title: Ectopic expression of wild-type FGFR3 cooperates with MYC to accelerate development of B-cell lineage neoplasms.
abstract: The t(4;14) translocation in multiple myeloma (MM) simultaneously dysregulates two apparent oncogenes: fibroblast growth factor receptor 3 (FGFR3) controlled by the 3' immunoglobulin heavy chain enhancer on der(14) and MMSET controlled by the intronic Emu enhancer on der(4). Although all MM tumors and cell lines with a t(4;14) translocation have dysregulated MMSET, about 25% do not express FGFR3. Therefore, the function of dysregulated wild-type (WT) FGFR3 in the pathogenesis of MM remains unclear. We developed a murine transgenic (TG) model in which WT FGFR3 is overexpressed in B lymphoid cells. Although high levels of FGFR3 resulted in lymphoid hyperplasia in about one-third of older mice, no increase in tumorigenesis was observed. However, double TG FGFR3/Myc mice develop mature B lymphoma tumors that occur with a higher penetrance and shorter latency than in single TG Myc mice (P=0.006). We conclude that expression of high levels of WT FGFR3 can be oncogenic and cooperate with MYC to generate B lymphoid tumors. This suggests that dysregulated FGFR3 expression is likely to be essential at least for the early stages of pathogenesis of MM tumors that have a t(4;14) translocation.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889-5105, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zingone
authors.forename: C M
authors.initials: CM
authors.lastname: Cultraro
authors.forename: D-M
authors.initials: DM
authors.lastname: Shin
authors.forename: C M
authors.initials: CM
authors.lastname: Bean
authors.forename: H C
authors.initials: HC
authors.lastname: Morse
authors.forename: S
authors.initials: S
authors.lastname: Janz
authors.forename: W M
authors.initials: WM
authors.lastname: Kuehl
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015139:Blotting, Southern; D015153:Blotting, Western; D005260:Female; D020869:Gene Expression Profiling; D005803:Genes, Immunoglobulin; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000209:etiology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):459-65
references.pmid: 15701828
references.citation: Blood. 2005 Apr 1;105(7):2941-8
references.pmid: 15598814
references.citation: J Clin Invest. 2009 May;119(5):1216-29
references.pmid: 19381019
references.citation: Cancer Cell. 2008 Feb;13(2):167-80
references.pmid: 18242516
references.citation: Blood. 2001 Apr 15;97(8):2413-9
references.pmid: 11290605
references.citation: Blood. 2005 Mar 1;105(5):2135-7
references.pmid: 15522957
references.citation: Best Pract Res Clin Haematol. 2007 Dec;20(4):571-96
references.pmid: 18070707
references.citation: Blood. 2003 Jun 1;101(11):4569-75
references.pmid: 12576322
references.citation: Blood. 2005 Jul 1;106(1):328-37
references.pmid: 15784730
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49
references.pmid: 15863030
references.citation: J Clin Oncol. 2005 Sep 10;23(26):6333-8
references.pmid: 16155016
references.citation: Nat Genet. 1995 Mar;9(3):321-8
references.pmid: 7773297
references.citation: Blood. 2002 Jul 1;100(1):246-58
references.pmid: 12070034
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):233-47
references.pmid: 15863038
references.citation: Blood. 2006 May 15;107(10):4039-46
references.pmid: 16467200
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13931-6
references.pmid: 8943038
references.citation: Hum Mol Genet. 2009 Jun 1;18(11):1951-61
references.pmid: 19286672
references.citation: Blood. 2007 Feb 15;109(4):1692-700
references.pmid: 17023574
references.citation: J Pathol. 2006 Feb;208(3):431-8
references.pmid: 16353171
references.citation: Nat Rev Cancer. 2002 Mar;2(3):175-87
references.pmid: 11990854
references.citation: Curr Opin Hematol. 2002 Jul;9(4):288-93
references.pmid: 12042702
references.citation: Blood. 2006 Sep 15;108(6):2020-8
references.pmid: 16728703
references.citation: Exp Cell Res. 2005 Apr 1;304(2):417-31
references.pmid: 15748888
references.citation: Blood. 1998 Nov 1;92(9):3025-34
references.pmid: 9787135
references.citation: Bioinformatics. 2002 Jan;18(1):207-8
references.pmid: 11836235
references.citation: Blood. 2003 Jul 15;102(2):772-3
references.pmid: 12835230
references.citation: Oligonucleotides. 2005 Spring;15(1):1-11
references.pmid: 15788896
references.citation: J Pathol. 2007 Sep;213(1):91-8
references.pmid: 17668422
references.citation: Br J Haematol. 2004 Mar;124(5):595-603
references.pmid: 14871245
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):179-86
references.pmid: 15863033
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references.pmid: 11309499
references.citation: Blood. 2006 Nov 15;108(10):3465-71
references.pmid: 16849642
references.citation: EMBO J. 1997 Dec 1;16(23):7019-31
references.pmid: 9384581
references.citation: Blood. 2004 May 1;103(9):3521-8
references.pmid: 14715624
references.citation: Blood. 2004 Jan 1;103(1):20-32
references.pmid: 12969978
references.citation: Nat Genet. 1997 Jul;16(3):260-4
references.pmid: 9207791
references.citation: Leuk Lymphoma. 2006 Nov;47(11):2289-300
references.pmid: 17107900
references.citation: J Pathol. 2006 May;209(1):44-55
references.pmid: 16482495
references.citation: J Immunol. 2003 Aug 15;171(4):1875-80
references.pmid: 12902489
references.citation: Biochem Biophys Res Commun. 2005 May 13;330(3):1005-13
references.pmid: 15809095
references.citation: Blood. 2001 Feb 1;97(3):729-36
references.pmid: 11157491
references.citation: Cancer Res. 2005 Feb 15;65(4):1306-15
references.pmid: 15735016
references.citation: CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
references.pmid: 17237035