NFKBIE encodes IκBε, a cytoplasmic protein that functions as a key negative regulator of the NF-κB signaling pathway by sequestering NF-κB transcription factor complexes, including NFKB1-RELA (p50-p65) and NFKB1-REL (p50-c-Rel) complexes, in the cytoplasm and preventing their nuclear translocation and transcriptional activity 1. Loss-of-function mutations in NFKBIE, particularly a recurrent 4-bp frameshift deletion, occur in 3-7% of chr6 lymphocytic leukemia (CLL) patients and lead to constitutive NF-κB pathway activation 1. These mutations promote CLL cell migration, proliferation, and accelerated disease progression with shortened survival in both xenograft and genetically modified mouse models 1. NFKBIE-mutated CLL cells are selected by microenvironmental NF-κB-activating signals and contribute to immune escape through expansion of exhausted CD8+ T-cells and increased PD-L1 expression 2. Clinically, NFKBIE mutations are associated with poor prognosis in CLL patients, serving as independent predictors of short time-to-first-treatment specifically in IGHV-mutated CLL cases 3. Additionally, NFKBIE mutations confer resistance to BTK inhibitor ibrutinib therapy 2. Beyond hematologic malignancies, NFKBIE variants influence methotrexate uptake in rheumatoid arthritis cells by regulating SLC19A1 expression 4.