Systemic Kras ablation disrupts myeloid cell homeostasis in adult mice

• 成果类型: Article
• 署名作者: Zamorano-Dominguez, Elena; Morales-Cacho, Lucia; Barrero, Rebeca; Parrado, Silvia Jimenez-; Dhawahir, Alma; Hernandez-Porras, Isabel; Simon-Carrasco, Lucia; Barrambana, Sara; Sun, Pian; Galvan-del-Rey, Ana; Rosas-Perez, Blanca; Liaki, Vasiliki; Drosten, Matthias; Musteanu, Monica; Virga, Federico; Santos, Eugenio; Mulero, Francisca; Caleiras, Eduardo; Guerra, Carmen; Barbacid, Mariano
• 署名单位: CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; Instituto de Salud Carlos III; Consejo Superior de Investigaciones Cientificas (CSIC); Universidad Pablo de Olavide; University of Sevilla; CSIC - Centro Andaluz de Biologia Molecular y Medicina Regenerativa (CABIMER); University of Salamanca; Consejo Superior de Investigaciones Cientificas (CSIC); Complutense University of Madrid; Hospital Clinico San Carlos; Centro Nacional de Investigaciones Cardiovasculares (CNIC)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11684
• DOI: 10.1073/pnas.2512404122
• 发表日期: 2025-08-26
• 关键词: k-ras; essential gene; h-ras; differentiation; mouse; k562; induction; deletion; leads; line

摘要

The KRAS oncogene has been associated with many types of cancer, including pancreatic, lung, and colorectal. For decades, its gene products were thought to be undruggable. However, during the last decade, a large battery of KRAS inhibitors selective against specific mutations (KRASG12C and KRASG12D), panKRAS inhibitors active against all KRAS isoforms, or even panRAS inhibitors, capable of inhibiting the three members of the RAS family, have been developed. In mice, the Kras locus is essential for embryonic development and can sustain adult homeostasis in the absence of Hras and Nras expression. Thus, we considered of interest to interrogate the role of the Kras locus in an experimental system to generate potentially relevant information regarding the use of panKRAS or panRAS inhibitors in the clinic. Here, we report that systemic ablation of Kras expression in adult mice does not induce significant changes in overall survival, body weight, glucose levels, metabolic profile, or heart function. In contrast, flow cytometry and histopathological analyses of organs such as blood, bone marrow, and spleen showed a significant increase of the myeloid lineage leading to myelomonocytic metaplasia. In this context, replacement of the KRAS isoforms by HRAS is sufficient to maintain adult homeostasis, suggesting that the unique properties of the Kras locus are primarily due to its pattern of expression rather than to the activity of its gene products.