TY - JOUR
T1 - STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells
AU - Hazan-Halevy, Inbal
AU - Harris, David
AU - Liu, Zhiming
AU - Liu, Jie
AU - Li, Ping
AU - Chen, Xiaomin
AU - Shanker, Sreejesh
AU - Ferrajoli, Alessandra
AU - Keating, Michael J.
AU - Estrov, Zeev
PY - 2010/4/8
Y1 - 2010/4/8
N2 - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western hemisphere, but its pathogenesis is still poorly understood. Constitutive tyrosine phosphorylation (p) of signal transducer and activator of transcription (STAT) 3 occurs in several solid tumors and hematologic malignancies. In CLL, however, STAT3 is constitutively phosphorylated on serine 727, not tyrosine 705, residues. Because the biologic significance of serine pSTAT3 in CLL is not known, we studied peripheral blood cells of 106 patients with CLL and found that, although tyrosine pSTAT3 was inducible, serine pSTAT3 was constitutive in all patients studied, regardless of blood count, disease stage, or treatment status. In addition, we demonstrated that constitutive serine pSTAT3 translocates to the nucleus by the karyopherin-β nucleocytoplasmic system and binds DNA. Dephosphorylation of inducible tyrosine pSTAT3 did not affect STAT3-DNA binding, suggesting that constitutive serine pSTAT3 binds DNA. Furthermore, infection of CLL cells with lentiviral STAT3-small hairpin RNA reduced the expression of several STAT3-regulated survival and proliferation genes and induced apoptosis, suggesting that constitutive serine pSTAT3 initiates transcription in CLL cells. Taken together, our data suggest that constitutive phosphorylation of STAT3 on serine 727 residues is a hallmark of CLL and that STAT3 be considered a therapeutic target in this disease.
AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western hemisphere, but its pathogenesis is still poorly understood. Constitutive tyrosine phosphorylation (p) of signal transducer and activator of transcription (STAT) 3 occurs in several solid tumors and hematologic malignancies. In CLL, however, STAT3 is constitutively phosphorylated on serine 727, not tyrosine 705, residues. Because the biologic significance of serine pSTAT3 in CLL is not known, we studied peripheral blood cells of 106 patients with CLL and found that, although tyrosine pSTAT3 was inducible, serine pSTAT3 was constitutive in all patients studied, regardless of blood count, disease stage, or treatment status. In addition, we demonstrated that constitutive serine pSTAT3 translocates to the nucleus by the karyopherin-β nucleocytoplasmic system and binds DNA. Dephosphorylation of inducible tyrosine pSTAT3 did not affect STAT3-DNA binding, suggesting that constitutive serine pSTAT3 binds DNA. Furthermore, infection of CLL cells with lentiviral STAT3-small hairpin RNA reduced the expression of several STAT3-regulated survival and proliferation genes and induced apoptosis, suggesting that constitutive serine pSTAT3 initiates transcription in CLL cells. Taken together, our data suggest that constitutive phosphorylation of STAT3 on serine 727 residues is a hallmark of CLL and that STAT3 be considered a therapeutic target in this disease.
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U2 - 10.1182/blood-2009-10-230060
DO - 10.1182/blood-2009-10-230060
M3 - Article
C2 - 20154216
AN - SCOPUS:77951018948
SN - 0006-4971
VL - 115
SP - 2852
EP - 2863
JO - Blood
JF - Blood
IS - 14
ER -