Max deletion destabilizes MYC protein and abrogates Eµ-Myc lymphomagenesis
- Haritha Mathsyaraja,
- Brian Freie,
- Pei-Feng Cheng,
- Ekaterina Babaeva,
- Jonathen T. Catchpole,
- Derek Janssens,
- Steven Henikoff and
- Robert N. Eisenman
- Corresponding author: eisenman{at}fhcrc.org
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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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.325878.119.
- Received February 22, 2019.
- Accepted June 14, 2019.
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