TY - JOUR
T1 - Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice
AU - Della-Valle, Veronique
AU - Roos-Weil, Damien
AU - Scourzic, Laurianne
AU - Mouly, Enguerran
AU - Aid, Zakia
AU - Darwiche, Walaa
AU - Lecluse, Yann
AU - Damm, Frederik
AU - Mémet, Sylvie
AU - Mercher, Thomas
AU - Aoufouchi, Said
AU - Nguyen-Khac, Florence
AU - Bernard, Olivier A.
AU - Ghamlouch, Hussein
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.
AB - Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.
UR - http://www.scopus.com/inward/record.url?scp=85081731776&partnerID=8YFLogxK
U2 - 10.1038/s41408-020-0305-6
DO - 10.1038/s41408-020-0305-6
M3 - Article
C2 - 32170099
AN - SCOPUS:85081731776
SN - 2044-5385
VL - 10
JO - Blood Cancer Journal
JF - Blood Cancer Journal
IS - 3
M1 - 38
ER -