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

Abstract

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 Is a Predictive Factor of Survival and Is Correlated With Immune Infiltration, Antigen Processing, And Presentation In Hepatocellular Carcinoma

“…NFKBIE de ciency results in increased NFκB activation in cells. NFKBIE de ciency increases in vitro B cell proliferation [23]. In this investigation, we discovered that NFKBIB, NFKBID, and NFKBIE were overexpressed in a range of malignancies.…”

Implementation of International Prognostic Index with flow cytometry immunophenotyping for better risk stratification of chronic lymphocytic leukemia

“…Indeed, mutated CLL cells frequently show a CD5 + CD27 + memory B cell phenotype, while unmutated IGHV cells a CD5 + CD27 − B cell phenotype related to a T‐cell independent B lymphocyte activation 8 . Other somatic mutations occurring at the hematopoietic stem cell (HSC) level are also related to an increased risk of CLL development, such as mutations in SF3B1 , NOTCH1 NFKB1E , and other genes related to the NF‐κB signaling pathway 8–10 …”

“…8 Other somatic mutations occurring at the hematopoietic stem cell (HSC) level are also related to an increased risk of CLL development, such as mutations in SF3B1, NOTCH1 NFKB1E, and other genes related to the NF-κB signaling pathway. [8][9][10] Tumor microenvironment also plays an important role in CLL development as promotes CLL cell survival, proliferation, homing to lymphoid tissues and bone marrow (BM), and disease progression. [11][12][13] Several cell types and molecules are involved in the deep cross-talk between leukemic cells and tumor environment, such as T helper (Th) 17 lymphocytes or nurse-like cells, by directly interacting with tumor cells through ligand-receptor interactions (e.g., a4β1 integrin binding to vascular cell adhesion molecule-1 [VCAM1], ICAM, and others), or by indirectly releasing cytokines and chemokines (e.g., CXCL12 or CXCL13), facilitating tumor cell migration, homing and survival.…”

Caracterización fenotípica y funcional de la sub-población de linfocitos B que expresan el receptor de IL-33 durante la gestación: Potencial implicancia en la protección del parto prematuro

“…Incluso, deficiencias en IKKβ, cuyo mensajero se observó disminuido en LB de ratones P, están relacionadas con el desarrollo de infecciones recurrentes, debido a una respuesta deficiente a través de la vía de NF-κB (128). Se conoce además que la deficiencia en las proteínas del signalosoma CBM, inducen una reducción en la diferenciación de LB maduras, una respuesta deficiente ante antígenos TI y T-dependientes y la producción de menores niveles de anticuerpos (Igs) (80,129,130). Sumado a su rol principal como productores de anticuerpos, los LB juegan un papel crítico como CPA a las células T, controlando así su activación y diferenciación hacia diferentes perfiles (Th1/Th17/Treg).…”

“…Reforzando esta idea, se observó un perfil transcriptómico diferencial similar al perfil característico previamente descripto para los LBregs, en el cual se observa una modulación idéntica de factores que trabajan a nivel transcripción (Bcl6, Zfp318, Klf2) en ratones P comparado con ratones NP (120). Adicionalmente, en cuanto a la distribución de las poblaciones B, nuestros resultados muestran una disminución del mensajero que codifica para el gen Nfkbie en ratones P comparado con ratones NP, que se relaciona con una aumento de las poblaciones MZ y B1 de LB (130). Estos datos en su conjunto permitirían explicar la distribución de las principales poblaciones de LB descriptas anteriormente durante la preñez, caracterizada por un aumento en las poblaciones MZ.…”