Open AccessProliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins
Author(s) -
Shigeki Takemoto,
James C. Mulloy,
Anna Cereseto,
Thi-Sao Migone,
Barvin K. R. Patel,
Masao Matsuoka,
Kuzunari Yamaguchi,
Kiyoshi Takatsuki,
Shimeru Kamihira,
Jeffrey D. White,
Warren J. Leonard,
Thomas A. Waldmann,
Genoveffa Franchini
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.25.13897
Subject(s) - stat , jak stat signaling pathway , stat4 , biology , stat protein , leukemia , cancer research , janus kinase , microbiology and biotechnology , phosphorylation , signal transduction , stat3 , immunology , tyrosine kinase
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 thein vitro model of HTLV-I transformation has relevance to viral leukemogenesisin 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.