Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation

Cancer Discovery - Tập 3 Số 9 - Trang 993-1001 - 2013
Jin Xu1,2,3,4,5, Kevin M. Haigis1,2,3,4,5, Ari Firestone1,2,3,4,5, Megan E. McNerney1,2,3,4,5, Qing Li1,2,3,4,5, Elizabeth L. Davis1,2,3,4,5, Shann-Ching Chen1,2,3,4,5, Joy Nakitandwe1,2,3,4,5, James R. Downing1,2,3,4,5, Tyler Jacks1,2,3,4,5, Michelle M. Le Beau1,2,3,4,5, Kevin Shannon1,2,3,5
1Authors' Affiliations: 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
2Authors' Affiliations:Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California
3Department of Medicine, Division of Hematology Oncology, University of Michigan, Ann Arbor, Michigan
4Department of Pathology, Institute for Genomics and Systems Biology, Ben May Department for Cancer Research, Section of Hematology/Oncology and Comprehensive Cancer Center, University of Chicago, Chicago, Illinois
5Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee

Tóm tắt

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 NrasG12D in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased NrasG12D gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of NrasG12D/G12D hematopoietic cells. Modulating NrasG12D 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 NrasG12D. 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. Significance: 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. Cancer Discov; 3(9); 993–1001. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 953

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Cancer Discovery

Tập 3 Số 9

993-1001

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