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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.

Titel:	NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.
Autor/in / Beteiligte Person:	Sachs, Z ; LaRue, RS ; Nguyen, HT ; Sachs, K ; Noble, KE ; Mohd Hassan, NA ; Diaz-Flores, E ; Rathe, SK ; Sarver, AL ; Bendall, SC ; Ha, NA ; Diers, MD ; Nolan, GP ; Shannon, KM ; Largaespada, DA
Link:	Full Text Finder (Volltext)
Zeitschrift:	Blood, Jg. 124 (2014-11-20), Heft 22, S. 3274-83
Veröffentlichung:	2021- : [New York] : Elsevier ; <i>Original Publication</i>: New York, Grune & Stratton [etc.], 2014
Medientyp:	academicJournal
ISSN:	1528-0020 (electronic)
DOI:	10.1182/blood-2013-08-521708
Schlagwort:	Amino Acid Substitution Animals Cell Transformation, Neoplastic genetics Disease Models, Animal GTP Phosphohydrolases genetics Gene Expression Regulation, Leukemic Glycine genetics Humans Membrane Proteins genetics Mice Mice, SCID Oncogenes physiology Transcriptome Tumor Cells, Cultured Valine genetics Cell Proliferation genetics GTP Phosphohydrolases physiology Leukemia, Myeloid, Acute genetics Leukemia, Myeloid, Acute pathology Membrane Proteins physiology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Blood] 2014 Nov 20; Vol. 124 (22), pp. 3274-83. <i>Date of Electronic Publication: </i>2014 Oct 14. MeSH Terms: Cell Proliferation / genetics ; GTP Phosphohydrolases / physiology ; Leukemia, Myeloid, Acute / genetics ; Leukemia, Myeloid, Acute / pathology ; Membrane Proteins / *physiology ; Amino Acid Substitution ; Animals ; Cell Transformation, Neoplastic / genetics ; Disease Models, Animal ; GTP Phosphohydrolases / genetics ; Gene Expression Regulation, Leukemic ; Glycine / genetics ; Humans ; Membrane Proteins / genetics ; Mice ; Mice, SCID ; Oncogenes / physiology ; Transcriptome ; Tumor Cells, Cultured ; Valine / genetics References: Genes Dev. 2003 Sep 15;17(18):2298-307. (PMID: 12952893) ; Nat Biotechnol. 2010 May;28(5):511-5. (PMID: 20436464) ; Blood. 2008 Jan 1;111(1):379-82. (PMID: 17878402) ; Blood. 2013 Jun 27;121(26):5203-7. (PMID: 23687087) ; Int J Hematol. 2010 Jun;91(5):735-41. (PMID: 20454944) ; Nature. 2006 Aug 17;442(7104):818-22. (PMID: 16862118) ; Cold Spring Harb Symp Quant Biol. 2008;73:439-49. (PMID: 19022770) ; Blood. 2004 Dec 1;104(12):3679-87. (PMID: 15226186) ; Cell. 2012 Apr 27;149(3):656-70. (PMID: 22541435) ; Nature. 2012 Jan 11;481(7380):157-63. (PMID: 22237106) ; Blood. 2009 Jan 29;113(5):1086-96. (PMID: 18952898) ; JAMA. 2010 Dec 22;304(24):2706-15. (PMID: 21177505) ; Leukemia. 2007 Sep;21(9):2000-9. (PMID: 17597811) ; Blood. 2011 Oct 6;118(14):3824-31. (PMID: 21828134) ; Cell Stem Cell. 2012 Apr 6;10(4):412-24. (PMID: 22482506) ; Blood. 2012 Oct 25;120(17):3397-406. (PMID: 22898602) ; Leukemia. 2013 Feb;27(2):269-77. (PMID: 22874877) ; Leukemia. 2013 Jul;27(7):1479-86. (PMID: 23321953) ; J Clin Exp Hematop. 2010;50(2):91-8. (PMID: 21123966) ; Clin Cancer Res. 2008 Apr 15;14(8):2249-52. (PMID: 18413813) ; Blood. 2011 Jul 14;118(2):368-79. (PMID: 21586752) ; N Engl J Med. 2013 May 30;368(22):2059-74. (PMID: 23634996) ; Blood. 2005 Aug 1;106(3):1054-62. (PMID: 15831708) ; Cell Stem Cell. 2009 Feb 6;4(2):129-40. (PMID: 19200802) ; Nat Biotechnol. 2011 Oct 02;29(10):886-91. (PMID: 21964415) ; Nat Genet. 2003 Jul;34(3):267-73. (PMID: 12808457) ; Nat Rev Mol Cell Biol. 2011 Dec 22;13(1):39-51. (PMID: 22189424) ; Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12944-9. (PMID: 19651601) ; Bioinformatics. 2009 May 1;25(9):1105-11. (PMID: 19289445) ; Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) ; Nucleic Acids Res. 2009 Jan;37(Database issue):D674-9. (PMID: 18832364) ; Science. 2011 May 6;332(6030):687-96. (PMID: 21551058) ; Cancer Cell. 2007 Dec;12(6):528-41. (PMID: 18068630) ; Genes Dev. 2003 Dec 15;17(24):3029-35. (PMID: 14701873) ; Science. 2010 Mar 26;327(5973):1650-3. (PMID: 20339075) ; Blood. 2013 Mar 7;121(10):1824-38. (PMID: 23299311) ; Cancer Cell. 2008 Oct 7;14(4):335-43. (PMID: 18835035) ; Cancer Cell. 2010 Dec 14;18(6):606-18. (PMID: 21156284) ; Curr Opin Hematol. 2012 Jul;19(4):280-6. (PMID: 22525581) ; Genes Dev. 2011 Aug 1;25(15):1628-40. (PMID: 21828272) ; Leukemia. 2009 Jan;23(1):109-16. (PMID: 18818703) ; Blood. 2011 Feb 10;117(6):2022-32. (PMID: 21163920) ; Nature. 2013 Dec 5;504(7478):143-147. (PMID: 24284627) Grant Information: P30 CA77598 United States CA NCI NIH HHS; T32 HL007062 United States HL NHLBI NIH HHS; T32HL007062 United States HL NHLBI NIH HHS; 1R01CA130826 United States CA NCI NIH HHS; R37 CA072614 United States CA NCI NIH HHS; R01 CA130826 United States CA NCI NIH HHS; P30 CA077598 United States CA NCI NIH HHS; N01-HV-00242 United States HV NHLBI NIH HHS; R37CA72614 United States CA NCI NIH HHS Substance Nomenclature: 0 (Membrane Proteins) ; EC 3.6.1.- (GTP Phosphohydrolases) ; EC 3.6.1.- (NRAS protein, human) ; HG18B9YRS7 (Valine) ; TE7660XO1C (Glycine) Entry Date(s): Date Created: 20141016 Date Completed: 20150224 Latest Revision: 20211021 Update Code: 20231215 PubMed Central ID: PMC4239336

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NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.