Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1).
Animals
CRISPR-Cas Systems
/ genetics
Cell Line
Cell Proliferation
/ drug effects
Cytokines
/ genetics
DNA Damage
/ drug effects
Deubiquitinating Enzymes
/ genetics
Doxorubicin
/ pharmacology
Granulocyte Colony-Stimulating Factor
/ genetics
HEK293 Cells
Humans
Inflammasomes
/ genetics
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Mutation
/ genetics
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
20
02
2019
accepted:
29
07
2019
revised:
28
06
2019
pubmed:
3
10
2019
medline:
5
8
2020
entrez:
3
10
2019
Statut:
ppublish
Résumé
BRCA1/BRCA2-containing complex 3 (BRCC3) is a Lysine 63-specific deubiquitinating enzyme (DUB) involved in inflammasome activity, interferon signaling, and DNA damage repair. Recurrent mutations in BRCC3 have been reported in myelodysplastic syndromes (MDS) but not in de novo AML. In one of our recent studies, we found BRCC3 mutations selectively in 9/191 (4.7%) cases with t(8;21)(q22;q22.1) AML but not in 160 cases of inv(16)(p13.1q22) AML. Clinically, AML patients with BRCC3 mutations had an excellent outcome with an event-free survival of 100%. Inactivation of BRCC3 by CRISPR/Cas9 resulted in improved proliferation in t(8;21)(q22;q22.1) positive AML cell lines and together with expression of AML1-ETO induced unlimited self-renewal in mouse hematopoietic progenitor cells in vitro. Mutations in BRCC3 abrogated its deubiquitinating activity on IFNAR1 resulting in an impaired interferon response and led to diminished inflammasome activity. In addition, BRCC3 inactivation increased release of several cytokines including G-CSF which enhanced proliferation of AML cell lines with t(8;21)(q22;q22.1). Cell lines and primary mouse cells with inactivation of BRCC3 had a higher sensitivity to doxorubicin due to an impaired DNA damage response providing a possible explanation for the favorable outcome of BRCC3 mutated AML patients.
Identifiants
pubmed: 31576005
doi: 10.1038/s41375-019-0578-6
pii: 10.1038/s41375-019-0578-6
pmc: PMC7214237
doi:
Substances chimiques
Cytokines
0
Inflammasomes
0
Granulocyte Colony-Stimulating Factor
143011-72-7
Doxorubicin
80168379AG
BRCC3 protein, human
EC 3.4.19.12
Deubiquitinating Enzymes
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
404-415Références
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