LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
BRCA1 Protein
/ metabolism
Biopsy
Cell Line, Tumor
DNA Breaks, Double-Stranded
/ drug effects
Drug Synergism
Humans
LIM Domain Proteins
/ metabolism
Lymphoma, Large B-Cell, Diffuse
/ drug therapy
Mice
Palatine Tonsil
/ pathology
Poly (ADP-Ribose) Polymerase-1
/ antagonists & inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Poly(ADP-ribose) Polymerases
/ metabolism
Primary Cell Culture
Proto-Oncogene Proteins
/ metabolism
Recombinational DNA Repair
/ drug effects
Synthetic Lethal Mutations
/ drug effects
Tumor Suppressor p53-Binding Protein 1
Xenograft Model Antitumor Assays
53BP1
BRCA1
DNA damage
LMO2
PARP
R-CHOP
acute lymphoblastic leukemia
diffuse large B cell lymphoma (DLBCL)
homologous recombination
olaparib
synthetic lethality
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
16 09 2019
16 09 2019
Historique:
received:
23
01
2019
revised:
25
06
2019
accepted:
26
07
2019
pubmed:
27
8
2019
medline:
19
5
2020
entrez:
27
8
2019
Statut:
ppublish
Résumé
Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL.
Identifiants
pubmed: 31447348
pii: S1535-6108(19)30334-4
doi: 10.1016/j.ccell.2019.07.007
pmc: PMC6752209
mid: NIHMS1536737
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
BRCA1 Protein
0
BRCA1 protein, human
0
LIM Domain Proteins
0
LMO2 protein, human
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Proto-Oncogene Proteins
0
TP53BP1 protein, human
0
Tumor Suppressor p53-Binding Protein 1
0
PARP1 protein, human
EC 2.4.2.30
PARP2 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
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
237-249.e6Subventions
Organisme : NCI NIH HHS
ID : R01 CA233945
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA124435
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR003142
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM121595
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA240139
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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