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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.

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice