BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint.
The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation. Overall design: ChIP-seq using BACH2 and BCL6 antibodies in OCI-Ly7 cells