Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression

Large granular lymphocyte (LGL) leukemia is characterized by the expansion of antigen-activated cytocoxic T lymphocytes. These leukemic cells are resi stant to Fas-mediated apoptosis despite expressing high levels of Fas. We f ound that leukemic LGL from 19 patients displayed high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inh ibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA b inding activity. Moreover, using an antisense oligonucleotide approach to d iminish STAT3 expression, we found that Fas sensitivity was restored in leu kemic LGL, AG-490-induced apoptosis in leukemic LGL was independent of Bcl- x(L) or Bcl-2 expression. However, we found that the Bcl-2-family protein M cl-1 was significantly reduced by AG-490 treatment. Activated STAT3 was sho wn to bind an SIE-related element in the murine, mcl-1 promoter. Using a lu ciferase reporter assay, we demonstrated that v-src overexpression in NIH3T 3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activ ation contributed to accumulation of the leukemic LGL clones. These finding s suggest that investigation should focus on novel strategies targeting STA T3 in the treatment of LGL leukemia.