Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation
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Author(s)
Xu, Jin
Haigis, Kevin M.
Firestone, Ari J.
McNerney, Megan E.
Li, Qing
Davis, Elizabeth
Chen, Shann-Ching
Nakitandwe, Joy
Downing, James
Le Beau, Michelle M.
Date Issued
June 2013
Journal
Cancer Discovery
Publisher
American Association for Cancer Research
Citation
Xu, Jin, Kevin M. Haigis, Ari J. Firestone, Megan E. McNerney, Qing Li, Elizabeth Davis, Shann-Ching Chen, et al. “Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation.” Cancer Discovery 3, no. 9 (June 3, 2013): 993–1001.
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Author's final manuscript
Abstract
Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic Nras[superscript G12D] in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased Nras[superscript G12D] gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras[superscript G12D over G12D] hematopoietic cells. Modulating Nras[superscript G12D] dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK) inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras-mutant cells nor inhibited myeloid transformation by exogenous Nras[superscript G12D]. Importantly, NRAS expression increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1158/2159-8290.cd-13-0096
