Differences in phosphorylation of the IL-2R associated JAK/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia

Leuk Res. 1999 Apr;23(4):373-84. doi: 10.1016/s0145-2126(98)00173-8.

Abstract

To determine activation status of the IL-2R-associated (Jak/STAT) pathway in the HTLV-I infected cells, we examined tyrosine phosphorylation of Jak3, STAT3, and STAT5 in several HTLV-I(+) T-cell lines and in uncultured leukemic T cells isolated from patients with adult T-cell lymphoma/leukemia (ATLL). Constitutive basal phosphorylation of Jak3 and, usually, STAT3 and STAT5 was detected in all four IL-2-independent cell lines tested, but in none of the three IL-2-dependent cell lines. Similarly, there was no detectable basal phosphorylation of Jak3 and STAT5 in the leukemic cells from ATLL patients (0/8 and 0/3, respectively). However, stimulation with IL-2 resulted in Jak3 and STAT5 phosphorylation in both leukemic ATLL cells and IL-2-dependent lines. Furthermore, expression of SHP-1 phosphatase which is a negative regulator of cytokine receptor signaling, was lost in most IL-2 independent cell lines (3/4) but not in the leukemic ATLL cells (0/3). Finally, the HTLV-I(+) T-cell lines (313) but not the control, HTLV-I(-) T-cell lines were resistant to rapamycin and its novel analog RAD. We conclude that (1) HTLV-I infection per se does not result in a constitutive phosphorylation of the Jak3, STAT3, and STAT5 proteins; (2) malignant transformation in at least some cases of ATLL does not require the constitutive, but may require IL-2-induced, activation of the IL-2R Jak/STAT pathway; and (3) there are major differences in T-cell immortalization mechanism(s) which appear to involve SHP-1 and target molecules for rapamycin and RAD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • DNA-Binding Proteins / metabolism*
  • HTLV-I Infections / enzymology
  • HTLV-I Infections / metabolism*
  • HTLV-I Infections / virology
  • Human T-lymphotropic virus 1*
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Interleukin-2 / physiology*
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 3
  • Leukemia-Lymphoma, Adult T-Cell / enzymology
  • Leukemia-Lymphoma, Adult T-Cell / metabolism*
  • Leukemia-Lymphoma, Adult T-Cell / virology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Milk Proteins*
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / biosynthesis
  • Protein Tyrosine Phosphatases / metabolism
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Interleukin-2 / metabolism*
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Sirolimus / pharmacology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Immunosuppressive Agents
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Milk Proteins
  • Receptors, Interleukin-2
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • Trans-Activators
  • Protein-Tyrosine Kinases
  • JAK3 protein, human
  • Janus Kinase 3
  • PTPN11 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Sirolimus