2. Academic Validation
  3. MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues

MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues

  • bioRxiv. 2024 Sep 24:2024.09.21.614255. doi: 10.1101/2024.09.21.614255.
Brian Freie 1,  Ali H Ibrahim 2 3,  Patrick A Carroll 1,  Roderick T Bronson 4,  Arnaud Augert 2 5,  David MacPherson 2 6,  Robert N Eisenman 1
Affiliations

Affiliations

  • 1 Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle WA USA.
  • 2 Human Biology and Public Health Science Divisions, Fred Hutchinson Cancer Center, Seattle WA USA.
  • 3 Present address: Department of Internal Medicine, The University of Texas Health Science Center, Houston TX USA.
  • 4 Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
  • 5 Present address: Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 6 Department of Genome Sciences, University of Washington, Seattle WA USA.
PMID: 39386474 DOI: 10.1101/2024.09.21.614255
Abstract

The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung Cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Delet-ing Max across multiple mouse neuroendocrine tissues, we find Max inactivation alone produces pituitary adenomas while Max loss cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by Other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.

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