Palmitoylation of oncogenic NRAS is essential for leukemogenesis.

Abstract

Activating mutations of NRAS are common in acute myeloid leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. Like all RAS proteins, NRAS must undergo a series of post-translational modifications for differential targeting to distinct membrane subdomains. Although farnesylation is the obligatory first step in post-translational modifications of RAS, to date, successes of therapies targeting farnesyl protein transferase are modest. Other RAS modifications, such as palmitoylation, are required for optimal plasma membrane association of RAS proteins. However, the relative importance of these latter modifications of RAS in leukemogenesis is not clear. We have previously shown that expression of oncogenic NRAS using a bone marrow transduction and transplantation model efficiently induces a chronic myelomonocytic leukemia- or acute myeloid leukemia-like disease in mice. Here we examined the role of palmitoylation in NRAS leukemogenesis using this model. We found that palmitoylation is essential for leukemogenesis by oncogenic NRAS. We also found that farnesylation is essential for NRAS leukemogenesis, yet through a different mechanism from that of palmitoylation deficiency. This study demonstrates, for the first time, that palmitoylation is an essential process for NRAS leukemogenesis and suggests that the development of therapies targeting RAS palmitoylation may be effective in treating oncogenic NRAS-associated malignancies.

• Authors: Benjamin Cuiffo, Ruibao Ren
• Journal: Blood (Blood) Vol. 115 Issue 17 Pg. 3598-605 (Apr 29 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20200357 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Palmitic Acid
• Farnesyltranstransferase
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cell Membrane (enzymology, genetics)
• Cell Transformation, Neoplastic (genetics, metabolism)
• Disease Models, Animal
• Farnesyltranstransferase (genetics, metabolism)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (enzymology, genetics)
• Leukemia, Myeloid, Acute (enzymology, genetics)
• Lipoylation
• Mice
• NIH 3T3 Cells
• Palmitic Acid (metabolism)
• Protein Prenylation
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Transduction, Genetic