deletion destabilizes MYC protein and abrogates Eµ- lymphomagenesis.

Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of has a modest effect on B-cell development but completely abrogates Eµ-driven lymphomagenesis. While loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of -activated genes in premalignant Eµ- cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in premalignant B cells toward a MYC-driven transcriptional program. Moreover, we found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of autoregulation critical for lymphomagenesis yet partly dispensable for normal development.