BCR-ABL activates STAT3 via JAK and MEK pathways in human cells

被引:85
作者
Coppo, Paul
Flamant, Stephane
De Mas, Veronique
Jarrier, Peggy
Guillier, Martine
Bonnet, Marie-Laure
Lacout, Catherine
Guilhot, Francois
Vainchenker, William
Turhan, Ali G.
机构
[1] Inst Gustave Roussy, INSERM U362, Unite Hematopoiese & Cellules Souches, Villejuif, France
[2] Hop St Antoine, Dept Clin Haematol & Cell Therapy, F-75571 Paris, France
[3] Fac Paris 6, Paris, France
[4] Inst Gustave Roussy, Dept Biol Clin, Translat Res Cell Therapy Lab, F-94805 Villejuif, France
[5] Dept Oncol & Cell Therapy, Villejuif, France
关键词
BCR-ABL; chronic myeloid leukaemia; STAT3; JAK; MEK1;
D O I
10.1111/j.1365-2141.2006.06161.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Chronic myeloid leukaemia (CML) is characterised by a progression from a chronic towards an acute phase. We previously reported that signal transducer and activator of transcription 3 (STAT3), a major oncogenic signalling protein, is the target of p210-BCR-ABL in a murine embryonic stem (ES) cell model and in primary CD34(+) CML cells. This activation was associated with inhibition of differentiation in ES cells. The present study found that BCR-ABL greatly phosphorylated STAT3 Ser727 residue and, to a lesser extent, Tyr705 residue in BCR-ABL-expressing cell lines (UT7-p210, MO7E-p210, and K562) and in primary CD34(+) CML cells. Using BCR-ABL mutants, it was shown that BCR-ABL tyrosine kinase activity and its Tyr177 residue were necessary for STAT3 Ser727 phosphorylation. Constitutive STAT3 Tyr705 phosphorylation was associated with constitutive phosphorylation of Janus kinase (JAK)1 and JAK2, and was inhibited by the JAK inhibitor AG490, suggesting the involvement of JAK proteins in this process. Specific MEK [mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase] inhibitors PD98056 and UO126, as well as the use of a dominant-negative form of MEK1 abrogated STAT3 Ser727 phosphorylation, suggesting involvement of MAP-Kinase/Erk pathway. Inhibition of BCR-ABL with imatinib mesylate led to a dose-dependent downregulation of total STAT3 protein and mRNA, suggesting that BCR-ABL is involved in the transcriptional regulation of STAT3. Targeting JAK, MEK and STAT3 pathways could therefore be of therapeutic value, especially in advanced stage CML.
引用
收藏
页码:171 / 179
页数:9
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