title: Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas.
abstract: The Sleeping Beauty (SB) transposon system has been used as an insertional mutagenesis tool to identify novel cancer genes. To identify glioma-associated genes, we evaluated tumor formation in the brain tissue from 117 transgenic mice that had undergone constitutive SB-mediated transposition. Upon analysis, 21 samples (18%) contained neoplastic tissue with features of high-grade astrocytomas. These tumors expressed glial markers and were histologically similar to human glioma. Genomic DNA from SB-induced astrocytoma tissue was extracted and transposon insertion sites were identified. Insertions in the growth factor gene Csf1 were found in 13 of the 21 tumors (62%), clustered in introns 5 and 8. Using reverse transcription-PCR, we documented increased Csf1 RNAs in tumor versus adjacent normal tissue, with the identification of transposon-terminated Csf1 mRNAs in astrocytomas with SB insertions in intron 8. Analysis of human glioblastomas revealed increased levels of Csf1 RNA and protein. Together, these results indicate that SB-insertional mutagenesis can identify high-grade astrocytoma-associated genes and they imply an important role for CSF1 in the development of these tumors.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Bender
authors.forename: Lara S
authors.initials: LS
authors.lastname: Collier
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
authors.forename: Christina
authors.initials: C
authors.lastname: Tieu
authors.forename: Jon D
authors.initials: JD
authors.lastname: Larson
authors.forename: Chandralekha
authors.initials: C
authors.lastname: Halder
authors.forename: Eric
authors.initials: E
authors.lastname: Mahlum
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kollmeyer
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Gobinda
authors.initials: G
authors.lastname: Sarkar
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004251:DNA Transposable Elements; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000379:methods*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D019895:Transposases / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019895:Transposases
references.citation: Nat Genet. 2009 Aug;41(8):905-8
references.pmid: 19578366
references.citation: Br J Haematol. 1971 Oct;21(4):481-92
references.pmid: 5122671
references.citation: Cancer Res. 2005 Nov 1;65(21):9607-10
references.pmid: 16266976
references.citation: Nature. 2005 Jul 14;436(7048):272-6
references.pmid: 16015333
references.citation: Mol Reprod Dev. 1997 Jan;46(1):4-10
references.pmid: 8981357
references.citation: Cancer. 1991 Feb 15;67(4):990-6
references.pmid: 1825026
references.citation: Acta Neuropathol. 2004 Mar;107(3):277-82
references.pmid: 14730454
references.citation: Genetics. 2003 Sep;165(1):243-56
references.pmid: 14504232
references.citation: J Pathol. 2008 Sep;216(1):15-24
references.pmid: 18553315
references.citation: Nat Genet. 2002 Sep;32(1):153-9
references.pmid: 12185366
references.citation: J Exp Med. 2001 Mar 19;193(6):727-40
references.pmid: 11257139
references.citation: Trends Genet. 1999 Aug;15(8):326-32
references.pmid: 10431195
references.citation: PLoS Biol. 2004 Nov;2(11):e363
references.pmid: 15502875
references.citation: Neuro Oncol. 2009 Dec;11(6):803-18
references.pmid: 19304958
references.citation: J Neurosurg. 1994 Jun;80(6):1063-73
references.pmid: 7514661
references.citation: Cancer Res. 2008 Nov 15;68(22):9125-30
references.pmid: 19010882
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12530-5
references.pmid: 19617536
references.citation: Clin Cancer Res. 2006 Sep 15;12(18):5288-97
references.pmid: 17000661
references.citation: Cancer Res. 2007 Mar 1;67(5):1918-26
references.pmid: 17332318
references.citation: Genesis. 2001 Jun;30(2):82-8
references.pmid: 11416868
references.citation: Mol Chem Neuropathol. 1994 Feb-Apr;21(2-3):177-88
references.pmid: 8086034
references.citation: Oncogene. 2000 Dec 7;19(52):5964-72
references.pmid: 11146547
references.citation: Cancer Res. 1999 May 1;59(9):2217-22
references.pmid: 10232611
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: Nat Biotechnol. 2009 Mar;27(3):264-74
references.pmid: 19234449
references.citation: Nature. 2005 Jul 14;436(7048):221-6
references.pmid: 16015321
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):690-5
references.pmid: 16407111
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D523-7
references.pmid: 14681473
references.citation: Cancer Res. 2009 Nov 1;69(21):8429-37
references.pmid: 19843846
references.citation: Oncogene. 2000 Dec 18;19(55):6482-9
references.pmid: 11175364
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10769-73
references.pmid: 9724779
references.citation: Blood. 1996 Jun 15;87(12):5232-41
references.pmid: 8652838
references.citation: Yeast. 1999 Aug;15(11):1097-109
references.pmid: 10455233
references.citation: Mol Cancer Res. 2008 Aug;6(8):1375-84
references.pmid: 18708368
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: BMC Neurosci. 2007 May 02;8:28
references.pmid: 17474996
references.citation: Neuroscience. 2002;112(4):889-900
references.pmid: 12088748
references.citation: Int Immunopharmacol. 2008 Oct;8(10):1354-76
references.pmid: 18687298
references.citation: Science. 2003 Jun 13;300(5626):1749-51
references.pmid: 12805549
references.citation: Nat Genet. 2000 Dec;26(4):424-9
references.pmid: 11101838
references.citation: Cancer Res. 2009 May 15;69(10):4388-97
references.pmid: 19401450
references.citation: Stem Cells. 2007 Feb;25(2):371-9
references.pmid: 17038675
references.citation: Biochem Biophys Res Commun. 2007 Feb 23;353(4):902-7
references.pmid: 17196930
references.citation: Science. 2009 Mar 27;323(5922):1747-50
references.pmid: 19251594
references.citation: EMBO J. 1998 Sep 1;17(17):4964-74
references.pmid: 9724633