Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors.
ATAC-Seq
T-cell development
T-cell leukemia
chromatin accessibility
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 09 2020
07 09 2020
Historique:
received:
01
02
2020
revised:
19
06
2020
accepted:
24
06
2020
pubmed:
6
8
2020
medline:
19
8
2021
entrez:
6
8
2020
Statut:
ppublish
Résumé
We aimed at identifying the developmental stage at which leukemic cells of pediatric T-ALLs are arrested and at defining leukemogenic mechanisms based on ATAC-Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensation during T-cell maturation. Developmental stages were distinguished by 2,823 signature chromatin regions with 95% accuracy. Open chromatin surrounding SAE1 was identified to best distinguish thymic developmental stages suggesting a potential role of SUMOylation in T-cell development. Deconvolution using signature regions revealed that T-ALLs, including those with mature immunophenotypes, resemble the most immature populations, which was confirmed by TF-binding motif profiles. We integrated ATAC-Seq and RNA-Seq and found DAB1, a gene not related to leukemia previously, to be overexpressed, abnormally spliced and hyper-accessible in T-ALLs. DAB1-negative patients formed a distinct subgroup with particularly immature chromatin profiles and hyper-accessible binding sites for SPI1 (PU.1), a TF crucial for normal T-cell maturation. In conclusion, our analyses of chromatin accessibility and TF-binding motifs showed that pediatric T-ALL cells are most similar to immature thymic precursors, indicating an early developmental arrest.
Identifiants
pubmed: 32755029
doi: 10.15252/emmm.202012104
pmc: PMC7507092
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12104Subventions
Organisme : José Carreras Leukämie-Stiftung (José Carreras Leukämie-Stiftung e.V.)
Pays : International
Organisme : Manfred Lautenschläger-Stiftung (Manfred Lautenschläger Foundation)
Pays : International
Organisme : Aktion fuer krebskranke Kinder e.V. Heidelberg
Pays : International
Organisme : Baden-Württemberg Stiftung (Baden-Württemberg Foundation)
Pays : International
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Nat Commun. 2016 Jun 27;7:11938
pubmed: 27346425
Blood. 2011 Aug 18;118(7):1854-64
pubmed: 21670474
Nat Genet. 2017 Aug;49(8):1274-1281
pubmed: 28671687
Nat Genet. 2016 Oct;48(10):1193-203
pubmed: 27526324
EMBO Mol Med. 2020 Sep 7;12(9):e12104
pubmed: 32755029
Bioinformatics. 2019 Jul 15;35(14):2489-2491
pubmed: 30520945
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Cell. 1997 Mar 7;88(5):627-36
pubmed: 9054502
Nat Biotechnol. 2010 May;28(5):495-501
pubmed: 20436461
Mol Cell Biol. 2007 Oct;27(20):7113-24
pubmed: 17698586
Immunology. 1997 Jul;91(3):340-5
pubmed: 9301521
Genome Res. 2018 Oct;28(10):1508-1519
pubmed: 30171019
Nature. 1985 Mar 7-13;314(6006):103-7
pubmed: 2983227
Front Cell Neurosci. 2016 Jun 30;10:166
pubmed: 27445693
Database (Oxford). 2017 Jan 1;2017:
pubmed: 28605766
EMBO Mol Med. 2018 Dec;10(12):
pubmed: 30389682
Cold Spring Harb Perspect Biol. 2018 May 1;10(5):
pubmed: 28716889
Genome Biol. 2019 Feb 26;20(1):45
pubmed: 30808370
Nature. 1987 Mar 5-11;326(6108):79-81
pubmed: 3102971
Leukemia. 2008 Dec;22(12):2142-50
pubmed: 18818707
Leukemia. 1995 Oct;9(10):1783-6
pubmed: 7564526
Dev Biol. 2002 Jun 1;246(1):103-21
pubmed: 12027437
Nat Rev Immunol. 2008 Jan;8(1):9-21
pubmed: 18097446
Genome Biol. 2014;15(12):550
pubmed: 25516281
Genome Res. 2009 Jul;19(7):1316-23
pubmed: 19498102
Br J Haematol. 2008 Oct;143(2):153-68
pubmed: 18691165
Blood. 2017 Mar 2;129(9):1113-1123
pubmed: 28115373
Nat Immunol. 2013 Jun;14(6):619-32
pubmed: 23644507
Nat Methods. 2015 May;12(5):453-7
pubmed: 25822800
Neuron. 2008 Oct 23;60(2):273-84
pubmed: 18957219
J Clin Invest. 2012 Oct;122(10):3398-406
pubmed: 23023710
Nat Genet. 2014 Apr;46(4):364-70
pubmed: 24584072
Stem Cell Reports. 2015 Nov 10;5(5):728-740
pubmed: 26489895
Cell. 2019 Feb 7;176(4):897-912.e20
pubmed: 30686579
Front Cell Neurosci. 2016 May 09;10:122
pubmed: 27242434
Lancet Oncol. 2009 Feb;10(2):147-56
pubmed: 19147408
Nucleic Acids Res. 2013 Jan;41(Database issue):D991-5
pubmed: 23193258
Br J Haematol. 2012 Feb;156(3):358-65
pubmed: 22128890
Immunity. 1999 Dec;11(6):653-63
pubmed: 10626888
Nat Rev Mol Cell Biol. 2011 Jan;12(1):36-47
pubmed: 21179060
Nat Rev Immunol. 2014 Aug;14(8):529-45
pubmed: 25060579
Pediatr Blood Cancer. 2016 Jul;63(7):1185-92
pubmed: 26928953
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Nucleic Acids Res. 2018 Jan 4;46(D1):D260-D266
pubmed: 29140473
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Immunity. 2002 Feb;16(2):285-96
pubmed: 11869688
Annu Rev Immunol. 1999;17:523-54
pubmed: 10358767
Development. 2012 Dec 1;139(23):4321-9
pubmed: 23132242
Nat Med. 2018 Jun;24(6):868-880
pubmed: 29785028