HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
06 04 2023
06 04 2023
Historique:
accepted:
28
11
2022
received:
06
04
2022
pmc-release:
06
04
2024
medline:
10
4
2023
pubmed:
29
12
2022
entrez:
28
12
2022
Statut:
ppublish
Résumé
HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.
Identifiants
pubmed: 36577137
pii: S0006-4971(22)08494-4
doi: 10.1182/blood.2022016528
pmc: PMC10113176
doi:
Substances chimiques
Homeodomain Proteins
0
Transcription Factors
0
Nuclear Matrix-Associated Proteins
0
Chromatin
0
SAFB protein, human
0
Receptors, Estrogen
0
Matrix Attachment Region Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1737-1754Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R009708/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023 by The American Society of Hematology.
Références
Leukemia. 2008 Nov;22(11):2041-7
pubmed: 18668134
Nature. 2017 Jul 13;547(7662):236-240
pubmed: 28636604
J Exp Med. 2013 Feb 11;210(2):301-19
pubmed: 23359070
EMBO J. 1988 Nov;7(11):3337-44
pubmed: 3208739
Mol Cell Biol. 2005 Apr;25(8):2995-3006
pubmed: 15798188
Blood. 2018 Aug 23;132(8):837-848
pubmed: 29760161
Cancer Cell. 2017 Apr 10;31(4):549-562.e11
pubmed: 28399410
Hum Genet. 1989 Dec;84(1):6-10
pubmed: 2558068
Anticancer Res. 2017 Feb;37(2):693-698
pubmed: 28179318
J Clin Invest. 2007 Sep;117(9):2611-20
pubmed: 17694175
Biochemistry. 1996 Aug 27;35(34):11160-9
pubmed: 8780520
Oncogene. 2000 Feb 3;19(5):608-16
pubmed: 10698505
Leukemia. 2012 Apr;26(4):662-74
pubmed: 21979880
Nat Commun. 2019 Jan 4;10(1):46
pubmed: 30610188
J Biol Chem. 2001 Jan 5;276(1):850-5
pubmed: 11042172
Biochem J. 2016 Dec 1;473(23):4271-4288
pubmed: 27888239
J Korean Med Sci. 2013 Feb;28(2):237-46
pubmed: 23400519
Oncogene. 2016 Mar 3;35(9):1090-8
pubmed: 26028034
EMBO J. 1998 Jul 1;17(13):3714-25
pubmed: 9649441
BMB Rep. 2009 Apr 30;42(4):232-7
pubmed: 19403048
J Cell Biochem. 2010 Feb 1;109(2):312-9
pubmed: 20014070
Genes Dev. 2014 Feb 15;28(4):317-27
pubmed: 24532712
Nucleic Acids Res. 2003 Jan 1;31(1):258-61
pubmed: 12519996
Nature. 2017 Jul 13;547(7662):241-245
pubmed: 28636597
Blood. 2011 Jun 2;117(22):5918-30
pubmed: 21471525
Blood. 2012 Jan 12;119(2):388-98
pubmed: 22072553
EMBO J. 2013 Apr 3;32(7):982-95
pubmed: 23455154
Cell Stem Cell. 2011 Jun 3;8(6):649-62
pubmed: 21624810
BMC Bioinformatics. 2017 May 31;18(1):287
pubmed: 28569135
Cancer Cell. 2021 Feb 8;39(2):174-192
pubmed: 33417833
Nature. 2019 Nov;575(7782):390-394
pubmed: 31618757
Mol Cell. 2020 Jan 16;77(2):368-383.e7
pubmed: 31677973
Cell Rep. 2016 Oct 18;17(4):1193-1205
pubmed: 27760321
Cancer Cell. 2018 Oct 8;34(4):643-658.e5
pubmed: 30270123
Cancer Res. 1990 Jun 1;50(11):3199-206
pubmed: 2185883
Cell. 2017 Feb 23;168(5):890-903.e15
pubmed: 28162770
Cancer Discov. 2018 May;8(5):616-631
pubmed: 29496663
Gene Ther Mol Biol. 2009;13(1):231-243
pubmed: 20948980
J Cell Biochem. 1997 Nov 1;67(2):275-86
pubmed: 9328833
J Cell Biochem. 1993 May;52(1):14-22
pubmed: 8320271
Nucleic Acids Res. 2019 Aug 22;47(14):7247-7261
pubmed: 31265077
Future Oncol. 2014 Feb;10(3):475-95
pubmed: 24559452
Oncogene. 2020 Dec;39(50):7239-7252
pubmed: 33037410
N Engl J Med. 2016 Jun 9;374(23):2209-2221
pubmed: 27276561
Blood. 2014 Apr 17;123(16):2451-9
pubmed: 24608975
Nat Protoc. 2016 Feb;11(2):316-26
pubmed: 26797456
N Engl J Med. 2015 Sep 17;373(12):1136-52
pubmed: 26376137
Blood. 2009 Mar 12;113(11):2375-85
pubmed: 19056693
Genes Chromosomes Cancer. 2003 Jun;37(2):149-58
pubmed: 12696063
Science. 1999 Oct 15;286(5439):531-7
pubmed: 10521349
Elife. 2019 Jun 24;8:
pubmed: 31232687
Genome Res. 2002 Aug;12(8):1231-45
pubmed: 12176931
Blood Cancer J. 2015 May 15;5:e313
pubmed: 25978433