Loss of <i>Golga7</i> Suppresses Oncogenic <i>Nras</i>‐Driven Leukemogenesis without Detectable Toxicity in Adult Mice
NRAS mutations are prevalent in human hematological malignancies and are also common in certain solid tumors, including melanoma and colon cancer. Despite their crucial role in oncogenesis, no effective therapies targeting NRAS have been developed. Inhibiting NRAS localization to the plasma membrane (PM) represents a promising strategy for cancer therapy, as its oncogenic signaling relies on PM localization. Knocking out Golgin subfamily A member 7 (Golga7), an accessory protein of RAS palmitoyltransferases, through a conditional gene editing approach drastically suppresses the development of myeloid leukemia induced by the activation of Nras<sup>G12D/G12D</sup> knock-in alleles in mice. The loss of Golga7 disrupts NRAS<sup>G12D</sup> PM localization in bone marrow cells without altering the level of NRAS<sup>G12D</sup> palmitoylation. Notably, Golga7 is dispensable for normal hematopoiesis in adult mice. While constitutive Golga7 knockout leads to embryonic lethality, the ubiquitous knockout of Golga7 induced in adult mice does not manifest any measurable toxic effects. These findings indicate that GOLGA7 is an effective and safe therapeutic target for NRAS-driven leukemias.
Authors
- Shiyu Ji (ORCID: https://orcid.org/0000-0003-3413-5766)
- Chenxuan Liu
- Wei Huang (ORCID: https://orcid.org/0000-0002-7885-4378)
- Peihong Wang (ORCID: https://orcid.org/0000-0001-6386-8446)
- Min Wu (ORCID: https://orcid.org/0000-0001-5462-6920)
- Zhizhou Xia (ORCID: https://orcid.org/0000-0002-3140-0678)
- Jiaoyang Li
- Jinzeng Wang (ORCID: https://orcid.org/0009-0000-9267-3525)
- Fang Zhou (ORCID: https://orcid.org/0000-0002-5542-2994)
- Donghe Li (ORCID: https://orcid.org/0000-0001-6773-3143)
- Shengyue Wang (ORCID: https://orcid.org/0000-0001-9589-7719)
- Ruibao Ren (ORCID: https://orcid.org/0000-0002-9783-0064)
- Qianqian Zhang (ORCID: https://orcid.org/0000-0001-6481-0780)
- Ping Liu (ORCID: https://orcid.org/0000-0003-4741-7156)
- Xinru Wang (ORCID: https://orcid.org/0000-0003-2636-9546)
- Bo Jiao (ORCID: https://orcid.org/0000-0001-6475-8986)
- Lei Yan
- Pengfei Xu (ORCID: https://orcid.org/0000-0002-1903-138X)
- Rui Zhang (ORCID: https://orcid.org/0000-0002-1360-2452)
Institutions
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- Shanghai Institute of Hematology (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1002/advs.202412208
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Samuel Waxman Cancer Research Foundation
- Shanghai Science and Technology Development Foundation
- National Natural Science Foundation of China