Induction of apoptosis in large granular lymphocyte (Lgl) Leukemia by jak tyrosine kinase inhibitor AG-490: Role of STAT3-regulated MCL-1
- 作者：Epling-Burnette ; P.K. ; Catlett-Falcone ; R. ; Kothapalli ; R. ; Oshiro ; M.M. ; Jove ; R. ; Loughran Jr ; T.P.
- 刊名：Experimental Hematology
- 出版年：2000
- 期刊代码：100_0301472x
- 类别：med
- 出版时间：July 1, 2000
- 卷：28
- 期：7, Supplement 1
- 页码：90-91
- 文件大小：21.8 K
摘要
Large granular lymphocyte (LGL) leukemia is characterized by the expansion of antigen-activated cytotoxic T lymphocytes. These leukemic cells are resistant to Fas-mediated apoptosis despite expressing high levels of Fas. We found that leukemic LGL from 19 patients displayed constitutively activated STAT3. Treatment of leukemic LGL from 11 patients with the JAK-selective tyrosine kinase inhibitor, AG-490, induced apoptosis with a corresponding decrease in STAT-DNA binding activity. AG-490-induced apoptosis in leukemic LGL was independent of Bcl-XL or BCl-2 expression. However, we found that the Bcl-2-family protein, Mcl-1, was significantly reduced by AG-490 treatment. Activated STAT3 was shown to bind an SIE-related element in the murine mcl-1 promoter. Moreover, using a luciferase reporter assay, we demonstrated that v-src expression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter. We conclude that one mechanism involved in AG-490-induced apoptosis in leukemic LGL may be mediated by inhibition of STAT3-regulated Mcl-1 expression. These findings suggest that AG-490 warrants further study as a possible therapeutic modality for the treatment of LGL leukemia.