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

Research output: Contribution to journalJournal articleResearchpeer-review

Kristine Niss Arfelt, Line Barington, Tau Benned-Jensen, Valentina Kubale, Alexander L Kovalchuk, Viktorija Daugvilaite, Jan Pravsgaard Christensen, Allan Randrup Thomsen, Kristoffer L Egerod, Maria R Bassi, Katja Spiess, Thue W Schwartz, Hongsheng Wang, Herbert C Morse, Peter J Holst, Mette M Rosenkilde

Human and mouse chronic lymphocytic leukemia (CLL) develop 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 development and the B1a cell population is increased in mice with reduced germinal center formation. As a major mediator of follicular B cell migration, the G protein-coupled receptor (GPCR) Epstein Barr virus-induced gene 2 (EBI2 or GPR183) directs B cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells towards the extrafollicular area, whereas downregulation is essential for germinal center formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to chronic lymphocytic leukemia. Here we demonstrate that B cell-targeted expression of human EBI2 in mice reduces germinal center-dependent immune responses, reduces total 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.

Original languageEnglish
JournalBlood
Volume129
Issue number7
Pages (from-to)866-878
ISSN0006-4971
DOIs
Publication statusPublished - 2017

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