Loss of Golga7 Suppresses Oncogenic Nras-Driven Leukemogenesis without Detectable Toxicity in Adult Mice

被引：0

作者：

Jiao, Bo ^{[1
]}

Yan, Lei ^{[1
]}

Zhang, Rui ^{[1
]}

Huang, Wei ^{[1
]}

Wang, Xinru ^{[1
]}

Liu, Chenxuan ^{[1
]}

Wang, Peihong ^{[1
]}

Xu, Pengfei ^{[1
]}

Wang, Jinzeng ^{[1
]}

Fang, Zhou ^{[1
]}

Li, Donghe ^{[1
]}

Xia, Zhizhou ^{[1
]}

Li, Jiaoyang ^{[1
]}

Ji, Shiyu ^{[1
]}

Zhang, Qianqian ^{[1
]}

Wu, Min ^{[1
]}

Wang, Shengyue ^{[1
]}

Liu, Ping ^{[1
]}

Ren, Ruibao ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Ruijin Hosp, Natl Res Ctr Translat Med Shanghai, Shanghai Inst Hematol,State Key Lab Med Genom,Sch, Shanghai 200025, Peoples R China

[2] Hainan Med Univ, Dept Hematol, Int Ctr Aging & Canc, Affiliated Hosp 1, Haikou 571199, Peoples R China

来源：

ADVANCED SCIENCE | 2025年

基金：

上海市科技启明星计划; 中国国家自然科学基金;

关键词：

Golga7; membrane trafficking; palmitoylation; Ras; therapeutic target; POSTTRANSLATIONAL MODIFICATION; PLASMA-MEMBRANE; N-RAS; MUTATIONS; PALMITOYLATION; LOCALIZATION; GENE; IDENTIFICATION; MALIGNANCIES; KRAS(G12C);

D O I：

10.1002/advs.202412208

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 NrasG12D/G12D knock-in alleles in mice. The loss of Golga7 disrupts NRASG12D PM localization in bone marrow cells without altering the level of NRASG12D 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.

引用

页数：14