title: Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia.
abstract: As STAT5 is critical for the differentiation, proliferation, and survival of progenitor B cells, this transcription factor may play a role in acute lymphoblastic leukemia (ALL). Here, we show increased expression of activated signal transducer and activator of transcription 5 (STAT5), which is correlated with poor prognosis, in ALL patient cells. Mutations in EBF1 and PAX5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1, but this had little effect on most EBF1 or PAX5 target genes. Only a subset of target genes was deregulated; this subset included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL.
authors: Department of Laboratory Medicine and Pathology, The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Lynn M
authors: LM
authors: Heltemes-Harris
authors: Mark J L
authors: MJ
authors: Willette
authors: Laura B
authors: LB
authors: Ramsey
authors: Yi Hua
authors: YH
authors: Qiu
authors: E Shannon
authors: ES
authors: Neeley
authors: Nianxiang
authors: N
authors: Zhang
authors: Deborah A
authors: DA
authors: Thomas
authors: Thearith
authors: T
authors: Koeuth
authors: Emily C
authors: EC
authors: Baechler
authors: Steven M
authors: SM
authors: Kornblau
authors: Michael A
authors: MA
authors: Farrar
references: Mol Cell Biol. 1999 Nov;19(11):7870-85
references: 10523675
references: Cell Cycle. 2007 Jan 1;6(1):95-103
references: 17245118
references: Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1000-5
references: 16418296
references: J Clin Oncol. 2005 Jun 10;23(17):3886-96
references: 15897551
references: Mitochondrion. 2010 Apr;10(3):243-52
references: 20005987
references: J Cancer Res Clin Oncol. 2006 Jul;132(7):417-26
references: 16456675
references: J Immunol. 2005 Jun 15;174(12):7753-63
references: 15944278
references: Blood. 2009 Jan 1;113(1):154-64
references: 18840713
references: Cancer Sci. 2007 May;98(5):698-706
references: 17374122
references: Nature. 1988 Mar 10;332(6160):171-3
references: 3347254
references: J Immunol. 2004 Apr 15;172(8):4770-8
references: 15067053
references: Nature. 1999 Jan 28;397(6717):315-23
references: 9950424
references: Proc Natl Acad Sci U S A. 1991 May 15;88(10):4367-71
references: 2034676
references: Oncogene. 2001 Sep 27;20(43):6188-95
references: 11593427
references: Blood. 2010 Aug 12;116(6):962-70
references: 20519628
references: Blood. 2010 Jun 10;115(23):4810-9
references: 20354172
references: Immunity. 1998 Jul;9(1):35-45
references: 9697834
references: Nature. 1995 Jul 20;376(6537):263-7
references: 7542362
references: Nat Immunol. 2010 Feb;11(2):171-9
references: 19946273
references: EMBO J. 1998 Apr 15;17(8):2319-33
references: 9545244
references: J Exp Med. 1996 Mar 1;183(3):811-20
references: 8642285
references: Blood. 2005 Mar 1;105(5):2107-14
references: 15536149
references: Blood. 2004 Jun 15;103(12):4396-407
references: 14551133
references: Oncogene. 1991 Oct;6(10):1887-93
references: 1923511
references: Nature. 2007 Sep 27;449(7161):473-7
references: 17851532
references: J Exp Med. 2010 Jun 7;207(6):1209-21
references: 20498019
references: Apoptosis. 2009 Apr;14(4):584-96
references: 19156528
references: Science. 1995 Sep 29;269(5232):1875-7
references: 7569929
references: Nature. 1986 Feb 20-26;319(6055):682-5
references: 3081813
references: EMBO J. 1992 Apr;11(4):1663-70
references: 1373383
references: Leuk Lymphoma. 2009 Dec;50 Suppl 2:9-15
references: 20017606
references: Blood. 2009 Feb 12;113(7):1483-92
references: 19047679
references: Genes Dev. 1997 Feb 15;11(4):476-91
references: 9042861
references: Cancer Cell. 2002 Mar;1(2):133-43
references: 12086872
references: Immunity. 2008 Jun;28(6):751-62
references: 18538592
references: Lancet Oncol. 2009 Feb;10(2):125-34
references: 19138562
references: J Biol Chem. 2003 Nov 14;278(46):46171-8
references: 12952963
references: Blood. 2010 Nov 4;116(18):3409-17
references: 20656928
references: Blood. 2000 Sep 15;96(6):2277-83
references: 10979977
references: Nature. 1999 Oct 7;401(6753):556-62
references: 10524622
references: J Immunol. 2004 Jun 1;172(11):6684-91
references: 15153484
references: Nature. 2007 Apr 12;446(7137):758-64
references: 17344859
references: Immunity. 2006 Mar;24(3):269-81
references: 16546096
references: Nat Genet. 1996 Dec;14(4):482-6
references: 8944033
references: J Exp Med. 2009 Aug 3;206(8):1739-53
references: 19620627
references: Blood. 2006 Jun 15;107(12):4898-906
references: 16493008
references: Hematology. 2010 Jun;15(3):132-4
references: 20557670
references: Lancet. 2008 Mar 22;371(9617):1030-43
references: 18358930
references: J Immunol. 2000 Mar 1;164(5):2533-41
references: 10679091
references: Cell. 1992 Mar 6;68(5):855-67
references: 1547487
references: Blood. 1996 Apr 15;87(8):3124-34
references: 8605326
references: Clin Cancer Res. 2002 Apr;8(4):945-54
references: 11948098
references: Immunity. 2007 Jul;27(1):49-63
references: 17658281
references: J Immunol. 1997 Nov 15;159(10):4720-8
references: 9366395
references: Blood. 1996 Aug 1;88(3):809-16
references: 8704235
references: J Biol Chem. 2004 Apr 23;279(17):17905-13
references: 14960572
references: Curr Opin Immunol. 2006 Apr;18(2):127-34
references: 16464566
references: Immunity. 2007 Jun;26(6):715-25
references: 17582344
references: J Immunol. 2008 Feb 1;180(3):1719-28
references: 18209069
references: Genes Chromosomes Cancer. 2001 Dec;32(4):353-63
references: 11746976
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9414-8
references: 19470474
references: Mol Cell Biol. 2007 Jan;27(2):579-94
references: 17101802
references: Immunity. 1999 Jul;11(1):21-31
references: 10435576
references: J Immunol. 2003 Dec 1;171(11):5853-64
references: 14634095
references: J Immunol. 2009 May 15;182(10):6079-87
references: 19414759
references: Leukemia. 2007 Jun;21(6):1258-66
references: 17443227
references: Cell. 1994 Dec 2;79(5):901-12
references: 8001127
references: Nat Immunol. 2008 Aug;9(8):927-36
references: 18568028
references: N Engl J Med. 2009 Jan 29;360(5):470-80
references: 19129520
references: Immunity. 2010 May 28;32(5):714-25
references: 20451411
references: EMBO Mol Med. 2010 Mar;2(3):98-110
references: 20201032
references: Cell. 1985 Dec;43(2 Pt 1):393-404
references: 2416464
references: J Biol Chem. 1996 Dec 6;271(49):31704-10
references: 8940193
references: Nat Immunol. 2008 Feb;9(2):203-15
references: 18176567
references: Oncogene. 2000 Aug 3;19(33):3739-49
references: 10949928
references: Mol Cell. 2000 Sep;6(3):693-704
references: 11030348