of clinical subtypes of adult T‐cell leukaemia‐lymphoma , 1991, British journal of haematology.

[29]  W. Paul,et al.  Interleukin-4 : A Prototypic Immunoregulatory Lymphokine , 2003 .

[30]  T. Uchiyama,et al.  Expression of Cytokine mRNA in Leukemic Cells from Adult T Cell Leukemia Patients , 1989, Japanese journal of cancer research : Gann.

[31]  J. Goedert,et al.  Modelling the risk of adult T‐cell leukemia/lymphoma in persons infected with human T‐lymphotropic virus type I , 1989, International journal of cancer.

[32]  T. Uchiyama,et al.  Leukemic cells from some adult T-cell leukemia patients proliferate in response to interleukin-4. , 1988, Blood.

[33]  R C Gallo,et al.  The first human retrovirus. , 1986, Scientific American.

[34]  Y. Yamamoto,et al.  Autocrine growth of interleukin 2-producing leukemic cells in a patient with adult T cell leukemia. , 1986, Blood.

[35]  Geo. E. Williams.  The Solar Cycle in Precambrian Time , 1986 .

[36]  J. Yodoi,et al.  Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. , 1985, The Journal of clinical investigation.

[37]  B. Hahn,et al.  Clonal selection of human T-cell leukemia virus-infected cells in vivo and in vitro. , 1984, Molecular biology & medicine.

[38]  D. Mann,et al.  Transformation of human umbilical cord blood T cells by human T-cell leukemia/lymphoma virus. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Salahuddin,et al.  Restricted expression of human T-cell leukemia--lymphoma virus (HTLV) in transformed human umbilical cord blood lymphocytes. , 1983, Virology.

[40]  R. Gallo,et al.  Infection and transformation of fresh human umbilical cord blood cells by multiple sources of human T‐cell leukemia‐lymphoma virus (HTLV) , 1983, International journal of cancer.

[41]  Y. Ohtsuki,et al.  Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells , 1981, Nature.

[42]  K. Nagata,et al.  Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[43]  John D. Minna,et al.  Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma , 1980, Proceedings of the National Academy of Sciences.