Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
Nat Med. 2013 Aug;19(8):1014-22. doi: 10.1038/nm.3247. Epub 2013 Jul 14.
The B cell-specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2(+/+) pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint-control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.
B 细胞特异性转录因子 BACH2 是 B 细胞亲和力成熟所必需的。在这里，我们表明 Bach2 介导的 p53 激活对于严格消除未能有效重排免疫球蛋白 VH-DJH 基因片段的前 B 细胞是必需的。在有效 VH-DJH 基因重排后，前 B 细胞受体信号通过 B 细胞淋巴瘤 6（BCL6）介导的 p53 抑制结束 Bach2 介导的负选择。在前 B 急性淋巴细胞白血病患者中，BACH2 介导的检查点控制因缺失、罕见的体细胞突变和其上游激活物 PAX5 的丢失而受损。这些患者中 Bach2 表达水平低代表预后不良的强烈独立预测因子。在这项研究中，我们证明 Bach2(+/+)前 B 细胞通过 Bach2 依赖性上调 p53 抵抗 Myc 的白血病转化，并且不会在移植受体小鼠中引发致命性白血病。我们进行的染色质免疫沉淀测序和基因表达分析表明，BACH2 与 BCL6 竞争启动子结合，并逆转 BCL6 介导的 p53 和其他细胞周期检查点控制基因的抑制。这些发现确定 BACH2 是前 B 细胞受体检查点负选择的关键介质，是防止白血病发生的保障。
