SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21
SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21
复制标题
SATB1 过表达通过抑制 p21 促进皮肤 CD30 淋巴细胞增殖性疾病中的恶性 T 细胞增殖。
DOI：
10.1182/blood-2013-10-534693
复制
发表时间：
2014-05-29
期刊：
影响因子：
20.3
通讯作者：
Tu, Ping
中科院分区：
文献类型：
--
作者：
Wang, Yang;Gu, Xiaoguang;Tu, Ping
皮肤CD 30（+）淋巴组织增生性疾病（CD 30（+）LPD）以存在CD 30（+）间变性大T细胞为特征，是第二常见的皮肤T细胞淋巴瘤（CTCL）。然而，对CD 30（+）淋巴瘤细胞的病理生物学以及疾病进展的机制知之甚少。在此，我们报道了胸腺细胞特异性染色质组织者特异性AT富集区结合蛋白1（SATB 1）在大多数CD 30（+）LPD的CD 30（+）淋巴瘤细胞中过表达，并且其表达在疾病进展过程中上调。我们的研究结果表明，SATB 1沉默在CD 30（+）LPD细胞导致G1期细胞周期阻滞介导的p21激活。使用染色质免疫沉淀，荧光素酶测定和突变分析，我们证明，SATB 1直接调节p21的转录在p53的独立方式。此外，SATB 1启动子的特定CpG富集区域上的DNA去甲基化与疾病进展期间SATB 1的上调相关。这些实验确定了恶性CD 30（+）T淋巴细胞中的新SATB 1-p21通路，这为CD 30（+）LPD的发病机制提供了新的分子见解，并可能导致新的治疗方法。
Cutaneous CD30(+) lymphoproliferative disease (CD30(+)LPD), characterized by the presence of CD30(+) anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma (CTCL). However, little is known about the pathobiology of the CD30(+) lymphoma cells, as well as the mechanisms of disease progression. Here we report that Special AT-rich region binding protein 1 (SATB1), a thymocyte specific chromatin organizer, is over-expressed in CD30(+) lymphoma cells in most CD30(+)LPDs, and its expression is upregulated during disease progression. Our findings show that SATB1 silencing in CD30(+)LPD cells leads to G1 cell cycle arrest mediated by p21 activation. Using chromatin immunoprecipitation, luciferase assays, and mutational analysis, we demonstrate that SATB1 directly regulates the transcription of p21 in a p53-independent manner. Moreover, DNA demethylation on a specific CpG-rich region of the SATB1 promoter is associated with the upregulation of SATB1 during disease progression. These experiments define a novel SATB1-p21 pathway in malignant CD30(+) T lymphocytes, which provides novel molecular insights into the pathogenesis of CD30(+)LPDs and possibly leads to new therapies.