Inhibiting the palmitoylation/depalmitoylation cycle selectively reduces the growth of hematopoietic cells expressing oncogenic Nras.
The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-Ras(G12D) formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations.
Duke Scholars
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- Proto-Oncogene Proteins p21(ras)
- Protein Transport
- Protein Processing, Post-Translational
- Palmitoyl-CoA Hydrolase
- Osmolar Concentration
- Mutant Proteins
- Molecular Targeted Therapy
- Mice, Mutant Strains
- Mice, Inbred C57BL
- Mice, 129 Strain
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Proto-Oncogene Proteins p21(ras)
- Protein Transport
- Protein Processing, Post-Translational
- Palmitoyl-CoA Hydrolase
- Osmolar Concentration
- Mutant Proteins
- Molecular Targeted Therapy
- Mice, Mutant Strains
- Mice, Inbred C57BL
- Mice, 129 Strain