Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery.
Adult
Aged
Aged, 80 and over
Aneuploidy
Cell Cycle
Chromosome Banding
Female
Gene Dosage
Gene Expression Profiling
/ methods
Gene Expression Regulation, Leukemic
Gene Regulatory Networks
Genetic Predisposition to Disease
Genomics
/ methods
Humans
Leukemia, Myeloid, Acute
/ genetics
Male
Middle Aged
Mutation
Proteolysis
Exome Sequencing
Young Adult
acute myeloid leukemia
aneuploidy
cell cycle
genomics
mutation
ubiquitination
whole exome sequencing
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
13
04
2018
revised:
08
06
2018
accepted:
26
06
2018
pubmed:
28
11
2018
medline:
4
12
2019
entrez:
28
11
2018
Statut:
ppublish
Résumé
Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis. To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E-AML) cases. A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A-AML, which was associated with a 3-gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A-AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E-AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression. These findings indicate that aneuploidy-related and leukemia-specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.
Sections du résumé
BACKGROUND
Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis.
METHODS
To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E-AML) cases.
RESULTS
A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A-AML, which was associated with a 3-gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A-AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E-AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression.
CONCLUSIONS
These findings indicate that aneuploidy-related and leukemia-specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.
Identifiants
pubmed: 30480765
doi: 10.1002/cncr.31837
pmc: PMC6587451
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
712-725Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
Références
Blood. 2015 Jan 22;125(4):600-5
pubmed: 25499761
Nat Genet. 2004 Nov;36(11):1159-61
pubmed: 15475955
Cell Rep. 2014 Feb 27;6(4):670-83
pubmed: 24508461
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3925-30
pubmed: 17360454
Blood. 2007 Aug 15;110(4):1308-16
pubmed: 17485549
Cancer Discov. 2014 Sep;4(9):1014-21
pubmed: 24934408
J Clin Invest. 2012 Dec;122(12):4362-74
pubmed: 23187126
Blood. 2014 Aug 21;124(8):1304-11
pubmed: 24923295
Nature. 2005 Sep 1;437(7055):147-53
pubmed: 16007073
Blood. 2010 Jul 22;116(3):354-65
pubmed: 20385793
Science. 2011 Aug 19;333(6045):1026-30
pubmed: 21852501
Blood. 2017 Aug 10;130(6):699-712
pubmed: 28607134
Science. 2011 Aug 19;333(6045):1039-43
pubmed: 21852505
Cancer Res. 2017 Jan 1;77(1):207-218
pubmed: 27784745
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12644-9
pubmed: 22802626
Blood. 2013 Jan 10;121(2):369-77
pubmed: 23175688
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14188-93
pubmed: 20663956
Cell Death Differ. 2015 Dec;22(12):1946-56
pubmed: 26024389
Cell. 2010 Oct 1;143(1):71-83
pubmed: 20850176
J Cell Biol. 2009 Jul 13;186(1):27-40
pubmed: 19596847
Oncogene. 2004 Mar 25;23(13):2379-84
pubmed: 14767474
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13033-8
pubmed: 18728194
Nat Genet. 2015 Dec;47(12):1402-7
pubmed: 26551669
Blood. 2012 Jun 21;119(25):6109-17
pubmed: 22553315
Science. 2008 Oct 31;322(5902):703-9
pubmed: 18974345
Cancer Res. 2004 Oct 1;64(19):6941-9
pubmed: 15466185
Br J Haematol. 2014 Aug;166(4):550-6
pubmed: 24931631
N Engl J Med. 2013 May 30;368(22):2059-74
pubmed: 23634996
Elife. 2014 Jul 29;3:e03023
pubmed: 25073701
Science. 2011 Sep 30;333(6051):1895-8
pubmed: 21960636
N Engl J Med. 2016 Jun 9;374(23):2209-2221
pubmed: 27276561
Nat Rev Cancer. 2010 Feb;10(2):102-15
pubmed: 20094045
Blood. 2015 Nov 26;126(22):2491-501
pubmed: 26438511
Nat Commun. 2015 Oct 01;6:8399
pubmed: 26423134
Trends Biochem Sci. 2017 Mar;42(3):193-205
pubmed: 28202332
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10200-5
pubmed: 10468586
Genes Dev. 2016 Jun 15;30(12):1395-408
pubmed: 27313317
Blood. 2017 Jan 26;129(4):424-447
pubmed: 27895058
Nat Genet. 2006 Sep;38(9):1043-8
pubmed: 16921376
J Clin Oncol. 2008 Oct 10;26(29):4791-7
pubmed: 18695255
Cancer Res. 2009 Dec 15;69(24):9245-53
pubmed: 19951996
Development. 2010 Jun;137(11):1907-17
pubmed: 20460369
Eur J Haematol. 2012 Feb;88(2):136-43
pubmed: 21933280
Blood. 2013 Feb 7;121(6):975-83
pubmed: 23212519
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Blood. 2012 Mar 1;119(9):2114-21
pubmed: 22186996
Leuk Res. 2015 Mar;39(3):265-72
pubmed: 25592059
J Cell Biol. 2010 Feb 8;188(3):369-81
pubmed: 20123995
Mol Cancer Res. 2013 Nov;11(11):1326-36
pubmed: 24008673
Science. 2007 Aug 17;317(5840):916-24
pubmed: 17702937
Int J Oncol. 2002 Nov;21(5):1041-51
pubmed: 12370753
Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1124-9
pubmed: 11158605