STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells
STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells
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DOI：
10.1182/blood-2009-10-230060
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发表时间：
2010-04-08
期刊：
影响因子：
20.3
通讯作者：
Estrov, Zeev
中科院分区：
文献类型：
--
作者：
Hazan-Halevy, Inbal;Harris, David;Estrov, Zeev
慢性淋巴细胞白血病（CLL）是西半球最常见的白血病，但其发病机制尚不清楚。信号换能器和转录激活因子（STAT） 3的组成型酪氨酸磷酸化(p)发生在几种实体肿瘤和血液恶性肿瘤中。然而，在CLL中，STAT3在丝氨酸727而不是酪氨酸705残基上被组成性磷酸化。由于丝氨酸pSTAT3在CLL中的生物学意义尚不清楚，我们研究了106例CLL患者的外周血细胞，发现尽管酪氨酸pSTAT3是可诱导的，但丝氨酸pSTAT3在所有被研究的患者中都是组成型的，与血细胞计数、疾病分期或治疗状态无关。此外，我们还证明了组成丝氨酸pSTAT3通过核磷脂- β核质系统易位到细胞核并结合DNA。诱导型酪氨酸pSTAT3的去磷酸化不影响STAT3-DNA的结合，表明组成型丝氨酸pSTAT3与DNA结合。此外，用慢病毒stat3小发夹RNA感染CLL细胞，降低了几个stat3调控的存活和增殖基因的表达，并诱导了细胞凋亡，这表明组成丝氨酸pSTAT3在CLL细胞中启动了转录。综上所述，我们的数据表明STAT3在727丝氨酸残基上的组成性磷酸化是CLL的一个标志，STAT3被认为是这种疾病的治疗靶点。（Blood. 2010; 115(14): 2852-2863）
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-beta 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. (Blood. 2010; 115(14): 2852-2863)