title: Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia.
abstract: Notch signaling is a key developmental pathway that is subject to frequent genetic and epigenetic perturbations in many different human tumors. Here we investigate whether long noncoding RNA (lncRNA) genes, in addition to mRNAs, are key downstream targets of oncogenic Notch1 in human T cell acute lymphoblastic leukemia (T-ALL). By integrating transcriptome profiles with chromatin state maps, we have uncovered many previously unreported T-ALL-specific lncRNA genes, a fraction of which are directly controlled by the Notch1/Rpbjκ activator complex. Finally we have shown that one specific Notch-regulated lncRNA, LUNAR1, is required for efficient T-ALL growth in vitro and in vivo due to its ability to enhance IGF1R mRNA expression and sustain IGF1 signaling. These results confirm that lncRNAs are important downstream targets of the Notch signaling pathway, and additionally they are key regulators of the oncogenic state in T-ALL.
authors.affiliation: Howard Hughes Medical Institute, Laura and Isaac Perlmutter Cancer Center, and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, NY 10598, USA.
authors.forename: Erhan
authors.initials: E
authors.lastname: Bilal
authors.affiliation: Howard Hughes Medical Institute, Laura and Isaac Perlmutter Cancer Center, and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ntziachristos
authors.affiliation: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fabbri
authors.affiliation: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.affiliation: Department of Pathology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA; Center for Health Informatics and Bioinformatics, NYU School of Medicine, 227 East 30(th) Street, New York, NY 10016, USA. Electronic address: aristotelis.tsirigos@nyumc.org.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.affiliation: Howard Hughes Medical Institute, Laura and Isaac Perlmutter Cancer Center, and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address: iannis.aifantis@nyumc.org.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D055106:Genome-Wide Association Study; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D062085:RNA, Long Noncoding / Q000032:analysis* / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D013950:Thymus Gland / Q000473:pathology
chemical_list: C497761:NOTCH1 protein, human; D062085:RNA, Long Noncoding; D051881:Receptor, Notch1
references.citation: Science. 2009 Oct 9;326(5950):289-93
references.pmid: 19815776
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2876-81
references.pmid: 23382218
references.citation: Cell. 2013 Feb 14;152(4):743-54
references.pmid: 23415224
references.citation: Cell. 2013 Feb 14;152(4):727-42
references.pmid: 23415223
references.citation: Cell. 2013 Jan 31;152(3):570-83
references.pmid: 23352431
references.citation: Mol Cell. 2011 Nov 18;44(4):667-78
references.pmid: 21963238
references.citation: Nature. 2013 Jul 18;499(7458):360-3
references.pmid: 23792564
references.citation: Nucleic Acids Res. 2009 Oct;37(18):e123
references.pmid: 19620212
references.citation: Genes Dev. 2011 Sep 15;25(18):1915-27
references.pmid: 21890647
references.citation: Nature. 2013 Jan 10;493(7431):231-5
references.pmid: 23201690
references.citation: Science. 2004 Oct 8;306(5694):269-71
references.pmid: 15472075
references.citation: Science. 2013 Aug 16;341(6147):1237973
references.pmid: 23828888
references.citation: Cell. 2013 Jul 3;154(1):26-46
references.pmid: 23827673
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14908-13
references.pmid: 21737748
references.citation: Leukemia. 2011 Jun;25(6):1042-6
references.pmid: 21383747
references.citation: Science. 2005 Sep 2;309(5740):1564-6
references.pmid: 16141073
references.citation: J Exp Med. 2011 Aug 29;208(9):1809-22
references.pmid: 21807868
references.citation: PLoS Genet. 2013 Apr;9(4):e1003373
references.pmid: 23593011
references.citation: Nat Biotechnol. 2010 May;28(5):511-5
references.pmid: 20436464
references.citation: Science. 2012 Dec 14;338(6113):1435-9
references.pmid: 23239728
references.citation: Dev Cell. 2013 Jan 28;24(2):206-14
references.pmid: 23369715
references.citation: Cell. 2010 Aug 6;142(3):409-19
references.pmid: 20673990
references.citation: Leukemia. 2006 Jul;20(7):1279-87
references.pmid: 16688224
references.citation: Cell. 2010 Oct 1;143(1):46-58
references.pmid: 20887892
references.citation: Cell. 2011 Nov 11;147(4):773-88
references.pmid: 22078878
references.citation: J Exp Med. 2011 Jul 4;208(7):1389-401
references.pmid: 21670202
references.citation: Nature. 2013 Aug 29;500(7464):598-602
references.pmid: 23945587
references.citation: Bioinformatics. 2011 Jul 1;27(13):i275-82
references.pmid: 21685081
references.citation: Nat Genet. 2010 Dec;42(12):1113-7
references.pmid: 21057500
references.citation: Nature. 2012 Sep 6;489(7414):101-8
references.pmid: 22955620
references.citation: Science. 2005 Sep 2;309(5740):1559-63
references.pmid: 16141072
references.citation: Nat Biotechnol. 2011 Jul 31;29(8):742-9
references.pmid: 21804560
references.citation: Cell. 2007 Jun 29;129(7):1311-23
references.pmid: 17604720
references.citation: Nature. 2010 Apr 15;464(7291):1071-6
references.pmid: 20393566
references.citation: Cell. 2009 Apr 17;137(2):216-33
references.pmid: 19379690
references.citation: Nature. 2011 Apr 7;472(7341):120-4
references.pmid: 21423168
references.citation: Nature. 2013 Feb 28;494(7438):497-501
references.pmid: 23417068
references.citation: Blood. 2012 Oct 18;120(16):3288-97
references.pmid: 22936659
references.citation: Nat Struct Mol Biol. 2013 Jul;20(7):908-13
references.pmid: 23728290
references.citation: Nat Genet. 2013 Feb;45(2):186-90
references.pmid: 23263491
references.citation: Cell. 2013 Apr 11;153(2):307-19
references.pmid: 23582322
references.citation: Nat Genet. 2011 Jun 05;43(7):621-9
references.pmid: 21642992
references.citation: Nature. 2011 Feb 10;470(7333):279-83
references.pmid: 21160473
references.citation: Bioinformatics. 2009 May 1;25(9):1105-11
references.pmid: 19289445
references.citation: Cancer Cell. 2002 Feb;1(1):75-87
references.pmid: 12086890
references.citation: Cell. 2013 Jun 20;153(7):1552-66
references.pmid: 23791182
references.citation: Annu Rev Biochem. 2012;81:145-66
references.pmid: 22663078
references.citation: Clin Adv Hematol Oncol. 2004 Dec;2(12):779-80
references.pmid: 16166953
references.citation: Genome Res. 2012 Sep;22(9):1760-74
references.pmid: 22955987
references.citation: Nature. 2009 May 7;459(7243):108-12
references.pmid: 19295514
references.citation: Nat Med. 2012 Feb 06;18(2):298-301
references.pmid: 22237151
references.citation: PLoS Biol. 2011 Jul;9(7):e1000625; discussion e1001102
references.pmid: 21765801
references.citation: Science. 2010 Aug 6;329(5992):689-93
references.pmid: 20616235
references.citation: Hematology Am Soc Hematol Educ Program. 2009;:353-61
references.pmid: 20008221
references.citation: PLoS Genet. 2012;8(8):e1002855
references.pmid: 22916024
references.citation: Nature. 2012 Apr 11;485(7398):376-80
references.pmid: 22495300
references.citation: Nat Genet. 2013 Nov;45(11):1392-8
references.pmid: 24076601
references.citation: Nature. 2009 Mar 12;458(7235):223-7
references.pmid: 19182780
references.citation: J Exp Med. 2011 Apr 11;208(4):663-75
references.pmid: 21464222
references.citation: Science. 2008 Dec 19;322(5909):1849-51
references.pmid: 19056940
references.citation: Hum Mol Genet. 2001 Oct 1;10(20):2225-32
references.pmid: 11673405
references.citation: Mol Cell. 2004 Oct 8;16(1):93-105
references.pmid: 15469825
references.citation: Cell. 2013 Jul 3;154(1):240-51
references.pmid: 23810193
references.citation: Nat Protoc. 2007;2(7):1722-33
references.pmid: 17641637
references.citation: Nature. 2013 Jun 27;498(7455):516-20
references.pmid: 23728302
references.citation: Nature. 2011 Aug 28;477(7364):295-300
references.pmid: 21874018
references.citation: Elife. 2014 Feb 12;3:e02046
references.pmid: 24521543
references.citation: Nature. 2012 Jan 11;481(7380):157-63
references.pmid: 22237106