BACH2 Suppresses B-Cell Transformation via Activation of p53

During B-cell development, pre-B cells that fail to undergo functional V(D)J immunoglobulin heavy chain gene recombination are eliminated at the pre–B-cell receptor checkpoint. Recent studies have shown that B-cell lymphoma 6 (BCL6) represses p53 and ARF (encoded by cyclin-dependent kinase 2A, CDKN2A) and is required for the positive selection of productively rearranged cells; however, the mechanisms that mediate the negative selection of nonfunctional pre-B cells are unknown. Swaminathan and colleagues found that BTB and CNC homology 1, basic leucine zipper transcription factor 2 (BACH2), a B-cell–specific transcription factor, induced ARF and p53 expression at the pre–B-cell receptor checkpoint, suggesting that BACH2 promotes pre–B-cell negative selection. Consistent with this idea, BACH2 was necessary and sufficient for productive V(D)J recombination and clearance of nonfunctional, out-of-frame pre–B-cell clones. BACH2 and BCL6 bound to overlapping sites in the promoters of CDKN2A and TP53 and reciprocally modulated the expression of these and other checkpoint regulator genes, indicating that the balance between BACH2 and BCL6 controls the pre–B-cell receptor checkpoint. Intriguingly, BACH2 was frequently inactivated in primary pre-B acute lymphoblastic leukemia (ALL) samples via promoter hypermethylation, missense mutations, and deletions, or via loss of its upstream regulator paired box 5 (PAX5), supporting a tumor-suppressive role for BACH2. Indeed, BACH2 stimulated p53-dependent cell death in human pre-B ALL cells, inhibited MYC-driven leukemic transformation, and suppressed MYC-dependent tumor growth in vivo. Furthermore, BACH2 expression was decreased in relapsed leukemia samples, and low levels of BACH2 were strongly correlated with poor clinical outcome independent of established predictors in patients with ALL. These results establish BACH2 as a critical modulator of negative selection in B-cell development and identify BACH2-mediated p53 activation as a safeguard against malignant transformation of pre-B cells.

Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H, et al. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nat Med 2013;19:1014–22.

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