Max deletion destabilizes MYC protein and abrogates Eµ-Myc lymphomagenesis

Genes & Development
Haritha MathsyarajaRobert N Eisenman

Abstract

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 Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of Myc-activated genes in premalignant Eµ-Myc 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 Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.

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Citations

Feb 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·David A AndersonKenneth M Murphy
Feb 20, 2020·Nature Reviews. Molecular Cell Biology·Apoorva BaluapuriMartin Eilers
Mar 12, 2020·Proceedings of the National Academy of Sciences of the United States of America·Philipp RaffeinerPeter K Vogt
Jun 19, 2020·International Journal of Molecular Sciences·Eleonora VecchioIleana Quinto
May 16, 2020·Acta Neuropathologica Communications·Harish Shrikrishna BharambeNeelam Vishwanath Shirsat
Mar 24, 2021·Molecular Cell·Sungyun ChoJohn Blenis
Sep 9, 2021·Proceedings of the National Academy of Sciences of the United States of America·Paula LlabataMontse Sanchez-Cespedes

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