Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.
Animals
Antineoplastic Agents
/ pharmacology
Bone Marrow
/ pathology
CRISPR-Cas Systems
/ genetics
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Epigenesis, Genetic
/ drug effects
Female
Gene Expression Regulation, Leukemic
/ drug effects
HEK293 Cells
Humans
Kaplan-Meier Estimate
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Mice, Inbred C57BL
Sequence Analysis, RNA
Single-Cell Analysis
Trans-Activators
/ antagonists & inhibitors
Transcription, Genetic
/ drug effects
Treatment Outcome
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 06 2019
20 06 2019
Historique:
received:
13
03
2019
accepted:
21
05
2019
entrez:
22
6
2019
pubmed:
22
6
2019
medline:
10
7
2019
Statut:
epublish
Résumé
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.
Identifiants
pubmed: 31222014
doi: 10.1038/s41467-019-10652-9
pii: 10.1038/s41467-019-10652-9
pmc: PMC6586637
doi:
Substances chimiques
Antineoplastic Agents
0
Trans-Activators
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2723Subventions
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1106444
Pays : International
Organisme : Howard Hughes Medical Institute (HHMI)
ID : 55008729
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1085015
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1128984
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA174793
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA013106
Pays : United States
Références
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Nature. 2015 Sep 24;525(7570):543-547
pubmed: 26367798
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Nat Med. 2015 Oct;21(10):1172-81
pubmed: 26343801
Br J Cancer. 2015 Apr 14;112(8):1411-20
pubmed: 25742471
Nature. 2017 Nov 9;551(7679):247-250
pubmed: 29088702
Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74
pubmed: 21949397
Cancer Sci. 2015 Mar;106(3):227-36
pubmed: 25529853
Genome Biol. 2016 Apr 28;17:77
pubmed: 27121950
Cancer Cell. 2018 Dec 10;34(6):939-953.e9
pubmed: 30472020
Nature. 2012 Jan 11;481(7382):506-10
pubmed: 22237025
Blood. 2017 Mar 23;129(12):1685-1690
pubmed: 28126926
Nat Methods. 2007 Oct;4(10):847-9
pubmed: 17828270
Nat Struct Mol Biol. 2016 Jul;23(7):673-81
pubmed: 27294782
Bioinformatics. 2011 Jun 15;27(12):1696-7
pubmed: 21486936
Blood. 2018 Apr 12;131(15):1730-1742
pubmed: 29453291
Cell. 2010 Apr 2;141(1):69-80
pubmed: 20371346
Blood. 2017 Mar 23;129(12):1577-1585
pubmed: 28159741
Stem Cell Reports. 2016 Sep 13;7(3):571-582
pubmed: 27499199
Nat Med. 2016 Jul;22(7):792-9
pubmed: 27322744
Bioinformatics. 2010 Mar 1;26(5):589-95
pubmed: 20080505
Cancer Cell. 2012 Apr 17;21(4):473-87
pubmed: 22464800
Br J Haematol. 2016 Nov;175(3):476-489
pubmed: 27470916
Cancer Cell. 2010 Feb 17;17(2):186-97
pubmed: 20159610
Nature. 2017 Jul 6;547(7661):104-108
pubmed: 28658204
Nature. 2011 Oct 02;478(7370):529-33
pubmed: 21964340
Mol Cell. 2013 Mar 7;49(5):825-37
pubmed: 23473601
Nat Genet. 2018 Feb;50(2):250-258
pubmed: 29358654
BMC Bioinformatics. 2016 Apr 02;17:151
pubmed: 27038897
Nat Commun. 2014 Dec 02;5:5694
pubmed: 25452114
Clin Cancer Res. 2014 Apr 1;20(7):1965-77
pubmed: 24463458
Nat Genet. 2014 Apr;46(4):364-70
pubmed: 24584072
BMC Genomics. 2014 Apr 15;15:284
pubmed: 24735413
Science. 2017 Mar 17;355(6330):1147-1152
pubmed: 28302822
Cancer Res. 2014 Jul 1;74(13):3579-90
pubmed: 24812274
Nature. 2011 Aug 03;478(7370):524-8
pubmed: 21814200
Curr Protoc Mol Biol. 2015 Jan 05;109:21.29.1-21.29.9
pubmed: 25559105
Cytometry A. 2016 Jun;89(6):594-600
pubmed: 27144818
Cell. 2018 May 3;173(4):879-893.e13
pubmed: 29681456
Cancer Cell. 2015 Jul 13;28(1):57-69
pubmed: 26175415
Cell Stem Cell. 2009 Feb 6;4(2):129-40
pubmed: 19200802
Nature. 2017 Oct 12;550(7675):270-274
pubmed: 28976960
Leukemia. 2014 Feb;28(2):311-20
pubmed: 24220271
Blood. 2015 Nov 26;126(22):2491-501
pubmed: 26438511
Cell Stem Cell. 2018 Aug 02;23(2):226-238.e4
pubmed: 30017589
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Rev Genet. 2010 Apr;11(4):285-96
pubmed: 20300089
Nat Rev Cancer. 2013 Oct;13(10):714-26
pubmed: 24060863
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Rev Genet. 2012 Sep;13(9):613-26
pubmed: 22868264
Bioinformatics. 2017 Apr 15;33(8):1179-1186
pubmed: 28088763
Immunity. 2010 Mar 26;32(3):317-28
pubmed: 20206554
Cell. 2015 Sep 10;162(6):1271-85
pubmed: 26359985
Nat Commun. 2018 Aug 24;9(1):3440
pubmed: 30143629
Cell. 2018 Aug 9;174(4):843-855.e19
pubmed: 30017245
Cancer Cell. 2011 Jan 18;19(1):138-52
pubmed: 21251617
Genome Biol. 2016 Apr 27;17:75
pubmed: 27122128
Blood. 2017 Sep 14;130(11):1377-1380
pubmed: 28667012
Nat Biotechnol. 2014 Apr;32(4):381-386
pubmed: 24658644
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Nat Med. 2016 Mar;22(3):262-9
pubmed: 26828195
Cell. 2013 Dec 19;155(7):1507-20
pubmed: 24360274
Nature. 2015 Sep 24;525(7570):538-42
pubmed: 26367796
Science. 2017 Jun 30;356(6345):1397-1401
pubmed: 28619718
Blood. 2003 Jan 1;101(1):270-7
pubmed: 12393465
Nat Methods. 2015 Apr;12(4):357-60
pubmed: 25751142
Cell Stem Cell. 2017 Feb 2;20(2):233-246.e7
pubmed: 27989769
Cancer Cell. 2018 Dec 10;34(6):922-938.e7
pubmed: 30537514
Mol Cell. 2016 Jun 2;62(5):665-7
pubmed: 27259199
Lancet Haematol. 2016 Apr;3(4):e186-95
pubmed: 27063977
Nature. 2016 Dec 15;540(7633):433-437
pubmed: 27926740
Nat Biotechnol. 2015 Jun;33(6):661-7
pubmed: 25961408
PLoS Comput Biol. 2018 Aug 10;14(8):e1006361
pubmed: 30096152
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Nature. 2017 Jun 15;546(7658):431-435
pubmed: 28607484