title: B cell activator PAX5 promotes lymphomagenesis through stimulation of B cell receptor signaling.
abstract: The presumed involvement of paired box gene 5 (PAX5) in B-lymphomagenesis is based largely on the discovery of Pax5-specific translocations and somatic hypermutations in non-Hodgkin lymphomas. Yet mechanistically, the contribution of Pax5 to neoplastic growth remains undeciphered. Here we used 2 Myc-induced mouse B lymphoma cell lines, Myc5-M5 and Myc5-M12, which spontaneously silence Pax5. Reconstitution of these cells with Pax5-tamoxifen receptor fusion protein (Pax5ER(TAM)) increased neoplastic growth in a hormone-dependent manner. Conversely, expression of dominant-negative Pax5 in murine lymphomas and Pax5 knockdown in human lymphomas negatively affected cell expansion. Expression profiling revealed that Pax5 was required to maintain mRNA levels of several crucial components of B cell receptor (BCR) signaling, including CD79a, a protein with the immunoreceptor tyrosine-based activation motif (ITAM). In contrast, expression of 2 known ITAM antagonists, CD22 and PIR-B, was suppressed. The key role of BCR/ITAM signaling in Pax5-dependent lymphomagenesis was corroborated in Syk, an ITAM-associated tyrosine kinase. Moreover, we observed consistent expression of phosphorylated BLNK, an activated BCR adaptor protein, in human B cell lymphomas. Thus, stimulation of neoplastic growth by Pax5 occurs through BCR and is sensitive to genetic and pharmacological inhibitors of this pathway.
authors: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6051, USA.
authors: Diana
authors: D
authors: Cozma
authors: Duonan
authors: D
authors: Yu
authors: Suchita
authors: S
authors: Hodawadekar
authors: Anna
authors: A
authors: Azvolinsky
authors: Shannon
authors: S
authors: Grande
authors: John W
authors: JW
authors: Tobias
authors: Michele H
authors: MH
authors: Metzgar
authors: Jennifer
authors: J
authors: Paterson
authors: Jan
authors: J
authors: Erikson
authors: Teresa
authors: T
authors: Marafioti
authors: John G
authors: JG
authors: Monroe
authors: Michael L
authors: ML
authors: Atchison
authors: Andrei
authors: A
authors: Thomas-Tikhonenko
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C497282:Pax5 protein, mouse; D011947:Receptors, Antigen, B-Cell
references: Blood. 1992 Nov 15;80(10):2594-9
references: 1384792
references: Nat Immunol. 2004 Aug;5(8):853-61
references: 15258579
references: EMBO J. 1995 Nov 15;14(22):5638-45
references: 8521821
references: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6129-34
references: 8650231
references: Science. 1996 Jun 21;272(5269):1804-8
references: 8650582
references: Genes Dev. 1996 Sep 1;10(17):2198-211
references: 8804314
references: Blood. 1996 Dec 1;88(11):4110-7
references: 8943844
references: Annu Rev Immunol. 1997;15:453-79
references: 9143696
references: Trends Genet. 1997 Sep;13(9):375-6
references: 9287494
references: Cell. 1997 Sep 19;90(6):1073-83
references: 9323135
references: J Immunol. 2001 May 15;166(10):6091-8
references: 11342627
references: Cancer Res. 2001 Jun 15;61(12):4666-70
references: 11406533
references: Nature. 2001 Jul 19;412(6844):341-6
references: 11460166
references: J Exp Med. 2001 Dec 3;194(11):1583-96
references: 11733573
references: Blood. 2002 Jan 1;99(1):282-9
references: 11756183
references: Oncogene. 2002 Mar 14;21(12):1922-7
references: 11896625
references: Science. 2002 Jul 5;297(5578):110-3
references: 12098702
references: Immunity. 2002 Oct;17(4):473-85
references: 12387741
references: Carcinogenesis. 2004 Oct;25(10):1839-46
references: 15155532
references: Proc Natl Acad Sci U S A. 1982 Dec;79(24):7824-7
references: 6961453
references: Proc Natl Acad Sci U S A. 1982 Dec;79(24):7837-41
references: 6818551
references: Cell. 1982 Dec;31(2 Pt 1):443-52
references: 6819085
references: Nature. 1985 Dec 12-18;318(6046):533-8
references: 3906410
references: Proc Natl Acad Sci U S A. 1988 Aug;85(16):6047-51
references: 3261863
references: Mol Cell Biol. 1992 Jun;12(6):2662-72
references: 1375324
references: Blood. 2003 Mar 1;101(5):1950-5
references: 12406913
references: Genome Biol. 2003;4(5):P3
references: 12734009
references: Blood. 2003 Sep 1;102(5):1833-41
references: 12714522
references: Blood. 2004 Jan 1;103(1):188-93
references: 12881301
references: Immunol Rev. 2004 Feb;197:147-60
references: 14962193
references: Blood. 1998 Aug 15;92(4):1308-16
references: 9694719
references: Int J Biochem Cell Biol. 1997 Dec;29(12):1449-61
references: 9570138
references: Blood. 2004 Mar 1;103(5):1869-75
references: 14592832
references: Blood. 1998 Nov 15;92(10):3865-78
references: 9808580
references: Clin Cancer Res. 1995 Feb;1(2):207-14
references: 9815975
references: Cancer Res. 2005 Feb 15;65(4):1306-15
references: 15735016
references: Nat Rev Cancer. 2005 Apr;5(4):251-62
references: 15803153
references: Curr Opin Immunol. 2005 Jun;17(3):290-7
references: 15886119
references: Blood. 2005 Jun 15;105(12):4820-7
references: 15728130
references: Blood. 2005 Aug 15;106(4):1382-91
references: 15890690
references: Curr Opin Immunol. 2006 Apr;18(2):127-34
references: 16464566
references: Immunity. 2006 Mar;24(3):269-81
references: 16546096
references: Immunity. 2006 Mar;24(3):283-93
references: 16546097
references: Nat Rev Immunol. 2006 Apr;6(4):283-94
references: 16557260
references: J Immunol. 2006 May 15;176(10):5715-9
references: 16670274
references: Oncogene. 2006 May 4;25(19):2748-57
references: 16369490
references: Blood. 2006 Nov 1;108(9):3135-42
references: 16835385
references: J Immunol. 2006 Nov 1;177(9):6165-71
references: 17056545
references: Blood. 2007 Jan 1;109(1):281-9
references: 16968900
references: Exp Cell Res. 2007 Jan 15;313(2):331-40
references: 17098231
references: Blood. 2007 Apr 15;109(8):3417-23
references: 17179230
references: Nature. 2007 Apr 12;446(7137):758-64
references: 17344859
references: J Virol. 2000 Nov;74(22):10458-67
references: 11044090
references: Mol Cell Biol. 2000 Mar;20(6):1911-22
references: 10688639
references: J Exp Med. 2000 Oct 16;192(8):1183-90
references: 11034608
references: Hum Pathol. 2004 Apr;35(4):447-54
references: 15116325
references: Cell. 2004 Jun 11;117(6):787-800
references: 15186779
references: Mol Cell. 2004 Jun 18;14(6):696-7
references: 15200948
references: Cell. 1994 Dec 2;79(5):901-12
references: 8001127