Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Leukemia. 2013 Nov;27(11):2177-86. doi: 10.1038/leu.2013.91. Epub 2013 Mar 29.
The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 3 lysine 4 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq (chromatin immunoprecipitation coupled with whole genome sequencing) analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in nuclear factor (NF)-κB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrate that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-κB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.
骨髓增生异常综合征（MDS）的分子基础尚未完全阐明。三甲基化组蛋白 3 赖氨酸 4（H3K4me3）存在于活跃转录基因的启动子中，并被证明参与造血分化。我们对原发性 MDS 骨髓（BM）CD34+细胞进行了全基因组 H3K4me3 CHIP-Seq（染色质免疫沉淀与全基因组测序）分析。这导致鉴定了 36 个在 MDS 中具有明显更高水平启动子 H3K4me3 的基因。这些基因中的大多数参与核因子（NF）-κB 激活和先天免疫信号转导。然后，我们分析了组蛋白去甲基酶的表达，并在 MDS CD34+细胞中观察到 JmjC 结构域组蛋白去甲基酶 JMJD3（KDM6b）的显著过表达。此外，我们证明 JMJD3 对多个 CHIP-Seq 鉴定的参与 NF-κB 激活的基因的转录具有正向影响。在原发性 BM MDS CD34+细胞中使用 shRNA 抑制 JMJD3 会导致来自低危 MDS 患者样本中的红细胞集落数量增加。总之，这些数据表明 H3K4me3 的失调和相关的先天免疫信号的异常激活在 MDS 的发病机制中起作用，并且靶向这些信号可能在 MDS 中具有潜在的治疗价值。
