Mitophagy Promotes Resistance to BH3 Mimetics in Acute Myeloid Leukemia.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
07 07 2023
07 07 2023
Historique:
received:
23
05
2022
revised:
30
01
2023
accepted:
23
03
2023
pmc-release:
07
01
2024
medline:
10
7
2023
pubmed:
24
4
2023
entrez:
24
04
2023
Statut:
ppublish
Résumé
BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3 mimetics in AML. Insensitivity to BH3 mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux, which acts as a prosurvival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3 mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML. AML remains one of the most difficult-to-treat blood cancers. BH3 mimetics represent a promising therapeutic approach to eliminate AML blasts by activating the apoptotic pathway. Enhanced mitochondrial clearance drives resistance to BH3 mimetics and predicts poor prognosis. Reverting excessive mitophagy can halt BH3-mimetic resistance in AML. This article is highlighted in the In This Issue feature, p. 1501.
Identifiants
pubmed: 37088914
pii: 719030
doi: 10.1158/2159-8290.CD-22-0601
pmc: PMC10330144
mid: NIHMS1888395
doi:
Substances chimiques
Myeloid Cell Leukemia Sequence 1 Protein
0
Proto-Oncogene Proteins c-bcl-2
0
Antineoplastic Agents
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1656-1677Subventions
Organisme : NCI NIH HHS
ID : R01 CA173636
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA229086
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016087
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR029552
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA202027
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228135
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178394
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216421
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA202025
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024708
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA238229
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA242020
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA252602
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR023704
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013330
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
Références
Cell. 2010 May 14;141(4):656-67
pubmed: 20478256
Cancer Lett. 2013 May 28;332(2):202-5
pubmed: 22230093
Nat Cancer. 2020 Dec;1(12):1176-1187
pubmed: 33884374
Nat Protoc. 2017 Aug;12(8):1576-1587
pubmed: 28703790
Nat Commun. 2020 Aug 13;11(1):4056
pubmed: 32792483
Cell. 2015 Feb 26;160(5):977-989
pubmed: 25723171
Nature. 2008 Dec 4;456(7222):605-10
pubmed: 19052620
Elife. 2019 Jul 08;8:
pubmed: 31282856
Autophagy. 2017 Jan 2;13(1):214-215
pubmed: 27797294
Autophagy. 2011 Aug;7(8):914-6
pubmed: 21508685
Nat Immunol. 2019 Feb;20(2):163-172
pubmed: 30643263
Cancer Discov. 2019 Jul;9(7):910-925
pubmed: 31048320
Sci Transl Med. 2019 Oct 30;11(516):
pubmed: 31666400
Nature. 2016 Oct 27;538(7626):477-482
pubmed: 27760111
Cell Death Differ. 2020 Mar;27(3):843-857
pubmed: 31836831
Nat Cancer. 2020 Aug;1(8):826-839
pubmed: 33123685
Cancer Cell. 2017 Dec 11;32(6):748-760.e6
pubmed: 29232553
Nat Commun. 2022 Jul 7;13(1):3775
pubmed: 35798717
J Cell Biol. 2007 Feb 12;176(4):405-14
pubmed: 17296794
Int J Mol Sci. 2020 Mar 05;21(5):
pubmed: 32150829
Signal Transduct Target Ther. 2020 Feb 26;5(1):17
pubmed: 32296028
Cancer Cell. 2020 Dec 14;38(6):872-890.e6
pubmed: 33217342
Cancer Discov. 2019 Jul;9(7):890-909
pubmed: 31048321
Front Oncol. 2019 Dec 12;9:1205
pubmed: 31921615
Blood Adv. 2019 Dec 23;3(24):4326-4335
pubmed: 31869416
Nat Rev Mol Cell Biol. 2020 Apr;21(4):204-224
pubmed: 32071438
Nat Biotechnol. 2016 Feb;34(2):184-191
pubmed: 26780180
J Biol Chem. 2019 Jun 28;294(26):10300-10314
pubmed: 31110043
Cancer Discov. 2018 Dec;8(12):1566-1581
pubmed: 30185627
Front Cell Dev Biol. 2018 Oct 12;6:137
pubmed: 30370269
Cancer Discov. 2020 Apr;10(4):506-525
pubmed: 32014868
Mol Cell. 2013 Jul 11;51(1):20-34
pubmed: 23727017
J Biol Chem. 2015 Nov 27;290(48):28726
pubmed: 26614783
Autophagy. 2021 May;17(5):1142-1156
pubmed: 32249716
J Cell Sci. 2002 Apr 15;115(Pt 8):1663-74
pubmed: 11950885
Clin Cancer Res. 2020 Dec 15;26(24):6535-6549
pubmed: 32988967
Curr Oncol Rep. 2019 Feb 4;21(2):16
pubmed: 30715623
CA Cancer J Clin. 2018 Jan;68(1):7-30
pubmed: 29313949
Nat Cancer. 2023 Jan;4(1):27-42
pubmed: 36581735
Oncotarget. 2017 Nov 3;8(63):107206-107222
pubmed: 29291023
Cancer Discov. 2022 Feb;12(2):432-449
pubmed: 34531254
Nat Cell Biol. 2018 May;20(5):521-527
pubmed: 29686264
J Cell Sci. 2001 Mar;114(Pt 5):867-74
pubmed: 11181170
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Blood Cancer J. 2021 Feb 1;11(2):25
pubmed: 33563904
Mol Oncol. 2018 Mar;12(3):287-304
pubmed: 29063678
Cancer Discov. 2019 Jul;9(7):962-979
pubmed: 31068365
Sci Signal. 2016 Feb 16;9(415):ra17
pubmed: 26884599
Cancer Discov. 2016 Oct;6(10):1106-1117
pubmed: 27520294
Nat Rev Mol Cell Biol. 2014 Feb;15(2):81-94
pubmed: 24401948
Blood. 2023 Feb 9;141(6):634-644
pubmed: 36219880
Mol Cell. 2020 Mar 5;77(5):1124-1142.e10
pubmed: 32142685
Cancer Cell. 2019 May 13;35(5):721-737.e9
pubmed: 31056398
Trends Cell Biol. 2018 Jul;28(7):523-540
pubmed: 29588129
PLoS One. 2013 Oct 15;8(10):e77682
pubmed: 24143256
Cell Stem Cell. 2018 Jul 05;23(1):86-100.e6
pubmed: 29910151
N Engl J Med. 2013 May 30;368(22):2059-74
pubmed: 23634996
Blood. 2015 Mar 26;125(13):2120-30
pubmed: 25631767
EMBO J. 2013 Aug 28;32(17):2348-61
pubmed: 23921556
Nat Biotechnol. 2018 Jun;36(5):411-420
pubmed: 29608179
PLoS One. 2013;8(3):e58435
pubmed: 23472196
Nat Biotechnol. 2018 Dec 03;:
pubmed: 30531897
Nature. 2018 Oct;562(7728):526-531
pubmed: 30333627
Essays Biochem. 2017 Dec 12;61(6):585-596
pubmed: 29233870
Cell Res. 2010 Jul;20(7):748-62
pubmed: 20548331
Nature. 2013 Mar 21;495(7441):389-93
pubmed: 23455425
EMBO J. 2016 Aug 1;35(15):1677-93
pubmed: 27334614
Blood. 2009 Dec 3;114(24):5034-43
pubmed: 19808698
Oncotarget. 2015 Jul 10;6(19):16912-25
pubmed: 26219338
PLoS One. 2014 Oct 23;9(10):e110600
pubmed: 25340751
Cancer Discov. 2018 Dec;8(12):1582-1597
pubmed: 30254093
Nat Mach Intell. 2019 Dec;1(12):568-577
pubmed: 32368721
Nature. 2013 Apr 18;496(7445):372-6
pubmed: 23503661
Nature. 2014 Jun 19;510(7505):370-5
pubmed: 24896179
Cancer Res. 2016 Apr 15;76(8):2197-205
pubmed: 26941285
Science. 2013 Apr 26;340(6131):471-5
pubmed: 23620051
Nat Cancer. 2021 Nov;2(11):1204-1223
pubmed: 35122057
Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11249-11254
pubmed: 27647893
Cells. 2021 Mar 16;10(3):
pubmed: 33809551
Bioorg Med Chem Lett. 2018 Aug 15;28(15):2655-2659
pubmed: 29935771
Nat Commun. 2018 Dec 17;9(1):5341
pubmed: 30559424
Nucleic Acids Res. 2020 Jul 2;48(W1):W488-W493
pubmed: 32246720
Methods. 2013 Jun 1;61(2):156-64
pubmed: 23607990
Genes Dev. 2011 Aug 1;25(15):1628-40
pubmed: 21828272
Cell. 2020 Jan 23;180(2):387-402.e16
pubmed: 31978347
J Vis Exp. 2018 Aug 12;(138):
pubmed: 30148491
Haematologica. 2020 Dec 23;107(1):58-76
pubmed: 33353284
Neurology. 2011 May 17;76(20):1690-6
pubmed: 21508331
Autophagy. 2017 Apr 3;13(4):654-669
pubmed: 28368777
Blood. 2020 Mar 12;135(11):791-803
pubmed: 31932844
J Biol Chem. 2009 Nov 13;284(46):31635-46
pubmed: 19767391
Sci Rep. 2018 Nov 15;8(1):16837
pubmed: 30442990
Clin Lymphoma Myeloma Leuk. 2020 Sep;20 Suppl 1:S25-S26
pubmed: 32862856