| First Author | Swaminathan S | Year | 2013 |
| Journal | Nat Med | Volume | 19 |
| Issue | 8 | Pages | 1014-22 |
| PubMed ID | 23852341 | Mgi Jnum | J:200089 |
| Mgi Id | MGI:5506975 | Doi | 10.1038/nm.3247 |
| Citation | Swaminathan S, et al. (2013) BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nat Med 19(8):1014-22 |
| abstractText | 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. |
