Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes.
acute myeloid leukemia
hematopoiesis
myeloid malignancies
preleukemia
single-cell RNA-seq
Journal
Cell genomics
ISSN: 2666-979X
Titre abrégé: Cell Genom
Pays: United States
ID NLM: 9918284260106676
Informations de publication
Date de publication:
13 Dec 2023
13 Dec 2023
Historique:
received:
14
04
2023
revised:
13
07
2023
accepted:
29
09
2023
medline:
20
12
2023
pubmed:
20
12
2023
entrez:
20
12
2023
Statut:
epublish
Résumé
Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles. Our analysis infers mutation-driven perturbations in cell abundance, cellular lineage fate, cellular metabolism, and gene expression at the continuous resolution, pinpointing cell populations with transcriptional alterations associated with differentiation bias. We further develop an 11-gene scoring system (Stem11) on the basis of preleukemic transcriptional signatures that predicts AML patient outcomes. Our results demonstrate that a single-cell-resolution deep characterization of preleukemic biology has the potential to enhance our understanding of AML heterogeneity and inform more effective risk stratification strategies.
Identifiants
pubmed: 38116120
doi: 10.1016/j.xgen.2023.100426
pii: S2666-979X(23)00252-5
pmc: PMC10726426
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
100426Subventions
Organisme : Medical Research Council
ID : MR/X008371/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206328/Z/17/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : DRCRPG-NOV22/100014
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R24 DK106766
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V005502/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 25508
Pays : United Kingdom
Informations de copyright
© 2023 The Author(s).
Déclaration de conflit d'intérêts
Aspects of this work are included in United Kingdom patent application 2312684.0.
Références
Nature. 2022 Jun;606(7913):335-342
pubmed: 35650444
Cancer Cell. 2010 Nov 16;18(5):524-35
pubmed: 21074499
Nat Med. 2018 Jan;24(1):103-112
pubmed: 29227476
N Engl J Med. 2014 Dec 25;371(26):2488-98
pubmed: 25426837
Nat Med. 2019 Jan;25(1):103-110
pubmed: 30510255
Blood. 2022 Jun 9;139(23):3387-3401
pubmed: 35073399
Nat Biotechnol. 2021 May;39(5):619-629
pubmed: 33558698
Sci Adv. 2020 Nov 25;6(48):
pubmed: 33239297
Nat Immunol. 2003 Feb;4(2):124-31
pubmed: 12496962
Nature. 2019 Jul;571(7765):355-360
pubmed: 31270458
Blood. 2022 Sep 22;140(12):1345-1377
pubmed: 35797463
Blood. 2007 Feb 1;109(3):874-85
pubmed: 17008539
N Engl J Med. 2014 Dec 25;371(26):2477-87
pubmed: 25426838
Cell. 2012 Jul 6;150(1):12-27
pubmed: 22770212
Nature. 2005 Apr 28;434(7037):1144-8
pubmed: 15793561
Nat Commun. 2021 Feb 2;12(1):738
pubmed: 33531494
Cell. 2015 May 21;161(5):1202-1214
pubmed: 26000488
Blood. 2014 May 15;123(20):3139-51
pubmed: 24692758
Genome Res. 2021 Oct;31(10):1867-1884
pubmed: 34301623
Nat Commun. 2020 Jan 3;11(1):102
pubmed: 31900386
N Engl J Med. 2004 Apr 15;350(16):1617-28
pubmed: 15084694
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cell Chem Biol. 2017 Sep 21;24(9):1161-1180
pubmed: 28938091
Blood. 2018 Feb 8;131(6):649-661
pubmed: 29282219
Haematologica. 2020 Oct 09;106(1):26-38
pubmed: 33054125
Nat Med. 2022 Jul;28(7):1439-1446
pubmed: 35788175
J Cell Biol. 1999 Mar 8;144(5):857-68
pubmed: 10085286
Genome Biol. 2018 Feb 6;19(1):15
pubmed: 29409532
Trends Cancer. 2018 Aug;4(8):523-536
pubmed: 30064661
Blood. 2011 Dec 15;118(25):6553-61
pubmed: 22042701
EMBO J. 2020 Dec 15;39(24):e104983
pubmed: 33103827
Nature. 2018 Jan 24;553(7689):418-426
pubmed: 29364285
Nat Methods. 2019 Dec;16(12):1289-1296
pubmed: 31740819
Int J Oncol. 2019 Oct;55(4):775-788
pubmed: 31432151
Genome Biol. 2019 Mar 22;20(1):63
pubmed: 30902100
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5401-10
pubmed: 25516983
Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6224-9
pubmed: 16603627
Nature. 2010 Dec 9;468(7325):839-43
pubmed: 21057493
Nat Genet. 2018 Jun;50(6):883-894
pubmed: 29736013
Science. 2009 May 22;324(5930):1029-33
pubmed: 19460998
Nature. 2018 Oct;562(7727):373-379
pubmed: 30209392
Nat Genet. 2020 Apr;52(4):378-387
pubmed: 32203468
Sci Adv. 2022 Aug 5;8(31):eabn4886
pubmed: 35921412
Leukemia. 2016 Jun;30(6):1422-5
pubmed: 26585411
J Clin Oncol. 2015 Nov 1;33(31):3641-9
pubmed: 26304885
N Engl J Med. 2013 May 30;368(22):2059-74
pubmed: 23634996
Science. 2020 Jan 31;367(6477):586-590
pubmed: 32001657
Blood. 2012 Nov 15;120(20):4205-14
pubmed: 23012328
Cancer Cell. 2022 Mar 14;40(3):301-317.e12
pubmed: 35245447
Cell Stem Cell. 2023 Jun 1;30(6):781-799.e9
pubmed: 37267914
Nature. 2018 Oct;562(7728):526-531
pubmed: 30333627
Cancer Cell. 2011 Jul 12;20(1):11-24
pubmed: 21723200
Cell Stem Cell. 2015 Jun 4;16(6):712-24
pubmed: 26004780
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
Cell Syst. 2019 Apr 24;8(4):281-291.e9
pubmed: 30954476
Blood. 2018 May 24;131(21):e1-e11
pubmed: 29588278
J Clin Oncol. 2014 Feb 20;32(6):548-56
pubmed: 24378410
Cancer Discov. 2019 Sep;9(9):1228-1247
pubmed: 31189531
Nat Methods. 2016 Oct;13(10):845-8
pubmed: 27571553
Blood. 2020 Jul 2;136(1):61-70
pubmed: 32430500
Nature. 2012 Aug 30;488(7413):656-9
pubmed: 22763442
Blood. 2017 Jan 26;129(4):424-447
pubmed: 27895058
Blood. 2020 Oct 8;136(15):1707-1721
pubmed: 32609823
Nat Methods. 2022 Feb;19(2):159-170
pubmed: 35027767
Nat Commun. 2020 Mar 5;11(1):1201
pubmed: 32139671
Cancer Cell. 2007 Oct;12(4):367-80
pubmed: 17936561
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
Genome Biol. 2019 Mar 19;20(1):59
pubmed: 30890159
Leukemia. 2018 Jun;32(6):1338-1348
pubmed: 29563537
Blood Cancer Discov. 2022 Jul 6;3(4):346-367
pubmed: 35532363
Nat Genet. 2011 May;43(5):470-5
pubmed: 21441929
Nat Commun. 2021 Nov 3;12(1):6323
pubmed: 34732703
Blood. 2019 Nov 21;134(21):1832-1846
pubmed: 31511238
Blood. 2005 Dec 1;106(12):3747-54
pubmed: 16109776
Science. 2016 Apr 8;352(6282):189-96
pubmed: 27124452
Blood Cancer Discov. 2021 May;2(3):226-237
pubmed: 34027416
Nat Commun. 2021 Sep 28;12(1):5692
pubmed: 34584091
N Engl J Med. 2013 Dec 19;369(25):2379-90
pubmed: 24325356
Nature. 2016 Dec 15;540(7633):433-437
pubmed: 27926740
Mol Cell. 2019 Mar 21;73(6):1292-1305.e8
pubmed: 30765193
Blood. 2017 Aug 10;130(6):753-762
pubmed: 28655780
J Clin Oncol. 2013 Mar 20;31(9):1172-81
pubmed: 23382473
J Exp Med. 2019 Apr 1;216(4):966-981
pubmed: 30890554
Leukemia. 2018 Oct;32(10):2167-2177
pubmed: 29550834
Haematologica. 2016 Aug;101(8):e328-31
pubmed: 27175030