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

## TL;DR

Removing Golga7 stops leukemia caused by NRAS mutations in mice without harming normal blood cell development or causing toxicity.

## Contribution

Golga7 is shown to be a safe and effective therapeutic target for NRAS-driven leukemia in adult mice.

## Key findings

- Loss of Golga7 disrupts NRASG12D plasma membrane localization without affecting palmitoylation.
- Golga7 knockout in adult mice suppresses NrasG12D-driven leukemia without toxicity.
- Golga7 is essential for NRAS-driven oncogenesis but not for normal hematopoiesis.

## Abstract

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.

NRAS mutations are widespread in hematologic malignancies. Our study shows that GOLGA7 serves as a safe and effective therapeutic target for NRAS‐driven leukemia. Loss of Golga7 in adult mice effectively suppresses NrasG12D
‐driven myeloproliferative neoplasm by disrupting its PM localization and impairing subsequent MAPK signaling, without affecting normal hematopoiesis or causing detectable toxicity, although it leads to embryo lethality.