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

Leukemia. 2001 May;15(5):787-93. doi: 10.1038/sj.leu.2402093.


Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2Ralphabetagamma) triggers mitogenesis in T cells. IL-2Ralpha expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (>95%) of peripheral T cells are IL-2Ralpha negative. An aberrant expression of IL-2Ralpha has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2Ralpha 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) STAT3 (a transcription factor known to regulate IL-2Ralpha transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STAT3 binds constitutively to a STAT-binding sequence in the promotor of the IL-2Ralpha gene; (3) the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha 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 STAT3 activation in SS tumor cells. Moreover, our findings suggest that STAT3 activation might play an important role in the constitutive IL-2Ralpha expression, survival, and growth of malignant SS cells.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Janus Kinase 3
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Interleukin-2 / analysis
  • STAT3 Transcription Factor
  • Sezary Syndrome / drug therapy
  • Sezary Syndrome / metabolism*
  • Sezary Syndrome / pathology
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured
  • Tyrphostins / pharmacology*


  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Receptors, Interleukin-2
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Protein-Tyrosine Kinases
  • JAK3 protein, human
  • Janus Kinase 3