Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9.

Animals HEK293 Cells HL-60 Cells HeLa Cells Homeodomain Proteins / genetics Humans Intracellular Signaling Peptides and Proteins / genetics Leukemia, Myeloid, Acute / genetics Mice Myeloid-Lymphoid Leukemia Protein / genetics Neoplasm Transplantation Neoplastic Stem Cells / metabolism Oncogene Proteins, Fusion / genetics Receptors, G-Protein-Coupled / genetics Small Molecule Libraries / pharmacology THP-1 Cells Transcription Factor 7-Like 2 Protein / metabolism Wnt Signaling Pathway / drug effects

Journal

EBioMedicine

ISSN: 2352-3964

Titre abrégé: EBioMedicine

Pays: Netherlands

ID NLM: 101647039

Informations de publication

Date de publication:
Jan 2019

Historique:

received: 12 10 2018

revised: 16 11 2018

accepted: 16 11 2018

pubmed: 12 12 2018

medline: 14 6 2019

entrez: 12 12 2018

Statut: ppublish

Résumé

Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/β-catenin signaling has previously been shown to support MLL-AF9-driven leukemogenesis, the mechanism underlying this relationship remains unclear. We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs). We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/β-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML. By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/β-catenin-dependent growth of LICs. Small molecules disrupting WNT/β-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs).

FINDINGS RESULTS

We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/β-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML.

INTERPRETATION CONCLUSIONS

By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/β-catenin-dependent growth of LICs. Small molecules disrupting WNT/β-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.

Identifiants

DOI: 10.1016/j.ebiom.2018.11.039 PMID: 30528456 PMC: PMC6354558

pubmed: 30528456

pii: S2352-3964(18)30544-9

doi: 10.1016/j.ebiom.2018.11.039

pmc: PMC6354558

pii:

doi:

Substances chimiques

Homeodomain Proteins 0

Intracellular Signaling Peptides and Proteins 0

MLL-AF9 fusion protein, human 0

Oncogene Proteins, Fusion 0

Receptors, G-Protein-Coupled 0

SIX1 protein, human 0

Small Molecule Libraries 0

TCF7L2 protein, human 0

Transcription Factor 7-Like 2 Protein 0

WLS protein, human 0

Myeloid-Lymphoid Leukemia Protein 149025-06-9

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

145-158

Subventions

Organisme : NCI NIH HHS

ID : R01 CA168761

Pays : United States

Informations de copyright

Références

Genes Dev. 2000 Sep 15;14(18):2265-70

pubmed: 10995383

Bioinformatics. 2002 Feb;18(2):333-4

pubmed: 11847087

J Biol Chem. 2002 May 3;277(18):15393-9

pubmed: 11856745

Nucleic Acids Res. 2003 Jul 1;31(13):3651-3

pubmed: 12824386

Nature. 2003 Nov 20;426(6964):247-54

pubmed: 14628042

J Exp Med. 2004 Jan 19;199(2):221-9

pubmed: 14718516

Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6478-83

pubmed: 15123840

Blood. 2005 Apr 1;105(7):2724-32

pubmed: 15598809

Cell. 2005 Jan 28;120(2):223-35

pubmed: 15680328

Nature. 2006 Aug 17;442(7104):818-22

pubmed: 16862118

Am J Med Genet A. 2007 Jul 15;143A(14):1671-8

pubmed: 17238186

Nature. 2008 Jul 17;454(7202):345-9

pubmed: 18528331

Cancer Cell. 2008 Jun;13(6):483-95

pubmed: 18538732

Adv Cancer Res. 2008;101:93-126

pubmed: 19055944

Nat Chem Biol. 2009 Feb;5(2):100-7

pubmed: 19125156

Cell. 2009 Jul 10;138(1):51-62

pubmed: 19576624

Nature. 2009 Oct 1;461(7264):614-20

pubmed: 19759537

Science. 2010 Mar 26;327(5973):1650-3

pubmed: 20339075

Dev Dyn. 2010 Jun;239(6):1708-22

pubmed: 20503367

Genesis. 2010 Sep;48(9):554-8

pubmed: 20614471

Annu Rev Pharmacol Toxicol. 2011;51:289-310

pubmed: 20887197

Cancer Cell. 2010 Dec 14;18(6):606-18

pubmed: 21156284

Cancer Res. 2010 Dec 15;70(24):10234-42

pubmed: 21159644

Cell. 2011 Mar 4;144(5):646-74

pubmed: 21376230

Blood. 2011 May 5;117(18):4759-68

pubmed: 21398221

Blood. 2011 Jun 23;117(25):6895-905

pubmed: 21518926

Blood. 2011 Jun 23;117(25):6912-22

pubmed: 21521783

Cell. 2011 Jun 10;145(6):926-40

pubmed: 21663795

Cancer Cell. 2011 Jul 12;20(1):66-78

pubmed: 21741597

Blood. 2011 Sep 8;118(10):2849-56

pubmed: 21765021

Annu Rev Pathol. 2012;7:283-301

pubmed: 22017583

Cancer Res. 2012 Jun 1;72(11):2822-32

pubmed: 22440753

Cell Stem Cell. 2012 Apr 6;10(4):412-24

pubmed: 22482506

J Biol Chem. 2012 Jun 29;287(27):23246-54

pubmed: 22593577

Differentiation. 2012 Sep;84(2):203-13

pubmed: 22784633

Pediatr Nephrol. 2013 Jun;28(6):843-54

pubmed: 22806561

J Cell Biol. 2012 Sep 3;198(5):815-32

pubmed: 22945933

J Med Chem. 2013 Mar 28;56(6):2700-4

pubmed: 23477365

Curr Opin Genet Dev. 2013 Aug;23(4):385-90

pubmed: 23540564

N Engl J Med. 2013 May 30;368(22):2059-74

pubmed: 23634996

Blood. 2014 Feb 13;123(7):992-1001

pubmed: 24385538

Blood. 2014 Mar 20;123(12):1870-82

pubmed: 24501218

J Biol Chem. 2014 Jun 6;289(23):16349-61

pubmed: 24755226

Curr Protoc Mol Biol. 2015 Jan 05;109:21.29.1-9

pubmed: 25559105

Nat Cell Biol. 2015 May;17(5):665-77

pubmed: 25915125

Cell Rep. 2015 May 5;11(5):808-20

pubmed: 25921540

Blood. 2015 Aug 27;126(9):1086-94

pubmed: 26089398

Curr Med Chem. 2015;22(35):4091-103

pubmed: 26310918

Nature. 2015 Sep 24;525(7570):538-42

pubmed: 26367796

Nature. 2015 Sep 24;525(7570):543-547

pubmed: 26367798

Oncotarget. 2015 Nov 24;6(37):40112-26

pubmed: 26473286

Genes Dev. 2015 Oct 15;29(20):2123-39

pubmed: 26494788

Nucleic Acids Res. 2016 Jan 4;44(D1):D917-24

pubmed: 26507857

Nat Rev Mol Cell Biol. 2016 Mar;17(3):183-93

pubmed: 26883003

Cancer Cell. 2016 Apr 11;29(4):464-476

pubmed: 27070701

Cancer Cell. 2016 Jul 11;30(1):43-58

pubmed: 27344946

Arthritis Res Ther. 2016 Jul 13;18:162

pubmed: 27412348

Nat Rev Genet. 2016 Sep 15;17(10):630-41

pubmed: 27629931

Genes Dev. 2016 Sep 15;30(18):2021-2041

pubmed: 27798847

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1649-1654

pubmed: 28143939

Cell. 2017 Jun 1;169(6):985-999

pubmed: 28575679

Cell. 2017 Aug 24;170(5):1028-1043.e19

pubmed: 28841410

Nat Cell Biol. 2017 Oct;19(10):1226-1236

pubmed: 28945232

Annu Rev Pharmacol Toxicol. 2018 Jan 6;58:187-207

pubmed: 28992434

Nat Med. 2018 Jan;24(1):103-112

pubmed: 29227476

Nat Biotechnol. 2018 Nov 9;36(11):1028-1029

pubmed: 30412206

Leukemia. 1998 May;12(5):792-800

pubmed: 9593283

Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12608-13

pubmed: 9770533