Dominant role of oncogene dosage and absence of tumor suppressor activity in Nras-driven hematopoietic transformation.

TitleDominant role of oncogene dosage and absence of tumor suppressor activity in Nras-driven hematopoietic transformation.
Publication TypeJournal Article
Year of Publication2013
AuthorsXu J, Haigis KM, Firestone AJ, McNerney ME, Li Q, Davis E, Chen S-C, Nakitandwe J, Downing J, Jacks T, Le Beau MM, Shannon K
JournalCancer discovery
Volume3
Issue9
Pagination993-1001
Date Published2013 Sep
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(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(G12D) gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras(G12D/G12D) hematopoietic cells. Modulating Nras(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(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.

DOI10.1371/journal.pone.0064663
Alternate JournalCancer Discov