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Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice.
Blood. 2020 May 14; 135(20):1772-1782.Blood

Abstract

Oncogenic RAS mutations pose substantial challenges for rational drug discovery. Sequence variations within the hypervariable region of Ras isoforms underlie differential posttranslational modification and subcellular trafficking, potentially resulting in selective vulnerabilities. Specifically, inhibiting the palmitoylation/depalmitoylation cycle is an appealing strategy for treating NRAS mutant cancers, particularly as normal tissues would retain K-Ras4b function for physiologic signaling. The role of endogenous N-RasG12D palmitoylation in signal transduction, hematopoietic differentiation, and myeloid transformation is unknown, and addressing these key questions will inform efforts to develop mechanism-based therapies. To evaluate the palmitoylation/depalmitoylation cycle as a candidate drug target in an in vivo disease-relevant model system, we introduced a C181S mutation into a conditional NrasG12D "knock-in" allele. The C181S second-site amino acid substitution abrogated myeloid transformation by NrasG12D, which was associated with mislocalization of the nonpalmitoylated N-Ras mutant protein, reduced Raf/MEK/ERK signaling, and alterations in hematopoietic stem and progenitor populations. Furthermore, hematologic malignancies arising in NrasG12D/G12D,C181S compound heterozygous mice invariably acquired revertant mutations that restored cysteine 181. Together, these studies validate the palmitoylation cycle as a promising therapeutic target in NRAS mutant cancers.

Authors+Show Affiliations

Department of Pediatrics. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.Department of Pediatrics. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.Department of Chemistry, The Scripps Research Institute, La Jolla, CA.Department of Pediatrics. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.Department of Pediatrics. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.Department of Pediatrics.Department of Pediatrics.Department of Chemistry, The Scripps Research Institute, La Jolla, CA.Department of Pediatrics.Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA. Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA.Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA; and. Department of Medicine, Harvard University Medical School, Boston, MA.Department of Chemistry, The Scripps Research Institute, La Jolla, CA.Department of Pediatrics. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32219446

Citation

Zambetti, Noemi A., et al. "Genetic Disruption of N-RasG12D Palmitoylation Perturbs Hematopoiesis and Prevents Myeloid Transformation in Mice." Blood, vol. 135, no. 20, 2020, pp. 1772-1782.
Zambetti NA, Firestone AJ, Remsberg JR, et al. Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice. Blood. 2020;135(20):1772-1782.
Zambetti, N. A., Firestone, A. J., Remsberg, J. R., Huang, B. J., Wong, J. C., Long, A. M., Predovic, M., Suciu, R. M., Inguva, A., Kogan, S. C., Haigis, K. M., Cravatt, B. F., & Shannon, K. (2020). Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice. Blood, 135(20), 1772-1782. https://doi.org/10.1182/blood.2019003530
Zambetti NA, et al. Genetic Disruption of N-RasG12D Palmitoylation Perturbs Hematopoiesis and Prevents Myeloid Transformation in Mice. Blood. 2020 May 14;135(20):1772-1782. PubMed PMID: 32219446.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice. AU - Zambetti,Noemi A, AU - Firestone,Ari J, AU - Remsberg,Jarrett R, AU - Huang,Benjamin J, AU - Wong,Jasmine C, AU - Long,Amanda M, AU - Predovic,Marina, AU - Suciu,Radu M, AU - Inguva,Anagha, AU - Kogan,Scott C, AU - Haigis,Kevin M, AU - Cravatt,Benjamin F, AU - Shannon,Kevin, PY - 2019/10/01/received PY - 2020/02/26/accepted PY - 2021/05/14/pmc-release PY - 2020/3/29/pubmed PY - 2020/3/29/medline PY - 2020/3/29/entrez SP - 1772 EP - 1782 JF - Blood JO - Blood VL - 135 IS - 20 N2 - Oncogenic RAS mutations pose substantial challenges for rational drug discovery. Sequence variations within the hypervariable region of Ras isoforms underlie differential posttranslational modification and subcellular trafficking, potentially resulting in selective vulnerabilities. Specifically, inhibiting the palmitoylation/depalmitoylation cycle is an appealing strategy for treating NRAS mutant cancers, particularly as normal tissues would retain K-Ras4b function for physiologic signaling. The role of endogenous N-RasG12D palmitoylation in signal transduction, hematopoietic differentiation, and myeloid transformation is unknown, and addressing these key questions will inform efforts to develop mechanism-based therapies. To evaluate the palmitoylation/depalmitoylation cycle as a candidate drug target in an in vivo disease-relevant model system, we introduced a C181S mutation into a conditional NrasG12D "knock-in" allele. The C181S second-site amino acid substitution abrogated myeloid transformation by NrasG12D, which was associated with mislocalization of the nonpalmitoylated N-Ras mutant protein, reduced Raf/MEK/ERK signaling, and alterations in hematopoietic stem and progenitor populations. Furthermore, hematologic malignancies arising in NrasG12D/G12D,C181S compound heterozygous mice invariably acquired revertant mutations that restored cysteine 181. Together, these studies validate the palmitoylation cycle as a promising therapeutic target in NRAS mutant cancers. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/32219446/Genetic_disruption_of_N-RasG12D_palmitoylation_perturbs_hematopoiesis_and_prevents_myeloid_transformation_in_mice L2 - https://ashpublications.org/blood/article-lookup/doi/10.1182/blood.2019003530 DB - PRIME DP - Unbound Medicine ER -
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