The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL.
Animals
Gene Expression Regulation, Leukemic
Humans
Internal Ribosome Entry Sites
Male
Mice
Mice, Inbred NOD
Mutation
Oxidative Stress
/ drug effects
Phosphorylation
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
Protein Biosynthesis
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Ribosomal Protein L10
Ribosomal Proteins
/ genetics
Ribosomes
/ metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
12
12
2017
accepted:
21
05
2018
revised:
16
05
2018
pubmed:
23
6
2018
medline:
21
5
2019
entrez:
23
6
2018
Statut:
ppublish
Résumé
The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression. RPL10 R98S selective sensitivity to the clinically available Bcl-2 inhibitor Venetoclax (ABT-199) was supported by suppression of splenomegaly and the absence of human leukemia cells in the blood of T-ALL xenografted mice. These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL.
Identifiants
pubmed: 29930300
doi: 10.1038/s41375-018-0176-z
pii: 10.1038/s41375-018-0176-z
pmc: PMC6169730
mid: EMS77878
doi:
Substances chimiques
Internal Ribosome Entry Sites
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins c-bcl-2
0
RPL10 protein, human
0
Ribosomal Proteins
0
Rpl10 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
319-332Subventions
Organisme : European Research Council
ID : 334946
Pays : International
Commentaires et corrections
Type : ErratumIn
Références
Nat Commun. 2017 May 11;8:15267
pubmed: 28492237
Leukemia. 2018 Mar;32(3):809-819
pubmed: 28744013
Biochim Biophys Acta. 2012 Sep;1822(9):1363-73
pubmed: 22178243
Curr Opin Biotechnol. 2015 Aug;34:189-201
pubmed: 25731751
J Biol Chem. 2004 Jul 9;279(28):29066-74
pubmed: 15123638
J Biol Chem. 2001 Jun 29;276(26):23357-61
pubmed: 11283020
Nat Genet. 2013 Feb;45(2):186-90
pubmed: 23263491
Cancer Cell. 2013 Sep 9;24(3):318-30
pubmed: 24029231
Cancer Lett. 2008 Oct 18;270(1):1-9
pubmed: 18467025
Metab Eng. 2017 Sep;43(Pt B):187-197
pubmed: 27847310
Blood. 2010 Feb 18;115(7):1416-24
pubmed: 20008792
Mol Cell Biol. 2013 Dec;33(23):4660-71
pubmed: 24061479
J Hematol Oncol. 2015 Nov 20;8:129
pubmed: 26589495
Blood. 2015 Mar 12;125(11):1759-67
pubmed: 25645356
N Engl J Med. 2016 Jan 28;374(4):311-22
pubmed: 26639348
Mol Cell Proteomics. 2011 May;10(5):R110.006924
pubmed: 21543789
J BUON. 2010 Apr-Jun;15(2):330-6
pubmed: 20658731
Neural Regen Res. 2013 Jul 25;8(21):2003-14
pubmed: 25206509
Free Radic Res. 2009;43(11):1090-100
pubmed: 19669995
Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6726-30
pubmed: 8341691
Int J Cardiol. 2016 Jun 15;213:8-14
pubmed: 26316329
Cell Rep. 2016 Oct 11;17(3):837-848
pubmed: 27732858
Blood. 2012 Jan 5;119(1):262-72
pubmed: 22058113
Blood. 2017 Mar 2;129(9):1113-1123
pubmed: 28115373
Biochem Biophys Res Commun. 1997 Jan 13;230(2):331-4
pubmed: 9016777
Lancet Oncol. 2016 Jun;17(6):768-778
pubmed: 27178240
Nat Genet. 2017 Aug;49(8):1211-1218
pubmed: 28671688
Am J Physiol. 1998 Dec;275(6):C1640-52
pubmed: 9843726
Proteomics. 2006 Apr;6 Suppl 1:S293-9
pubmed: 16521150
Mol Autism. 2014 Feb 10;5(1):10
pubmed: 24512814
Blood. 2012 Nov 1;120(18):3764-73
pubmed: 22976955
Cell Rep. 2013 Nov 27;5(4):1047-59
pubmed: 24268771
Clin Biochem. 2008 May;41(7-8):511-8
pubmed: 18313403
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D125-30
pubmed: 16381829
J Biol Chem. 2002 Sep 27;277(39):36489-98
pubmed: 12138090
Cancer Res. 2010 Jun 1;70(11):4767-77
pubmed: 20501855
Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5640-5
pubmed: 24706786
J Biol Chem. 2006 Sep 29;281(39):29011-21
pubmed: 16849329
Blood. 2014 Dec 11;124(25):3738-47
pubmed: 25301704
Exp Mol Med. 2000 Mar 31;32(1):42-6
pubmed: 10762061
Dev Dyn. 2007 Feb;236(2):447-60
pubmed: 17195189
Leukemia. 2017 Oct;31(10):2037-2047
pubmed: 28074072
Blood. 2017 Mar 16;129(11):e26-e37
pubmed: 28122742
Cancer Discov. 2014 Sep;4(9):1074-87
pubmed: 24994123
Nucleic Acids Res. 2013 Sep;41(17):8308-18
pubmed: 23821664
Mol Cell. 2008 May 23;30(4):447-59
pubmed: 18450493
Pediatr Clin North Am. 2015 Feb;62(1):61-73
pubmed: 25435112
Nat Med. 2013 Mar;19(3):368-71
pubmed: 23377281
Nature. 2012 Jan 11;481(7380):157-63
pubmed: 22237106
Science. 2006 May 12;312(5775):902-6
pubmed: 16690864