Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
11 05 2021
11 05 2021
Historique:
received:
05
10
2020
accepted:
16
03
2021
entrez:
5
5
2021
pubmed:
6
5
2021
medline:
1
6
2021
Statut:
ppublish
Résumé
The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future.
Identifiants
pubmed: 33950175
pii: S2473-9529(21)00305-0
doi: 10.1182/bloodadvances.2020003541
pmc: PMC8114551
doi:
Substances chimiques
Pharmaceutical Preparations
0
Lenalidomide
F0P408N6V4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2391-2402Informations de copyright
© 2021 by The American Society of Hematology.
Références
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Clin Cancer Res. 2016 Nov 15;22(22):5419-5427
pubmed: 28151709
Cancer Cell. 2010 Oct 19;18(4):367-81
pubmed: 20951946
Blood. 2011 Apr 7;117(14):3847-57
pubmed: 21289309
Blood Adv. 2019 Jul 9;3(13):1930-1938
pubmed: 31248884
Br J Haematol. 2014 Mar;164(6):811-21
pubmed: 24328678
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Leukemia. 2018 Sep;32(9):1908-1919
pubmed: 29491455
Cancer Discov. 2015 Sep;5(9):972-87
pubmed: 26080835
Nucleic Acids Res. 2019 Jan 8;47(D1):D941-D947
pubmed: 30371878
Leukemia. 2018 Feb;32(2):383-390
pubmed: 28761118
Mol Cell Biol. 2008 Dec;28(24):7309-22
pubmed: 18838540
Mol Cancer Ther. 2017 Dec;16(12):2862-2870
pubmed: 28958990
Leukemia. 2020 Feb;34(2):404-415
pubmed: 31576005
Cancer Cell. 2007 Aug;12(2):131-44
pubmed: 17692805
Blood. 2016 Sep 1;128(9):1226-33
pubmed: 27458004
Nat Commun. 2018 Oct 15;9(1):4275
pubmed: 30323222
Am J Hematol. 2016 Oct;91(10):E442-7
pubmed: 27420405
Blood. 2021 Jan 14;137(2):232-237
pubmed: 33443552
Clin Adv Hematol Oncol. 2017 Oct;15(10):785-795
pubmed: 29040258
Leukemia. 2018 Jan;32(1):120-130
pubmed: 28642592
Blood. 2008 Aug 15;112(4):1338-45
pubmed: 18515658
Science. 2014 Jan 17;343(6168):301-5
pubmed: 24292625
Blood. 2005 Jul 15;106(2):698-705
pubmed: 15802532
Nat Commun. 2017 Sep 20;8(1):619
pubmed: 28931820
J Clin Oncol. 2002 Nov 15;20(22):4420-7
pubmed: 12431963
Clin Pharmacokinet. 2019 Feb;58(2):157-168
pubmed: 29802543
Blood. 2011 Nov 3;118(18):4771-9
pubmed: 21860026
Haematologica. 2019 Nov 14;105(10):2440-2447
pubmed: 33054085
Nat Med. 2016 Jul;22(7):735-43
pubmed: 27294876
Nat Protoc. 2017 Apr;12(4):828-863
pubmed: 28333914
J Biol Chem. 2014 Sep 12;289(37):25639-54
pubmed: 25077969
Nat Rev Cancer. 2018 Feb;18(2):89-102
pubmed: 29242642
Leukemia. 2019 Jan;33(1):171-180
pubmed: 30026574
Blood. 2018 Sep 20;132(12):1293-1303
pubmed: 30042095
Nat Commun. 2019 May 2;10(1):2031
pubmed: 31048683
N Engl J Med. 2012 May 10;366(19):1770-81
pubmed: 22571201
Blood Cancer J. 2017 Feb 24;7(2):e535
pubmed: 28234347
Cancer Cell. 2014 Jan 13;25(1):91-101
pubmed: 24434212
Leukemia. 2018 Jan;32(1):102-110
pubmed: 28584253
Trends Cancer. 2020 Nov;6(11):974-984
pubmed: 32517958
Oncol Rep. 2015 Aug;34(2):747-54
pubmed: 26081897
Nat Commun. 2014;5:2997
pubmed: 24429703
Leukemia. 2020 Apr;34(4):1192-1196
pubmed: 31712777
Nature. 2011 Mar 24;471(7339):467-72
pubmed: 21430775
Cold Spring Harb Perspect Biol. 2010 Jan;2(1):a001008
pubmed: 20182602
Haematologica. 2019 Jul;104(7):1440-1450
pubmed: 30733268
Blood. 2016 Jun 16;127(24):2955-62
pubmed: 27002115
Sci Signal. 2015 Sep 01;8(392):ra88
pubmed: 26329582
Haematologica. 2013 Oct;98(10):1586-92
pubmed: 23716545
J Clin Oncol. 2015 Nov 20;33(33):3911-20
pubmed: 26282654
Blood. 2018 Sep 27;132(13):1461
pubmed: 30262586
Cancer Biol Ther. 2006 Sep;5(9):1154-60
pubmed: 16855375
Blood Cancer J. 2017 Sep 1;7(9):e600
pubmed: 28862698
Sci Rep. 2019 Dec 2;9(1):18062
pubmed: 31792264
J Hematol Oncol. 2018 Dec 13;11(1):137
pubmed: 30545397
Leukemia. 2018 Dec;32(12):2636-2647
pubmed: 29895955
Blood. 2016 Sep 29;128(13):1735-44
pubmed: 27516441
Science. 2014 Jan 17;343(6168):305-9
pubmed: 24292623