Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1)

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 rece...

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Bibliographic Details
Published in:Leukemia 2020-02, Vol.34 (2), p.404-415
Main Authors: Meyer, Tatjana, Jahn, Nikolaus, Lindner, Stefanie, Röhner, Linda, Dolnik, Anna, Weber, Daniela, Scheffold, Annika, Köpff, Simon, Paschka, Peter, Gaidzik, Verena I, Heckl, Dirk, Wiese, Sebastian, Ebert, Benjamin L, Döhner, Hartmut, Bullinger, Lars, Döhner, Konstanze, Krönke, Jan
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
AML1 protein
Animals
Biological response modifiers
Biotechnology
BRCA1 protein
BRCA2 protein
Breast cancer
Cell Line
Cell Proliferation - drug effects
Cell Proliferation - genetics
Cells (biology)
CRISPR
CRISPR-Cas Systems - genetics
Cytokines
Cytokines - genetics
Damage
Deactivation
Deoxyribonucleic acid
Deubiquitinating Enzymes - genetics
DNA
DNA damage
DNA Damage - drug effects
DNA Damage - genetics
DNA repair
Doxorubicin
Doxorubicin - pharmacology
Enzymes
Genetic aspects
Granulocyte colony-stimulating factor
Granulocyte Colony-Stimulating Factor - genetics
HEK293 Cells
Hematopoietic stem cells
Humans
Inactivation
Inflammasomes
Inflammasomes - genetics
Interferon
Leukemia
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Lysine
Mice
Mutation
Mutation - genetics
Myelodysplastic syndrome
Myelodysplastic syndromes
Myeloid leukemia
Progenitor cells
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Summary: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.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-019-0578-6