Presentation of Normal, Tumor B cell Differentiation & EnVIronmentaL Cues (B_DEVIL)



Our team is devoted to the analysis of terminal B cell differentiation, more precisely when a B cell activates and progresses towards its destiny. In a large majority of cases, B cells after having proliferated intensively undergo cell death. However, some cells which process properly numerous external signals and cues are going to differentiate either as memory B cells or metamorphose and give rise to plasmablasts, progenitors of plasma cells (PCs). This differentiation process is highly regulated, implicating a diversity of molecular events at the transcriptional and epigenetic levels. B-cell differentiation can be hijacked by oncogenetic events allowing the emergence of several forms of non-Hodgkin’s lymphomas, each entity emerging from a specific B cell maturation state. Finally, tumor B-cell genotype and phenotype impact tumor microenvironment. Exploring this relationship is of great interest and paves the way for new therapeutics.

In order to study the molecular events that control terminal B-cell differentiation we developed a defined primary culture system combining BCR signal, Toll like receptor activation and T cell help in the form of CD40L and cytokines to differentiate human naive B cells into PCs (LeGallou et al. JI 2012). It provides a highly accessible model to catch the transient states of activation and to follow single cell destiny. Furthermore, perturbing the differentiation path by transient inhibition of genes or pathways is a powerful way to elucidate the causality of events and could enable the discovery novel molecular mechanisms involved in the pathogenesis of lymphomas.

We have demonstrated that this model is well suited to study temporal dynamics of signaling, pathways regulating transcription factors in conjunction with cell survival, proliferation and differentiation and to investigate transcriptome and epigenome reprogramming during terminal B cell differentiation (Caron et al. Cell Rep 2015, Hipp et al. Nat Comm 2017, Pignarre et al. Blood 2021, Lemarié et al. Front Immunol 2021).

We are continuing our investigations in this area through several complementary approaches (Figure 1): i) in mice models and at the level of single cell fate decisions (Project 1); ii) by validating unappreciated factors in triggering plasma cell differentiation and functions (Projects 2 & 4); iii) by developing integrative genomic tools to explore regulatory networks (Project 3). Finally, we are taking advantage of all the acquired knowledge to gain insight on germinal center-derived lymphomas, i.e. Waldenström disease, indolent follicular lymphoma and aggressive diffuse large B cell lymphoma (Azzaoui I et al. Blood 2016, Rossille et al. Leukemia 2017, Allain et al. Haematologica 2018, Desmots et al. Clin Cancer Res 2019, Chatonnet et al. Haematologica 2020, Pangault et al. Cancers 2020, Roussel et al. Blood Adv 2021).



Thierry FEST                                                               Figure 1. Graphical summary of the organization of B_DEVIL research projects.

Research projects are organized in four axes related to plasma cell programming and B cell plasticity during normal humoral immune response and during diseases. Blue color stands for normal terminal B-cell differentiation while red cells illustrate lymphoproliferative disorders analyzed by the team.

Main research publications and achievements

1. Characterization of final commitment steps of human B cell differentiation into plasmablasts and translational in multiple myeloma with: *) Transcriptional and methylome characterization of the committal step (Caron, Cell Reports 2015), **) Molecular characterization of the PC commitment and cell signaling modifications (Pignarre, Blood 2021, Lemarié, Front Immunol 2021); ***) 5-Hydroxymethyl-DNA comparison between normal and tumor plasma cells (Chatonnet, Haematologica 2020).

2. B cell signalization and early plasma cell fate decision: description of the IL2/ERK/ELK1 control of BACH2 expression regulation plasma cell commitment (Hipp, Nat Com 2017).

3. Control of the BCL6 / PRDM1 balance in plasma cell differentiation : description that follicular lymphoma B cells have an IL-21 / STAT3 / PRDM1 defective pathway due to CREBBP inactivation (Desmots, Clin Cancer Res 2019).

4. New bioinformatic tools to integrate iterative & multiple genomic investigations:  development of a semantic web technics for structuring heterogeneous datasets (Louarn, Proc IEEE Int Conf Escience, 15th eScience 2019, San Diego, CA).

5. Investigations of lympho-plasmocytic IgM disorders: comparison between anti-myelin-associated glycoprotein neuropathies and IgM gammopathies (Allain, Haematologica 2018).

6. Malignant B cell lymphoma and prognosis factors: soluble PD-L1 as a prognostic marker in DLBCL (Rossille, Leukemia 2017)

7. Linking the KIR phenotype with STAT3 and TET2 mutations to identify  chronic lymphoproliferative disorders of NK cells (Pastoret, Blood 2021)