Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany.
Leuk Res. 2011 May;35(5):620-5. doi: 10.1016/j.leukres.2010.11.006. Epub 2010 Dec 22.
Epigenetic changes play a crucial role in leukemogenesis. HDACs are frequently recruited to target gene promoters by balanced translocation derived oncogenic fusion proteins. As important epigenetic effector mechanisms, histone deacetylases (HDAC) have emerged as potential therapeutic targets. However, the patterns of HDAC1 localization and the role of HDACs in leukemia pathogenesis remain to be elucidated. Using ChIP-Chip analyses we analyzed HDAC1 deposition patterns at more than 10,000 gene promoters in a large cohort of leukemia patients and CD34+ controls. HDAC1 binding was significantly increased in AML blasts compared to CD34+ progenitor cells at 130 gene promoters whereas decreased binding was observed at 66 gene promoters. Distinct HDAC1 binding patterns occurred in AML subtypes with balanced translocations t(15;17), t(8;21) and inv(16). In addition, a more generalized signature was established, that revealed an AML specific pattern of HDAC1 distribution. Many of the HDAC1-binding altered promoters regulate genes involved in hematopoiesis, transcriptional regulation and signal transduction. HDAC1 binding patterns were associated with patients' event free survival. This is the first study to determine HDAC1 modification patterns in a large number of AML and ALL specimens. Our findings suggest that dyslocalization of HDAC1 is a common feature in AML. Importantly, HDAC1 modifications possess prognostic power for patient survival. Our findings suggest that altered HDAC1 localization is an explanation for the observed benefit of HDAC inhibitors in AML therapy.
表观遗传改变在白血病发生中起着至关重要的作用。组蛋白去乙酰化酶（HDACs）经常被招募到靶基因启动子，通过平衡易位衍生的致癌融合蛋白。作为重要的表观遗传效应机制，组蛋白去乙酰化酶（HDACs）已成为潜在的治疗靶点。然而，HDAC1 的定位模式和 HDACs 在白血病发病机制中的作用仍有待阐明。我们使用 ChIP-Chip 分析方法，在一个大型白血病患者和 CD34+对照群体中，分析了超过 10000 个基因启动子上的 HDAC1 沉积模式。与 CD34+祖细胞相比，AML blasts 中 HDAC1 的结合显著增加，而在 66 个基因启动子中观察到结合减少。在具有平衡易位 t(15;17)、t(8;21)和 inv(16)的 AML 亚型中，出现了不同的 HDAC1 结合模式。此外，还建立了一个更普遍的特征，揭示了 AML 中 HDAC1 分布的特定模式。许多 HDAC1 结合改变的启动子调节参与造血、转录调节和信号转导的基因。HDAC1 结合模式与患者无事件生存相关。这是首次在大量 AML 和 ALL 标本中确定 HDAC1 修饰模式的研究。我们的研究结果表明，HDAC1 的定位失调是 AML 的一个共同特征。重要的是，HDAC1 的修饰对患者的生存预后具有预测能力。我们的研究结果表明，HDAC1 定位的改变可能是观察到 HDAC 抑制剂在 AML 治疗中获益的原因之一。
