Ge Zheng, Zhou Xilian, Gu Yan, Han Qi, Li Jianyong, Chen Baoan, Ge Qinyu, Dovat Elanora, Payne Jonathon L, Sun Tianyu, Song Chunhua, Dovat Sinisa
Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
International Cooperative Leukemia Group and International Cooperative Laboratory of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
Oncotarget. 2017 Jan 31;8(5):8022-8034. doi: 10.18632/oncotarget.14038.
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.
B细胞慢性淋巴细胞白血病/淋巴瘤6（BCL6）是一种原癌基因，在急性淋巴细胞白血病（ALL）中高度表达。BTB和CNC同源1碱性亮氨酸拉链转录因子2（BACH2）是一种转录抑制因子。BACH2-BCL6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，BCL6/BACH2轴的潜在机制和临床相关性尚不清楚。在这里，我们发现由IKZF1编码的肿瘤抑制因子Ikaros直接结合到BCL6和BACH2启动子上，在B细胞急性淋巴细胞白血病（B-ALL）细胞中抑制BCL6并促进BACH2表达。酪蛋白激酶2（CK2）抑制剂增加Ikaros功能，从而以Ikaros依赖的方式抑制BCL6并促进BACH2表达。我们还发现，B-ALL患者中BCL6的表达高于正常骨髓对照，而BACH2的表达则较低。高BCL6和低BACH2表达与白血病细胞的高增殖、不良的临床和实验室特征以及较差的预后相关。此外，IKZF1缺失与B-ALL患者的高BCL6和低BACH2表达相关。CK2抑制剂增加Ikaros与BCL6和BACH2启动子的结合，并在原发性B-ALL细胞中抑制BCL6同时促进BACH2表达。我们的数据表明，Ikaros调节B-ALL中BCL6/BACH2轴的表达。高BCL6和低BACH2表达与Ikaros失调相关，并对B-ALL的发展具有潜在影响。
