Deregulation of Aiolos expression in chronic lymphocytic leukemia is associated with epigenetic modifications
Deregulation of Aiolos expression in chronic lymphocytic leukemia is associated with epigenetic modifications
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DOI：
10.1182/blood-2010-09-307140
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发表时间：
2011-02-10
期刊：
影响因子：
20.3
通讯作者：
Rebollo, Angelita
中科院分区：
文献类型：
--
作者：
Billot, Katy;Soeur, Jeremie;Rebollo, Angelita
慢性淋巴细胞性白血病（CLL）的特征在于对凋亡具有抗性的成熟肿瘤性B细胞的克隆积累。Aiolos是Ikaros锌指转录因子家族的成员，在控制成熟B淋巴细胞分化和成熟中起重要作用。在这项研究中，我们发现Aiolos表达在B-CLL细胞中上调。这种过度表达不涉及同种型不平衡或干扰Aiolos亚细胞定位。CLL中Aiolos启动子处的染色质状态由DNA的去甲基化和常染色质相关组蛋白标记物的富集（例如组蛋白H3上赖氨酸4的二甲基化）定义。这些表观遗传修饰应该允许其上游效应物，例如在CLL中组成性激活的核因子-κ B，获得启动子，导致Aiolos的上调。为了确定Aiolos失调在CLL中的后果，我们分析了Aiolos过表达或下调对细胞凋亡的影响。Aiolos通过调节一些Bcl-2家族成员的表达参与细胞存活。我们的研究结果强烈表明，Aiolos失调表观遗传修饰可能是CLL的标志。（血。2011; 117（6）：1917-1927）
Chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Aiolos, a member of the Ikaros family of zinc-finger transcription factors, plays an important role in the control of mature B lymphocyte differentiation and maturation. In this study, we showed that Aiolos expression is up-regulated in B-CLL cells. This overexpression does not implicate isoform imbalance or disturb Aiolos subcellular localization. The chromatin status at the Aiolos promoter in CLL is defined by the demethylation of DNA and an enrichment of euchromatin associated histone markers, such as the dimethylation of the lysine 4 on histone H3. These epigenetic modifications should allow its upstream effectors, such as nuclear factor-kappa B, constitutively activated in CLL, to gain access to promoter, resulting up-regulation of Aiolos. To determine the consequences of Aiolos deregulation in CLL, we analyzed the effects of Aiolos overexpression or down-regulation on apoptosis. Aiolos is involved in cell survival by regulating the expression of some Bcl-2 family members. Our results strongly suggest that Aiolos deregulation by epigenetic modifications may be a hallmark of CLL. (Blood. 2011; 117(6): 1917-1927)