Coppo Paul, Flamant Stéphane, De Mas Véronique, Jarrier Peggy, Guillier Martine, Bonnet Marie-Laure, Lacout Catherine, Guilhot François, Vainchenker William, Turhan Ali G
INSERM U362 Unité Hématopoïèse et Cellules Souches, Institut Gustave Roussy, Villejuif, France.
Br J Haematol. 2006 Jul;134(2):171-9. doi: 10.1111/j.1365-2141.2006.06161.x.
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.
慢性髓性白血病（CML）的特征是从慢性期向急性期进展。我们之前报道过，信号转导及转录激活因子3（STAT3）是一种主要的致癌信号蛋白，在小鼠胚胎干细胞（ES）模型和原发性CD34 + CML细胞中是p210-BCR-ABL的靶点。这种激活与ES细胞分化的抑制有关。本研究发现，在表达BCR-ABL的细胞系（UT7-p210、MO7E-p210和K562）以及原发性CD34 + CML细胞中，BCR-ABL使STAT3的Ser727残基大量磷酸化，对Tyr705残基的磷酸化程度较低。使用BCR-ABL突变体表明，BCR-ABL酪氨酸激酶活性及其Tyr177残基对于STAT3 Ser727磷酸化是必需的。组成型STAT3 Tyr705磷酸化与Janus激酶（JAK）1和JAK2的组成型磷酸化相关，并被JAK抑制剂AG490抑制，这表明JAK蛋白参与了这一过程。特异性MEK[丝裂原活化蛋白（MAP）激酶/细胞外信号调节激酶（ERK）激酶]抑制剂PD98056和UO126，以及使用MEK1的显性负性形式消除了STAT3 Ser727磷酸化，表明MAP激酶/Erk途径参与其中。用甲磺酸伊马替尼抑制BCR-ABL导致总STAT3蛋白和mRNA的剂量依赖性下调，表明BCR-ABL参与了STAT3的转录调控。因此，靶向JAK、MEK和STAT3途径可能具有治疗价值，尤其是在晚期CML中。
