Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia.
Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia.
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Ikaros 对 BCL6/BACH2 轴的调节及其在急性淋巴细胞白血病中的临床相关性。
DOI：
10.18632/oncotarget.14038
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发表时间：
2017-01-31
期刊：
影响因子：
--
通讯作者：
Dovat S
中科院分区：
文献类型：
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作者：
Ge Z;Zhou X;Gu Y;Han Q;Li J;Chen B;Ge Q;Dovat E;Payne JL;Sun T;Song C;Dovat S
B细胞CLL/淋巴瘤6（BCL 6）是一种在急性淋巴细胞白血病（ALL）中高度表达的原癌基因。BTB和CNC同源1碱性亮氨酸拉链转录因子2（BACH 2）是转录抑制因子。BACH 2-BCL 6平衡通过调节p53表达来控制前B细胞受体检查点的选择。然而，BCL 6/BACH 2轴的潜在机制和临床相关性尚不清楚。在这里，我们发现由IKZF 1编码的肿瘤抑制因子Ikaros直接与BCL 6和BACH 2启动子结合，在B细胞ALL（B-ALL）细胞中抑制BCL 6并促进BACH 2表达。酪蛋白激酶2（CK 2）抑制剂增加Ikaros功能，从而以Ikaros依赖性方式抑制BCL 6并促进BACH 2表达。我们还发现B-ALL患者的BCL 6表达高于正常骨髓对照，而BACH 2表达低于正常骨髓对照。BCL 6高表达和BACH 2低表达与白血病细胞高增殖、不良临床和实验室特征以及不良结局相关。此外，IKZF 1缺失与B-ALL患者中BCL 6高表达和BACH 2低表达相关。CK 2抑制剂增加Ikaros与BCL 6和BACH 2启动子的结合，并抑制BCL 6，同时促进BACH 2在原代B-ALL细胞中的表达。我们的数据表明，Ikaros调节B-ALL中BCL 6/BACH 2轴的表达。高BCL 6和低BACH 2表达与Ikaros失调相关，并对B-ALL的发展有潜在影响。
B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2–BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B-ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL.