CD20 and CD19 promote proliferation driven by the IgM-TLR9-L265P MyD88 complex.

in International immunology by Yohei Kobayashi, Ryota Sato, Yuri Shimizu, Ryutaro Fukui, Takuma Shibata, Hiroki Tsukamoto, Takeshi Tsubata, Kensuke Miyake

TLDR

  • The study shows that CD19 and CD20 contribute differently to the proliferation driven by the My-T-BCR complex in activated B cell-like diffuse large B cell lymphoma.
  • CD19 promotes IgM-dependent AKT phosphorylation, while CD20 enhances IgM-TLR9 complex formation and IgM-mediated proliferation.

Abstract

The cancer driver mutation L265P MyD88 is found in approximately 30 % of cases in the activated B cell-like subgroup of diffuse large B cell-like lymphoma (ABC DLBCL). L265P MyD88 forms a complex with TLR9 and IgM, referred to as the My-T-BCR complex, to drive proliferation. We here show that the B cell surface molecules CD19 and CD20 enhance proliferation mediated by the My-T-BCR complex. Using the IL-3-dependent Ba/F3 line transduced to express the IgM complex (IgM, CD79a, and CD79b) and TLR9, we observed proliferation in the presence of anti-IgM antibody and the TLR9 ligand CpG-B. TLR9 was constitutively associated with IgM and L252P MyD88. CD19 promoted proliferation with anti-IgM and CpG-B specifically in L252P MyD88-expressing Ba/F3 cells, while CD20 enhanced the proliferation in both wild-type- and L252P MyD88-expressing Ba/F3 cells. Additionally, CD20 uniquely enabled IgM-mediated proliferation in L252P MyD88-expressing Ba/F3 cells. Although CpG-B was not required for this proliferation, TLR9 expression remained indispensable. In the ABC DLBCL line TMD8, anti-IgM Ab mediated growth was impaired by the lack of CD20 and CD19 or of TLR9. Mechanistically, CD19 promoted IgM-dependent AKT phosphorylation, whereas CD20 increased expression of cell surface IgM, thereby enhancing the formation of the IgM-TLR9 complex. These findings suggest that CD19 and CD20 differentially contribute to the proliferation driven by the My-T-BCR complex.

Overview

  • The study investigated the role of B cell surface molecules CD19 and CD20 in enhancing proliferation mediated by the My-T-BCR complex in activated B cell-like diffuse large B cell lymphoma.
  • The study used the IL-3-dependent Ba/F3 line and the ABC DLBCL line TMD8 to investigate the role of CD19 and CD20 in My-T-BCR complex-driven proliferation.
  • The study focused on understanding the mechanisms underlying the differential contribution of CD19 and CD20 in My-T-BCR complex-driven proliferation.

Comparative Analysis & Findings

  • CD19 promoted IgM-dependent AKT phosphorylation and enhanced proliferation in L252P MyD88-expressing Ba/F3 cells.
  • CD20 enhanced proliferation in both wild-type- and L252P MyD88-expressing Ba/F3 cells, but uniquely enabled IgM-mediated proliferation in L252P MyD88-expressing cells.
  • TLR9 expression was indispensable for IgM-mediated proliferation, and CD20's ability to enhance proliferation was dependent on TLR9 expression.

Implications and Future Directions

  • The study's findings suggest that targeting CD19 and CD20 may provide a novel therapeutic approach for treating activated B cell-like diffuse large B cell lymphoma.
  • Further studies are needed to explore the mechanisms underlying the differential contribution of CD19 and CD20 in My-T-BCR complex-driven proliferation.
  • The study's findings highlight the importance of considering the interactions between IgM, TLR9, and B cell surface molecules in understanding the pathogenesis of activated B cell-like diffuse large B cell lymphoma.
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