title: NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.
abstract: Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRAS(G12V)). Using computational approaches to explore our gene-expression data sets, we found that NRAS(G12V) enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9- and Myb-dependent leukemia self-renewal gene-expression program. NRAS(G12V) was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRAS(G12V)-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1(Low) cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS(G12V) withdrawal. NRAS(G12V) maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction.
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine.
authors.forename: Zohar
authors.identifier: http://orcid.org/0000-0001-9386-4163
authors.initials: Z
authors.lastname: Sachs
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, Department of Genetics, Cell Biology and Development, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: LaRue
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine.
authors.forename: Hanh T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA;
authors.forename: Karen
authors.initials: K
authors.lastname: Sachs
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine.
authors.forename: Klara E
authors.initials: KE
authors.lastname: Noble
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Nurul Azyan
authors.initials: NA
authors.lastname: Mohd Hassan
authors.affiliation: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA;
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Flores
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Susan K
authors.initials: SK
authors.lastname: Rathe
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.affiliation: Department of Pathology, Stanford School of Medicine, Stanford, CA; and.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Bendall
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Ngoc A
authors.initials: NA
authors.lastname: Ha
authors.affiliation: Department of Genetics, Cell Biology and Development, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors.forename: Miechaleen D
authors.initials: MD
authors.lastname: Diers
authors.affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA;
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.affiliation: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA;
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shannon
authors.affiliation: Department of Genetics, Cell Biology and Development, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Center for Genome Engineering and Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D005998:Glycine / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009857:Oncogenes / Q000502:physiology; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D014633:Valine / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D014633:Valine; D005998:Glycine