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.
Original language | English |
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Pages (from-to) | 373-384 |
Number of pages | 12 |
Journal | Leukemia Research |
Volume | 23 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1999 |
Keywords
- DNA-Binding Proteins/metabolism
- HTLV-I Infections/enzymology
- 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
- Lymphocyte Activation/drug effects
- Milk Proteins
- Phosphorylation
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
- Protein Tyrosine Phosphatases/biosynthesis
- Protein-Tyrosine Kinases/metabolism
- Receptors, Interleukin-2/metabolism
- STAT3 Transcription Factor
- STAT5 Transcription Factor
- Sirolimus/pharmacology
- T-Lymphocytes/immunology
- Trans-Activators/metabolism
- Tumor Cells, Cultured