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

P. K. Epling-Burnette, Jin Hong Liu, Robyn Catlett-Falcone, James Turkson, Marc Oshiro, Ravi Kothapalli, Yongxiang Li, Ju-Ming Wang, Hsin Fang Yang-Yen, James Karras, Richard Jove, Thomas P. Loughran

Research output: Contribution to journalArticle

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Abstract

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 high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inhibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA binding activity. Moreover, using an antisense oligonucleotide approach to diminish STAT3 expression, we found that Fas sensitivity was restored in leukemic LGL. 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. Using a luciferase reporter assay, we demonstrated that v-src overexpression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones. These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia.

Original languageEnglish
Pages (from-to)351-361
Number of pages11
JournalJournal of Clinical Investigation
Volume107
Issue number3
Publication statusPublished - 2001 Feb 27

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Lymphocytes
Apoptosis
Large Granular Lymphocytic Leukemia
Antisense Oligonucleotides
Cytotoxic T-Lymphocytes
Luciferases
Protein-Tyrosine Kinases
Proteins
Therapeutics
Clone Cells
Antigens
DNA
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Epling-Burnette, P. K., Liu, J. H., Catlett-Falcone, R., Turkson, J., Oshiro, M., Kothapalli, R., ... Loughran, T. P. (2001). Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. Journal of Clinical Investigation, 107(3), 351-361.
Epling-Burnette, P. K. ; Liu, Jin Hong ; Catlett-Falcone, Robyn ; Turkson, James ; Oshiro, Marc ; Kothapalli, Ravi ; Li, Yongxiang ; Wang, Ju-Ming ; Yang-Yen, Hsin Fang ; Karras, James ; Jove, Richard ; Loughran, Thomas P. / Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. In: Journal of Clinical Investigation. 2001 ; Vol. 107, No. 3. pp. 351-361.
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abstract = "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 high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inhibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA binding activity. Moreover, using an antisense oligonucleotide approach to diminish STAT3 expression, we found that Fas sensitivity was restored in leukemic LGL. 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. Using a luciferase reporter assay, we demonstrated that v-src overexpression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones. These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia.",
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Epling-Burnette, PK, Liu, JH, Catlett-Falcone, R, Turkson, J, Oshiro, M, Kothapalli, R, Li, Y, Wang, J-M, Yang-Yen, HF, Karras, J, Jove, R & Loughran, TP 2001, 'Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression', Journal of Clinical Investigation, vol. 107, no. 3, pp. 351-361.

Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. / Epling-Burnette, P. K.; Liu, Jin Hong; Catlett-Falcone, Robyn; Turkson, James; Oshiro, Marc; Kothapalli, Ravi; Li, Yongxiang; Wang, Ju-Ming; Yang-Yen, Hsin Fang; Karras, James; Jove, Richard; Loughran, Thomas P.

In: Journal of Clinical Investigation, Vol. 107, No. 3, 27.02.2001, p. 351-361.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression

AU - Epling-Burnette, P. K.

AU - Liu, Jin Hong

AU - Catlett-Falcone, Robyn

AU - Turkson, James

AU - Oshiro, Marc

AU - Kothapalli, Ravi

AU - Li, Yongxiang

AU - Wang, Ju-Ming

AU - Yang-Yen, Hsin Fang

AU - Karras, James

AU - Jove, Richard

AU - Loughran, Thomas P.

PY - 2001/2/27

Y1 - 2001/2/27

N2 - 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 high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inhibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA binding activity. Moreover, using an antisense oligonucleotide approach to diminish STAT3 expression, we found that Fas sensitivity was restored in leukemic LGL. 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. Using a luciferase reporter assay, we demonstrated that v-src overexpression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones. These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia.

AB - 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 high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inhibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA binding activity. Moreover, using an antisense oligonucleotide approach to diminish STAT3 expression, we found that Fas sensitivity was restored in leukemic LGL. 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. Using a luciferase reporter assay, we demonstrated that v-src overexpression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones. These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia.

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M3 - Article

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Epling-Burnette PK, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. Journal of Clinical Investigation. 2001 Feb 27;107(3):351-361.