Document Type
Article
Publication Date
1-1-2026
Original Citation
Ghamlouch H,
Degaud M,
Della-Valle V,
Eeckhoutte A,
Armand M,
Joudat A,
Decaudin C,
Dominguez P,
Rosikiewicz W,
Pawlikowska P,
Darwiche W,
Mouly E,
Li S,
Melnick A,
Aoufouchi S,
Bernard O.
Tet2 deficiency promotes IgG1+ B-cell expansion and differentiation blockade through deregulation of the Nfkbia-c-Rel axis Hemasphere. 2026;10(1):e70296.
Keywords
JGM
JAX Source
Hemasphere. 2026;10(1):e70296.
ISSN
2572-9241
PMID
41536808
DOI
https://doi.org/10.1002/hem3.70296
Abstract
The germinal center (GC) reaction is essential for orchestrating humoral immunity by producing plasma cells (PCs) and memory B cells (MBCs). TET2, an α-ketoglutarate-dependent dioxygenase, plays a critical role in B-cell exit from the GC and in plasma cell differentiation. Moreover, TET2 functions as a tumor suppressor in diffuse large B-cell lymphoma (DLBCL), with mutations frequently observed in the ST2 DLBCL subgroup, which is marked by elevated NF-κB and PI3K signaling and predominant expression of IgG B-cell receptors (BCRs). We used a combination of in vivo mouse models and in vitro differentiation systems to investigate the effects of Tet2 deficiency on IgG1+ GC B-cells. We performed flow cytometry, gene expression, and DNA methylation analysis to assess differentiation, proliferation, and molecular alterations. Tet2-deficient IgG1+ GC B-cells displayed impaired differentiation into both PCs and MBCs, accompanied by enhanced proliferation. These cells exhibited hypermethylation and repression of the Nfkbia locus, increased activation of the NF-κB subunit c-Rel, and sustained high levels of surface IgG1. Upon recall immunization, Tet2-deficient IgG1+ MBCs failed to efficiently differentiate into PCs, resulting in their accumulation and further GC expansion. These findings demonstrate that Tet2 is essential for balancing proliferation and terminal differentiation of IgG1+ GC B-cells during the humoral response. The impaired regulation of this balance due to Tet2 loss provides mechanistic insight into a contributory pathway that may facilitate DLBCL transformation in TET2-mutated cases.
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