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

To determine activation status of the IL-2R-associated (Jak/STAT) pathway i n the HTLV-I infected cells, we examined tyrosine phosphorylation of Jak3, STAT3, and STAT5 in several HTLV-I (+) T-cell lines and in uncultured leuke mic T cells isolated from patients with adult T-cell lymphoma/leukemia (ATL L). Constitutive basal phosphorylation of Jak3 and, usually, STAT3 and STAT 5 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 pat ients (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-depe ndent lines. Furthermore? expression of SHP-1 phosphatase which is a negati ve regulator of cytokine receptor signaling, was lost in most IL-2 independ ent cell Tines (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 o f the Jak3, STAT3, and STAT5 proteins; (2) malignant transformation in at l east 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 m ajor differences in T-cell immortalization mechanism(s) which appear to inv olve SHP-1 and target molecules for rapamycin and RAD. (C) 1999 Published b y Elsevier Science Ltd. All rights reserved.