EBI2 overexpression in mice leads to B1 B-cell expansion and chronic lymphocytic leukemia–like B-cell malignancies

Abstract

Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5 B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein-Barr virus-induced gene 2 ( or ) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (IgM) and IgG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5 B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies.

A Pan-cancer analysis of GPR183 correlated with tumor immunity

“…In previous studies, GPR183 was reported to participate in progression of chronic lymphocytic leukemia-like Bcell malignancies, colitis and neuroin ammation [19,27,28]. We found that GPR183 was associated with prognosis of ve cancers(BRCA, SKCM, LUSC, LGG and UVM).…”

EBI2 in splenic and local immune responses and in autoimmunity

“…33,34 In contrast, mice with constitutive overexpression of EBI2 in their B cells had a decreased number of GC B cells. 51 It is worth mentioning that the above findings about the roles of EBI2 in B cell migration in the spleen were not readily detectable when studying EBI2-deficient mice alone. EBI2-deficient mice were found to have a normal splenic architecture, which is in contrast to the disorganized splenic architecture of mice lacking either CXCR5 or CCR7.…”

“…Thus, EBI2‐deficient mice had decreased numbers of early plasmablasts and decreased early Ab titers in response to vaccination with T‐dependent Ags . In contrast, mice with constitutive overexpression of EBI2 in their B cells had a decreased number of GC B cells …”

A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

“…The development of B1 cells has an inherent genetic predisposition to produce limited B‐cell receptors and has an enhanced capacity for self‐renewal, both of which can contribute to chronic lymphocytic leukemia (CLL) progression . In addition, B1 cells regulatory characteristics may contribute to the overall immunosuppressive manifestations of CLL . Evidence suggests that B1 cells accelerate malignant melanoma metastasis through interactions with cell‐surface glycoprotein MUC18 of melanoma cells .…”

“…10 In addition, B1 cells regulatory characteristics may contribute to the overall immunosuppressive manifestations of CLL. 11 Evidence suggests that B1 cells accelerate malignant melanoma metastasis through interactions with cell-surface glycoprotein MUC18 of melanoma cells. 12 However, Azevedo et al 13 demonstrated that B1 cells could induce the generation of Th17 cell, the expression of IL-17, and suppress the activity of regulatory T cells (Tregs), thus having a protective role in mice bearing Ehrlich tumors.…”