Abstract 3327: Structure and function of the L-MYC N-terminus impacts strategies to inhibit the MYC family of oncoproteins

Abstract The MYC family of transforming oncogenes function as regulators of gene transcription and is composed of three members, MYC, MYCN and MYCL. As the c-MYC (MYC) protein is deregulated in 50% of human cancers, the role, regulation and structural features of MYC have been well-studied. By contrast, the L-MYC protein has been relatively understudied as historically, oncogenic deregulation was evident only in a subset of small cell lung carcinomas (SCLCs). However, with recent deep genomic analyses of primary patient samples, L-MYC has been shown to be deregulated in numerous human cancers. With this revelation it is important to understand how the L-MYC protein compares to MYC at the structural level, particularly for the development of broad-spectrum inhibitors of the MYC family. Here we first show that L-MYC expression is anti-correlated with MYC expression and is elevated in several primary patient tumor samples compared to normal, providing further evidence for L-MYC as a driver oncoprotein in primary human cancers. Next, we provide new insights into the biophysical features of an N-terminal region within the transactivation domain of L-MYC, which harbors two regions conserved amongst the MYC family: MYC box 0tbox0 (MB0) and MYC box I (MBI)tboxII. NMR spectroscopy of residues 1-80 of L-MYC confirms that, similar to MYC, it is largely intrinsically disordered and interacts with the known MYC MB0-interacting protein, PNUTS (Phosphatase 1 NUclear Targeting Subunit). On the other hand, L-MYC does not interact with the MYC MB1-interacting protein Bin1 (Bridging integrator 1), suggesting a potential mechanism by which L-MYC evades this tumor suppressor. Together, these results further substantiate the oncogenic role of L-MYC in human cancer and deeply enhance our understanding of the biophysical nature of L-MYC to better inform strategies for the development of anti-cancer therapeutics targeting the MYC family of oncoproteins. Citation Format: Tristan M. Kenney, Scott Houliston, Peter Chien-feng Lin, Nikan Movahedi, Cheryl Arrowsmith, Linda Z. Penn. Structure and function of the L-MYC N-terminus impacts strategies to inhibit the MYC family of oncoproteins abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3327.