Abstract 4583: An essential role for Cmtr2 in endothelial cell function and vascular development

Abstract Cancer genome sequencing studies have identified multiple novel tumor suppressor genes, including the FTSJD1 or CMTR2 gene that is subject to statistically significant levels of both nonsense and frameshift mutations in lung adenocarcinoma. However, these analyses are insufficient to determine the importance and modes of action of the gene in the disease. Follow-up functional studies are essential to elucidate these gene functions. The protein product of CMTR2 has been described as an mRNA cap methyltransferase, which O-methylates the ribose of the second guanine residue of the 5’ cap, likely serving to modify efficiency of transcript processing, translation and stability, but the details of how and why specific transcripts undergo methylation by the enzyme, as well as its role in oncogenesis, remain to be elucidated. In this study we report the first comprehensive analysis of the physiologic consequences of Cmtr2 deficiency in knockout (KO) mice and primary human cells. Constitutive deletion of Cmtr2 results in embryos that die in midgestation with defects in embryo size, placental malformation and yolk sac vascularization. Endothelial-specific deletion of Cmtr2 in mice also results in vascular defects and perinatal lethality, suggesting that vascular development is a key function of Cmtr2 in animals. In summary, our study reveals that Cmtr2 plays a critical role in vascular development, maturation and remodeling. Further studies of CMTR2 function may provide insight not only into lung cancer biology but also to its broader roles in ontogeny. Citation Format: Alena Yermalovich, Zarin Mohsenin, Bruno Giotti, Douglas Wheeler, Kelly Xu, Alexander Tsankov, Matthew Meyerson. An essential role for Cmtr2 in endothelial cell function and vascular development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4583.