BCR-ABL activates STAT3 via JAK and MEK pathways in human cells.
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.
Coppo
Paul
P
INSERM U362 Unité Hématopoïèse et Cellules Souches, Institut Gustave Roussy, Villejuif, France.
Flamant
Stéphane
S
De Mas
Véronique
V
Jarrier
Peggy
P
Guillier
Martine
M
Bonnet
Marie-Laure
ML
Lacout
Catherine
C
Guilhot
François
F
Vainchenker
William
W
Turhan
Ali G
AG
D018952:Antigens, CD34 / Q000032:analysis; D016044:Fusion Proteins, bcr-abl; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D020930:MAP Kinase Kinase Kinases