Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie (UPMC) Paris VI, Inserm, Paris, France.
Blood. 2011 Feb 10;117(6):1917-27. doi: 10.1182/blood-2010-09-307140. Epub 2010 Dec 7.
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-κB, 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.
慢性淋巴细胞白血病（CLL）的特征是成熟的肿瘤 B 细胞克隆性积累，这些细胞对凋亡有抗性。Aiolos 是锌指转录因子 Ikaros 家族的成员，在控制成熟 B 淋巴细胞分化和成熟方面发挥着重要作用。在这项研究中，我们表明 Aiolos 在 B-CLL 细胞中表达上调。这种过表达不涉及同工型失衡或扰乱 Aiolos 亚细胞定位。CLL 中 Aiolos 启动子的染色质状态由 DNA 的去甲基化和富含 euchromatin 的组蛋白标记物（如组蛋白 H3 赖氨酸 4 的二甲基化）决定。这些表观遗传修饰应该允许其上游效应物（如 CLL 中持续激活的核因子-κB）进入启动子，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。我们的结果强烈表明，表观遗传修饰导致的 Aiolos 失调可能是 CLL 的一个标志。
