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Effect of B cell receptor class-switching on lymphoma cells

ABSTRACT: Although immunoglobulin class-switching from IgM to IgG enhances B cell receptor (BCR) signalling and antibody responses, certain subsets of B cell lymphomas retain unswitched IgM BCRs despite signs of class-switching in the immunoglobulin heavy chain loci. This suggests that expression of the IgG BCR suppresses progression of specific lymphoma subsets. We found that inducing BCR class switching from IgM to IgG1 or IgG4 inhibits proliferation of EZB DLBCL lymphoma cell lines. To understand changes associated with class-switching we compared transcritional profiles of isogenic WSU-FSCCL and NU-DHL1 cell lines artificially class-switched to express IgM and IgG1 BCRs. In addition, we analysed transcriptional profiles of IgG1+ cell lines into which we introduced the IgG1 W375* mutation that truncates the intracellular IgG tail.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313929 | GEO | 2025/12/17

REPOSITORIES: GEO

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	GSE313929_Raw_counts_and_FPKM_values.xlsx	Xlsx

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Project description:Majority of B cell malignancies originate in the germinal centers (GCs), where B cells undergo activation to mutationally diversify their antibody genes and switch from the default Immunoglobulin M (IgM) or IgD B cell receptor (BCR) to IgG, IgA or IgE BCR isotypes. Similar to normal B cells, malignant B cells rely on signals emanating from the BCR for their survival and growth. While studies have primarily focused on elucidating the functions of IgM-mediated signaling in lymphoma pathogenesis, GC-derived lymphomas also express IgG and IgA BCR isotypes that greatly differ from IgM in their signaling potential. How these distinct non-IgM BCRs contribute to the pathogenesis of B cell malignancies is not well understood. Interestingly, B cell lymphoma patients expressing IgG BCR isotypes show better prognosis and survival than those expressing IgM BCR isotype. Consistent with this, we show that Diffuse Large B Cell Lymphoma (DLBCL) patients with higher IgG1 expression are associated with lower stages of disease than those with higher IgM expression. To directly test the roles of distinct BCR isotypes, we developed isogenic lymphoma cells that either express IgM or IgG1 BCRs. Interestingly, the IgG1-switched lymphoma cells fail to form tumors in mice whereas their IgM counterparts establish aggressive tumors. Moreover, co-transplantation of IgG1 and IgM expressing human and mouse lymphoma cells leads to emergence of tumors expressing IgM (and not IgG1), demonstrating that IgM BCRs are strongly favored over IgG1. Mechanistically, IgG1 expressing lymphoma cells and non-malignant activated B cells have reduced survival which is associated with a dysfunctional mitochondrial state triggered by stronger calcium responses in IgG1 in comparison to IgM cells. Genetic reversal of IgG1 to IgM or pharmacological dampening of the calcium signaling is sufficient to correct the mitochondrial defects and rescue the survival of IgG1 B cells. Our findings demonstrate that distinct BCR isotypes are inherently unique in their activities and can differentially impact B cell lymphoma pathogenesis.

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Effect of B cell receptor class-switching on lymphoma cells

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