title: Dominant role of oncogene dosage and absence of tumor suppressor activity in Nras-driven hematopoietic transformation.
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.
  
  
  CONCLUSIONS
  Understanding the mechanisms of Ras -induced transformation and adaptive cellular responses is fundamental. The observation that oncogenic Nras lacks tumor suppressor activity, whereas increased dosage strongly modulates cell growth and alters sensitivity to MEK inhibition, suggests new therapeutic opportunities in cancer.
authors.affiliation: 1Department of Pediatrics and 2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California; 3Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, 4Department of Biology, David H. Koch Institute for Integrative Cancer Research and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts; 5Department of Pathology, Institute for Genomics and Systems Biology, 6Ben May Department for Cancer Research, 7Section of Hematology/Oncology and Comprehensive Cancer Center, University of Chicago, Chicago, Illinois; 8Department of Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan; and 9Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Firestone
authors.forename: Megan E
authors.initials: ME
authors.lastname: McNerney
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Davis
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.forename: Joy
authors.initials: J
authors.lastname: Nakitandwe
authors.forename: James
authors.initials: J
authors.lastname: Downing
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D011905:Genes, ras / Q000235:genetics*; D006413:Hematopoietic System / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D020930:MAP Kinase Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human