title: Inhibiting the palmitoylation/depalmitoylation cycle selectively reduces the growth of hematopoietic cells expressing oncogenic Nras.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of California-San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Christian
authors.initials: C
authors.lastname: Hedberg
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Eugene
authors.initials: E
authors.lastname: Hwang
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D054878:Lipoylation / Q000187:drug effects*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000378:metabolism; D009994:Osmolar Concentration; D010170:Palmitoyl-CoA Hydrolase / Q000037:antagonists & inhibitors*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D021381:Protein Transport; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D010170:Palmitoyl-CoA Hydrolase; D016283:Proto-Oncogene Proteins p21(ras)