Protein arginine methyltransferase 1 regulates B cell fate after positive selection in the germinal center in mice

Abstract

Positively selected germinal center B cells (GCBC) can either resume proliferation and somatic hypermutation or differentiate. The mechanisms dictating these alternative cell fates are incompletely understood. We show that the protein arginine methyltransferase 1 (Prmt1) is upregulated in murine GCBC by Myc and mTORC-dependent signaling after positive selection. Deleting Prmt1 in activated B cells compromises antibody affinity maturation by hampering proliferation and GCBC light zone to dark zone cycling. Prmt1 deficiency also results in enhanced memory B cell generation and plasma cell differentiation, albeit the quality of these cells is compromised by the GCBC defects. We further demonstrate that Prmt1 intrinsically limits plasma cell differentiation, a function co-opted by B cell lymphoma (BCL) cells. Consistently, PRMT1 expression in BCL correlates with poor disease outcome, depends on MYC and mTORC1 activity, is required for cell proliferation, and prevents differentiation. Collectively, these data identify PRMT1 as a determinant of normal and cancerous mature B cell proliferation and differentiation balance.

B-cell intrinsic regulation of antibody mediated immunity by histone H2A deubiquitinase BAP1

“…We therefore proceeded to directly test the effects of Bap1 -loss on antibody class switching in vitro . Induced GC B cells (iGBs) of Bap1 fl/fl Cγ1- Cre and control Bap1 +/+ Cγ1- Cre genotypes were generated on the 40LB feeder cells that provide CD40L and BAFF, as described previously ( 58 , 60 ). iGBs were analyzed at day 4 for class switching to IgG1 and demonstrated no significant differences between the Bap1 fl/fl Cγ1- Cre and control Bap1 +/+ Cγ1- Cre cultures ( Figures 4A, B ).…”

“… Loss of BAP1 does not impair immunoglobulin class switching in primary B cells. (A–F) Induced GC B cells (iGB) of Bap1 fl/fl Cγ1-Cre and control Bap1 +/+ Cγ1-Cre genotypes were generated on 40LB feeders, as described previously ( 58 , 60 ), and analyzed at day 4 of culture for (A–C) immunoglobulin class switching to IgG1, and (C, D) cell proliferation using the CellTrace Violet (CTV) dilution method. (E) Growth curves of iGBs of Bap1 fl/fl Cγ1-Cre and control Bap1 +/+ Cγ1-Cre genotypes over a 6-day time course, evaluated with cell counting and demonstrating the impaired proliferation of Bap1 -deficient B cells.…”

“…The protocols were as described in our recent work ( 58 ). Briefly, naïve primary mouse B cells were purified from splenocytes using EasySep™ Mouse B Cell Isolation Kit (19854, Stem Cell Technologies) and were cultured at 37°C with 5% CO 2 in iGB media: RPMI-1640 (Wisent), supplemented with 10% FBS (Wisent), 1% penicillin/streptomycin (Wisent), 0.1 mM 2-mercaptoethanol (BioShop), 10 mM HEPES, and 1 mM sodium pyruvate.…”

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells

“…In addition, the combination treatment triggered the downregulation of arginine methylation and protein arginine methyltransferases (PRMTs). PRMTs expression correlates with the activation of resistance pathways associated with lower progression-free survival 24 and is upregulated through MYC and mTORC1 activation 41 , suggesting that Palbociclibsurviving cells might have acquired chemoresistance through an epigenetic mechanism.…”

“…In addition, the combination treatment triggered the downregulation of arginine methylation and protein arginine methyltransferases (PRMTs). PRMTs expression correlates with the activation of resistance pathways associated with lower progressionfree survival (Zhu et al, 2022) and is upregulated through MYC and mTORC1 activation (Litzler et al, 2023), suggesting that Palbociclib-surviving cells might have acquired chemoresistance through an epigenetic mechanism. Moreover, gene set enrichment analysis confirmed that tumors subjected to the double therapy exhibited a downregulation in metastasis, cell cycle progression, and MYC and mTOR oncogenic pathways, consistent with the downregulation of PRMTs observed (Litzler et al, 2023).…”