The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
03 02 2022
03 02 2022
Historique:
received:
27
04
2021
accepted:
03
09
2021
pubmed:
28
9
2021
medline:
8
3
2022
entrez:
27
9
2021
Statut:
ppublish
Résumé
Given the plasticity of hematopoietic stem and progenitor cells, multiple routes of differentiation must be blocked in the the pathogenesis of acute myeloid leukemia, the molecular basis of which is incompletely understood. We report that posttranscriptional repression of the transcription factor ARID3A by miR-125b is a key event in the pathogenesis of acute megakaryoblastic leukemia (AMKL). AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing the disease. The results of our study showed that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncovered Arid3a as the main miR-125b target behind this synergy. We demonstrated that, during normal hematopoiesis, this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFβ-induced apoptosis and cell cycle arrest in complex with SMAD2/3. Although Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a blockade of dual megakaryocytic/erythroid differentiation and subsequently of AMKL. Inversely, restoring ARID3A expression relieves the arrest of megakaryocytic differentiation in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of posttranscriptional gene regulation can interact to block multiple routes of hematopoietic differentiation and cause leukemia. In AMKL, surmounting this differentiation blockade through restoration of the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease.
Identifiants
pubmed: 34570885
pii: S0006-4971(21)01649-9
doi: 10.1182/blood.2021012231
pmc: PMC9632760
doi:
Substances chimiques
ARID3A protein, human
0
DNA-Binding Proteins
0
GATA1 Transcription Factor
0
GATA1 protein, human
0
MIRN125 microRNA, human
0
MicroRNAs
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
651-665Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 by The American Society of Hematology.
Références
Blood. 2001 Dec 1;98(12):3261-73
pubmed: 11719363
J Clin Invest. 1985 Sep;76(3):1102-6
pubmed: 2413071
Clin Sci (Lond). 2012 Jun;122(12):555-73
pubmed: 22390198
Cancer Cell. 2019 Aug 12;36(2):123-138.e10
pubmed: 31303423
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
J Clin Oncol. 2018 Apr 1;36(10):1007-1016
pubmed: 29432078
Nat Med. 2014 Nov;20(11):1321-6
pubmed: 25326798
Database (Oxford). 2016 Jul 03;2016:
pubmed: 27374120
Dev Biol. 2005 Feb 15;278(2):542-59
pubmed: 15680369
Nat Methods. 2013 Oct;10(10):977-9
pubmed: 23892898
Int J Oncol. 2015 Feb;46(2):459-64
pubmed: 25405282
Blood. 2009 Mar 19;113(12):2826-34
pubmed: 19136660
Genes Dev. 2010 Mar 1;24(5):478-90
pubmed: 20194440
Br J Haematol. 2009 Oct;147(1):3-12
pubmed: 19594743
Blood. 1992 Feb 1;79(3):619-26
pubmed: 1732007
Cell Physiol Biochem. 2009;23(4-6):347-58
pubmed: 19471102
Nat Commun. 2017 Aug 9;8(1):218
pubmed: 28794406
Nat Biotechnol. 2014 Apr;32(4):364-72
pubmed: 24633240
Nat Genet. 2013 Nov;45(11):1293-9
pubmed: 24056718
Elife. 2017 Jan 16;6:
pubmed: 28079019
Nat Genet. 2005 Jun;37(6):613-9
pubmed: 15895080
Nat Rev Cancer. 2005 Jan;5(1):11-20
pubmed: 15630411
Cancer Discov. 2019 Dec;9(12):1736-1753
pubmed: 31662298
Epigenetics Chromatin. 2019 Jul 12;12(1):42
pubmed: 31300027
Haematologica. 2014 Oct;99(10):1555-64
pubmed: 25107888
Nat Rev Mol Cell Biol. 2013 Nov;14(11):727-36
pubmed: 24129419
Genes Dev. 2019 Nov 1;33(21-22):1506-1524
pubmed: 31582430
Leukemia. 2010 Jan;24(1):89-96
pubmed: 19890372
Genes Dev. 2014 Oct 15;28(20):2219-32
pubmed: 25319825
Blood. 2010 Apr 1;115(13):2649-56
pubmed: 20118404
Haematologica. 2015 May;100(5):575-84
pubmed: 25682601
Cell Rep. 2016 May 10;15(6):1228-41
pubmed: 27134169
Science. 2000 May 12;288(5468):1053-8
pubmed: 10807576
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21558-63
pubmed: 21118985
Mol Cell Biol. 2011 Mar;31(5):1041-53
pubmed: 21199920
Science. 2021 Jul 9;373(6551):
pubmed: 34244384
Front Oncol. 2021 Mar 11;11:636633
pubmed: 33777792
Haematologica. 2022 Jan 01;107(1):100-111
pubmed: 34134471
Genome Biol. 2014;15(12):554
pubmed: 25476604
Blood. 2019 Nov 7;134(19):1619-1631
pubmed: 31409672
Leukemia. 2012 Oct;26(10):2224-32
pubmed: 22469780
N Engl J Med. 2013 May 30;368(22):2059-74
pubmed: 23634996
Cancer Cell. 2018 Nov 12;34(5):707-723.e7
pubmed: 30423293
Cell Death Differ. 2010 Nov;17(11):1672-83
pubmed: 20706276
Blood. 2013 Aug 8;122(6):988-98
pubmed: 23719302
Genes Dev. 2014 Apr 15;28(8):858-74
pubmed: 24736844
Nat Genet. 2017 Mar;49(3):451-456
pubmed: 28112737
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Blood. 2009 Feb 26;113(9):1875-91
pubmed: 18812465
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Genes Dev. 2010 Aug 1;24(15):1659-72
pubmed: 20679399
J Clin Invest. 2012 Jul;122(7):2439-43
pubmed: 22706301
Mol Cell Biol. 2005 Oct;25(19):8592-606
pubmed: 16166640
Dev Cell. 2011 May 17;20(5):597-609
pubmed: 21571218
Blood. 2005 Aug 15;106(4):1223-31
pubmed: 15860665
Nat Med. 2018 Jan;24(1):103-112
pubmed: 29227476
Cytometry B Clin Cytom. 2015 Jul-Aug;88(4):244-52
pubmed: 25361478
Br J Haematol. 2005 Feb;128(4):548-51
pubmed: 15686466
Genome Biol. 2003;4(10):231
pubmed: 14519192
Blood. 2009 Apr 2;113(14):3337-47
pubmed: 19168790
Biochem Biophys Res Commun. 2016 Sep 30;478(4):1758-63
pubmed: 27613090
Nat Genet. 2002 Sep;32(1):148-52
pubmed: 12172547
J Thromb Haemost. 2013 Apr;11(4):605-14
pubmed: 23336709
Haematologica. 2018 Aug;103(8):e336-e340
pubmed: 29567780
Cancer Manag Res. 2020 Feb 12;12:1079-1088
pubmed: 32104088
Mol Cancer. 2007 Mar 26;6:23
pubmed: 17386101
EMBO J. 1998 Jan 15;17(2):384-95
pubmed: 9430630
Cell Death Differ. 2004 Jul;11(7):747-59
pubmed: 15017387
J Immunol. 2016 Jan 15;196(2):614-23
pubmed: 26685208
J Clin Invest. 2012 Mar;122(3):948-62
pubmed: 22354171
J Clin Invest. 2015 Mar 2;125(3):993-1005
pubmed: 25621499
Cell Rep. 2016 Jan 26;14(3):520-533
pubmed: 26776511
Elife. 2015 Aug 12;4:
pubmed: 26267216
Stem Cell Reports. 2014 Jan 14;2(1):26-35
pubmed: 24511468