Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL).
IKZF1蛋白功能受损与高位前B细胞急性B淋巴细胞白血病高度相关
The mechanisms of Ikaros tumor suppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling.
IKZF1抑制肿瘤的活性在白血病中机制尚不清楚。IKZF1结合在靶基因上游的调控元件上，通过染色体重塑来调节他们的转录。
Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B).
我们在这里发现了IKZF1抑制组蛋白H3K4脱甲基酶，JARID1B的转录
Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation.
JARID1B的转录抑制与H3K4的甲基化水平相关
Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros.
IKZF1抑制JARID1B依赖于HDAC1，组蛋白脱乙酰酶的活性，HDAC1与IKZF1组合成复合物共同结合到JARID1B的上游调节元件上
In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2).
在白血病中，JARID1B是过表达的，抑制JARID1B的表达导致细胞生长停滞。IKZF1在白血病中抑制JARID1B的表达这一过程会被原癌酪蛋白激酶中断。
Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation.
抑制CK2会增加IKZF1-HDAC1复合物在JARID1B启动子区域的结合，三甲基化组蛋白H3赖氨酸27的形成增加，减少组蛋白H3-LYS-9的乙酰化
In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B.
在一例携带IKZF1杂合缺失的高风险B-ALL的病例中，CK2的靶向抑制会恢复IKZF1与JARID1B启动子的结合，并抑制JARID1B
In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.
综上所述，目前的数据发现了一种通过IKZF1与HDAC1调控白血病表观遗传特征的机制：调控JARID1B的转录。现有的数据证明JARID1B是B-ALL的一个新的治疗靶点，为利用CK2抑制剂治疗高风险B-ALL提供了理论依据
