Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia.
IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B-cell phenotype that underlies high-risk B-ALL.
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
Yeguang
Y
Hu
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
Zhihong
Z
Zhang
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
Mariko
M
Kashiwagi
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
Toshimi
T
Yoshida
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
Ila
I
Joshi
Department of Medicine, Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California 92868, USA; Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California 92868, USA;
Nilamani
N
Jena
Department for Clinical and Experimental Medicine, Linkoping University, 58185 Linkoping, Sweden;
Rajesh
R
Somasundaram
Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA;
Akinola Olumide
AO
Emmanuel
Department for Clinical and Experimental Medicine, Linkoping University, 58185 Linkoping, Sweden;
Mikael
M
Sigvardsson
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Julien
J
Fitamant
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nabeel
N
El-Bardeesy
Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA;
Fotini
F
Gounari
Department of Medicine, Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California 92868, USA; Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, California 92868, USA;
Richard A
RA
Van Etten
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
Katia
K
Georgopoulos
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology* / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000503:physiopathology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D063146:Polycomb-Group Proteins; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor
LHX2; PRC2; TEAD; YAP1; self-renewal
Cell. 2013 Nov 7;155(4):934-47
24119843
Genes Dev. 2011 Aug 1;25(15):1583-8
21828268
Science. 2006 Jun 30;312(5782):1946-9
16809539
Leukemia. 2010 Jul;24(7):1258-64
20445578
Nat Rev Genet. 2010 Nov;11(11):761-72
20940737
Immunity. 2007 Jun;26(6):715-25
17582344
J Exp Med. 2004 Jan 19;199(2):209-19
14718515
Nat Immunol. 2010 Jul;11(7):635-43
20543837
Mol Cell. 2015 Apr 16;58(2):362-70
25801169
Curr Opin Immunol. 2010 Apr;22(2):148-53
20207528
Nat Rev Immunol. 2013 Aug;13(8):578-91
23883968
Immunity. 1999 Mar;10(3):345-55
10204490
Cell. 2015 Nov 5;163(4):811-28
26544935
Nature. 1995 Nov 16;378(6554):303-6
7477353
Nat Immunol. 2014 Mar;15(3):294-304
24509510
Nat Rev Genet. 2011 Jan;12(1):7-18
21116306
Science. 1999 Dec 3;286(5446):1954-7
10583958
Cancer Cell. 2015 Sep 14;28(3):343-56
26321221
Bioinformatics. 2013 Jan 1;29(1):15-21
23104886
Immunity. 2009 Apr 17;30(4):493-507
19345118
Science. 1996 Apr 19;272(5260):411-4
8602530
Open Biol. 2015 Jun;5(6):150062
26108219
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
21106759
Cell. 2013 Apr 11;153(2):307-19
23582322
Annu Rev Immunol. 2001;19:595-621
11244048
J Biol Chem. 2013 Dec 13;288(50):35925-39
24174531
Mol Cell. 2011 May 6;42(3):330-41
21549310
Nat Rev Immunol. 2009 Mar;9(3):195-205
19240758
Nat Immunol. 2014 Mar;15(3):283-93
24509509
Mol Cell. 2010 May 28;38(4):576-89
20513432
Curr Opin Genet Dev. 2003 Oct;13(5):522-8
14550419
Blood. 2001 Jan 1;97(1):4-13
11133737
J Neurosci. 2014 Dec 10;34(50):16809-20
25505333
Bioessays. 2009 Jun;31(6):600-9
19444834
J Clin Oncol. 2009 Nov 1;27(31):5202-7
19770381
Genome Biol. 2008;9(9):R137
18798982
Science. 2014 Jan 17;343(6168):301-5
24292625
Nat Immunol. 2015 Jul;16(7):775-84
25985234
Nat Commun. 2015 Nov 09;6:8823
26549758
Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):E297-302
25564661
Curr Opin Immunol. 2010 Apr;22(2):154-60
20299195
Nat Immunol. 2006 Apr;7(4):382-91
16518393
Dev Cell. 2014 Jan 13;28(1):94-101
24374176
Lancet. 2013 Jun 1;381(9881):1943-55
23523389
Curr Opin Immunol. 2007 Apr;19(2):116-22
17307348
Nat Immunol. 2011 Nov 13;13(1):86-94
22080921
Nature. 2012 Oct 25;490(7421):543-6
22992523
PLoS Biol. 2010 May 11;8(5):e1000384
20485488
Science. 2014 Jan 17;343(6168):305-9
24292623
Nature. 2009 May 7;459(7243):108-12
19295514
Nat Immunol. 2008 Dec;9(12 ):1388-98
18978794
J Immunol Methods. 2009 Aug 15;347(1-2):70-8
19567251
Nature. 2015 May 21;521(7552):366-70
25799994
J Exp Med. 2013 Dec 16;210(13):2823-32
24297995
N Engl J Med. 2009 Jan 29;360(5):470-80
19129520
Curr Opin Immunol. 2010 Apr;22(2):161-7
20144854
Bioinformatics. 2009 Jul 15;25(14):1754-60
19451168
Cell. 2014 Apr 24;157(3):549-64
24766805
J Clin Invest. 2012 Oct;122(10):3407-15
23023711
Cancer Cell. 2012 Aug 14;22(2):153-66
22897847
BMC Genomics. 2014 Apr 15;15:284
24735413
Nature. 2007 Apr 12;446(7137):758-64
17344859
Science. 1999 Dec 3;286(5446):1949-54
10583957
Nat Immunol. 2006 May;7(5):489-97
16582912