Constitutive STAT3-activation in Sezary syndrome:: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells

Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2R alpha beta gamma) triggers mitogenesis in T cells. IL-2R alpha expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (> 95%) of peripheral T cells are IL-2Ra negative. An aberrant expression of IL-2Ra has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2R alpha expression and STATs in a tumor cell line obtained from peripheral blood from a patient with Sezary syndrome (SS), a leukemic variant of CTCL. We show that (1) STATE (a transcription factor known to regulate IL-PR(U transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STATE binds constitutively to a STAT-binding sequence in the promotor of the IL-2R alpha gene; (3) the Janus kinase inhibitor, tyrphostine AG490, inhibits STATE activation, STATE DNA binding, and IL-2R alpha mRNA and protein expression in parallel; and (4) tyrphostine AG490 inhibits IL-2 driven mitogenesis and triggers apoptosis in SS tumor cells. In conclusion, we provide the first example of a constitutive STATE activation in SS tumor cells. Moreover, our findings suggest that STATE activation might play an important role in the constitutive IL-2R alpha expression, survival, and growth of malignant SS cells.