Constitutive STAT3-activation in Sezary syndrome:: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells
Constitutive STAT3-activation in Sezary syndrome:: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells
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DOI：
10.1038/sj.leu.2402093
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发表时间：
2001-05-01
期刊：
影响因子：
11.4
通讯作者：
Odum, N
中科院分区：
文献类型：
--
作者：
Eriksen, KW;Kaltoft, K;Odum, N
白细胞介素-2（IL-2）是一种生长因子，其在与高亲和力受体（IL-2 R α β γ）结合后触发T细胞中的有丝分裂。IL-2 Ra表达限于最近遇到抗原的T细胞，并且在健康个体中，大多数（> 95%）外周T细胞是IL-2 Ra阴性的。IL-2 Ra的异常表达最近已被描述在皮肤T细胞淋巴瘤（CTCL）。在这里，我们研究了IL-2 R α表达和STATs的调节肿瘤细胞系从外周血中获得的患者与Sezary综合征（SS），CTCL的白血病变异。我们证明：（1）状态（已知调节IL-PR（U转录）的转录因子在SS肿瘤细胞中是组成型酪氨酸磷酸化的，但在非恶性T细胞中不是;（2）STATE与IL-2 R α基因启动子中的STAT结合序列组成型结合;（3）Janus激酶抑制剂，酪氨酸磷酸盐AG 490，平行地抑制STATE激活、STATE DNA结合和IL-2 R α mRNA和蛋白质表达;（4）Tyrphostine AG 490抑制IL-2驱动的SS肿瘤细胞的有丝分裂并触发凋亡。总之，我们提供了SS肿瘤细胞中组成性状态激活的第一个例子。此外，我们的研究结果表明，STATE激活可能在恶性SS细胞的组成性IL-2 R α表达、存活和生长中起重要作用。
Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2R alpha beta gamma) triggers mitogenesis in T cells. IL-2R alpha expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (> 95%) of peripheral T cells are IL-2Ra negative. An aberrant expression of IL-2Ra has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2R alpha expression and STATs in a tumor cell line obtained from peripheral blood from a patient with Sezary syndrome (SS), a leukemic variant of CTCL. We show that (1) STATE (a transcription factor known to regulate IL-PR(U transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STATE binds constitutively to a STAT-binding sequence in the promotor of the IL-2R alpha gene; (3) the Janus kinase inhibitor, tyrphostine AG490, inhibits STATE activation, STATE DNA binding, and IL-2R alpha mRNA and protein expression in parallel; and (4) tyrphostine AG490 inhibits IL-2 driven mitogenesis and triggers apoptosis in SS tumor cells. In conclusion, we provide the first example of a constitutive STATE activation in SS tumor cells. Moreover, our findings suggest that STATE activation might play an important role in the constitutive IL-2R alpha expression, survival, and growth of malignant SS cells.