Gersende Caron-Lacombe (research engineer), Maud Lemarié (postdoctoral fellow), Virginie Girault (research engineer), Sabrina Cherfa (engineer), Marion Haas (Ph.D. student), Vincent Olivier (Master 2), Olivier Decaux (PU-PH)
The differentiation of antibody-secreting cells (ASC) from B cells -generating both cycling plasmablasts (PB) and long-lived PCs – is crucial for adaptive immunity and involves several complex molecular mechanisms which dysfunctions lead to a great variety of hematological malignancies. We previously developed an in vitro model for B cell differentiation (Le Gallou et al., JI 2012), that, combined with integrated genomic approaches, allowed us to characterize late genomic events and undocumented mechanisms driving human ASC differentiation, such as epigenetic changes (Caron et al., Cell Rep 2015) and the extinction of IL-4 / STAT6 signaling and CBLB ubiquitin ligase expression concomitant to IRF4 induction (Pignarre et al., Blood 2020) (Figure 1).
Figure 1: PBs derive from CD23-negative activated B cells after the extinction of the IL-4 / STAT6 signaling pathway and IRF4 induction
Using this in vitro model, we identified three new actors involved in the terminal B cell differentiation process or in ASC biology.
The aim of this axis is to investigate their involvement in the terminal B cell differentiation, and in normal and tumoral ASC survival.
- To decipher the regulation of the scaffold protein Caveolin-1 during B cell differentiation and its role in PC biology. CAV1 can form and stabilize dynamic membrane signaling scaffolds thereby controlling B cell signaling pathways and PC survival.
- To characterize the mechanisms of the serine threonine kinase PIM-2 in apoptosis inhibition and G1 / S transition in normal and tumoral PC. PIM-2 confers to PB-committed cells and PC a cell-autonomous survival effect.
- To characterize the molecular effects of the long non-coding RNA LUMM on primary normal and tumoral B cells and study the therapeutic effects of silencing LUMM activity. The pro-oncogenic lncRNA LUMM regulates cell death and could present a target of interest for the treatment of multiple myeloma and plasmablastic lymphoproliferative diseases.