Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes.
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
27 02 2023
27 02 2023
Historique:
received:
20
05
2022
accepted:
03
12
2022
revised:
18
11
2022
entrez:
27
2
2023
pubmed:
28
2
2023
medline:
3
3
2023
Statut:
epublish
Résumé
Acute myeloid leukaemia (AML) patients harbouring certain chromosome abnormalities have particularly adverse prognosis. For these patients, targeted therapies have not yet made a significant clinical impact. To understand the molecular landscape of poor prognosis AML we profiled 74 patients from two different centres (in UK and Finland) at the proteomic, phosphoproteomic and drug response phenotypic levels. These data were complemented with transcriptomics analysis for 39 cases. Data integration highlighted a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia, which we term MLLGA and MLLGB. MLLGA presented increased DOT1L phosphorylation, HOXA gene expression, CDK1 activity and phosphorylation of proteins involved in RNA metabolism, replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples. MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and inosine-5-monosphosphate dehydrogenase (IMPDH) relative to other cases. Intermediate-risk KMT2A-MLLT3 cases were mainly represented in a third group closer to MLLGA than to MLLGB. The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia, suggesting a role of the nucleolar activity in sensitivity to treatment. In summary, our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.
Identifiants
pubmed: 36843114
doi: 10.1038/s41392-022-01288-1
pii: 10.1038/s41392-022-01288-1
pmc: PMC9968719
doi:
Substances chimiques
Nuclear Proteins
0
KMT2A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
80Subventions
Organisme : Blood Cancer UK
ID : 20008
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
Références
Nat Rev Genet. 2016 May;17(5):257-71
pubmed: 26996076
Cancers (Basel). 2020 Jan 20;12(1):
pubmed: 31968688
Leukemia. 2020 Dec;34(12):3161-3172
pubmed: 32231256
J Biochem. 2020 Oct 1;168(4):319-328
pubmed: 32702086
Leuk Res. 2018 Mar;66:20-27
pubmed: 29360622
Sci Signal. 2022 Apr 19;15(730):eabl7989
pubmed: 35439021
Nat Rev Cancer. 2010 Jul;10(7):457-69
pubmed: 20574448
N Engl J Med. 1999 Sep 30;341(14):1051-62
pubmed: 10502596
Cancer Res. 2019 Apr 15;79(8):1730-1739
pubmed: 30967400
Blood Cancer J. 2020 Oct 30;10(10):107
pubmed: 33127875
Cell Metab. 2018 Sep 4;28(3):369-382.e5
pubmed: 30043754
Blood Adv. 2020 Jul 14;4(13):3109-3122
pubmed: 32634241
Cancer Discov. 2013 Dec;3(12):1416-29
pubmed: 24056683
Cell Rep. 2015 May 5;11(5):808-20
pubmed: 25921540
Blood Res. 2020 Jul 31;55(S1):S14-S18
pubmed: 32719171
Cancer Cell. 2011 Jul 12;20(1):66-78
pubmed: 21741597
Nucleic Acids Res. 2011 Mar;39(5):1811-22
pubmed: 21036871
Cells. 2020 Jan 21;9(2):
pubmed: 31973211
Int J Cancer. 2001 Oct 15;94(2):275-81
pubmed: 11668509
Eur J Haematol. 2009 Nov;83(5):406-19
pubmed: 19558506
Mol Biol Cell. 2006 Oct;17(10):4459-72
pubmed: 16899510
Nucleic Acids Res. 2019 Jul 26;47(13):6811-6825
pubmed: 31114877
J Biomed Sci. 2020 Jul 21;27(1):81
pubmed: 32690020
Front Cell Dev Biol. 2019 May 15;7:81
pubmed: 31157223
Nature. 2016 May 02;534(7605):47-54
pubmed: 27135926
Biochim Biophys Acta Gene Regul Mech. 2020 Aug;1863(8):194564
pubmed: 32376390
Biochim Biophys Acta Gene Regul Mech. 2020 Jul;1863(7):194548
pubmed: 32320750
Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26340-26346
pubmed: 33020282
Cancer Cell. 2016 Nov 14;30(5):737-749
pubmed: 27846391
Cell. 2016 Jul 28;166(3):755-765
pubmed: 27372738
Nat Rev Cancer. 2015 Jun;15(6):334-46
pubmed: 25998713
Sci Signal. 2013 Mar 26;6(268):rs6
pubmed: 23532336
Oncotarget. 2016 Mar 29;7(13):16217-26
pubmed: 26908445
Blood Cancer J. 2021 Sep 29;11(9):162
pubmed: 34588432
Mol Cell Proteomics. 2012 Aug;11(8):453-66
pubmed: 22547687
Cancers (Basel). 2019 Sep 11;11(9):
pubmed: 31514446
Curr Biol. 2002 Jun 25;12(12):1052-8
pubmed: 12123582
Nat Rev Cancer. 2020 Dec;20(12):743-756
pubmed: 33033407
Cell. 2019 Oct 3;179(2):561-577.e22
pubmed: 31585088
N Engl J Med. 2016 Jun 9;374(23):2209-2221
pubmed: 27276561
Nat Commun. 2019 Aug 8;10(1):3578
pubmed: 31395880
Nat Rev Mol Cell Biol. 2010 Feb;11(2):138-48
pubmed: 20029420
Bioinformatics. 2020 Jun 1;36(11):3602-3604
pubmed: 32119072
Blood. 2010 Jul 22;116(3):354-65
pubmed: 20385793
Biol Blood Marrow Transplant. 2006 Jan;12(1):61-7
pubmed: 16399569
Haematologica. 2020 Mar;105(3):708-720
pubmed: 31296572
Brief Bioinform. 2019 May 21;20(3):767-777
pubmed: 29077858
Nat Med. 2018 Jan;24(1):103-112
pubmed: 29227476
Blood. 2010 Apr 8;115(14):2835-44
pubmed: 20032505
Blood. 2009 Sep 17;114(12):2489-96
pubmed: 19528532
Leukemia. 2011 Mar;25(3):560-3
pubmed: 21331072
Blood. 2017 Jan 26;129(4):424-447
pubmed: 27895058
Br J Haematol. 2020 May;189(4):672-683
pubmed: 32068246
Cell. 2020 Jul 9;182(1):226-244.e17
pubmed: 32649875
Leukemia. 2018 Jun;32(6):1338-1348
pubmed: 29563537
Nat Cell Biol. 2019 Aug;21(8):1003-1014
pubmed: 31371825
Front Oncol. 2015 Dec 21;5:278
pubmed: 26734566
Blood. 2009 Mar 12;113(11):2375-85
pubmed: 19056693
Proteomics. 2021 Feb;21(3-4):e1900312
pubmed: 32875713
Blood. 2012 Feb 23;119(8):1872-81
pubmed: 22210879
Nucleic Acids Res. 2020 Sep 25;48(17):9449-9461
pubmed: 32857853
Blood. 2003 Oct 1;102(7):2395-402
pubmed: 12805060
Cell. 2019 May 2;177(4):1035-1049.e19
pubmed: 31031003
Leukemia. 2018 Aug;32(8):1818-1822
pubmed: 29626197
Front Pediatr. 2017 Feb 09;5:4
pubmed: 28232907
Sci Rep. 2014 Jun 05;4:5193
pubmed: 24898935
Proc Natl Acad Sci U S A. 1999 May 25;96(11):6096-101
pubmed: 10339547
Mol Metab. 2020 May;35:100962
pubmed: 32244187