Biology subjects

Faumont, N.

Publications and source records attributed to Faumont, N..

5 recordsLinked to original sources

bioRxiv2023

REL deregulation stands as a primary hit for AID-imprinted B-cells along the germinal center competition

In diffuse large B-cell lymphomas (DLBCLs), gains and amplifications of the 2p15-16 region, which always encompass the REL gene, are mostly restricted to the germinal center (GC) B- cell DLBCL subtype (GCB-DLBCL) for which c-Rel is the pivotal Rel/NF-{kappa}B subunit. While REL is also known to play a key role in the GC reaction, its contribution to GCB-DLBCL transformation is still unclear. To understand the role of REL in the very first steps of GCB transformation, i.e when B-cells with deregulated REL are competing with other B-cells during chronic antigenic stimulation, we have created a dual-color mouse that allows to induce REL in a limited pool of AID- imprinted B-cells after immunization and to differentially stain AID-imprinted B-cells cells that overexpress REL or not. Our results demonstrate that dysregulation of REL at the GC B-cell stage promotes GC B-cell expansion and favors both class-switch recombination and plasma cell differentiation. Additionally, although REL overexpression was neutral on post-GC memory B-cell differentiation, it did confer a long-term competitive advantage allowing for GC persistence and continuous recirculation of REL-overexpressing B-cells. Functionally, REL enhanced the protection against apoptosis in the early steps of GCB differentiation. REL- overexpressing B-cells can my occasionally transform into in an aggressive B-cell tumor. Highlighting the role of repeated immune responses, our results confirm the role of REL in the germinal center reaction and provide evidence supporting the fact that genetic deregulation of c-Rel expression is most likely a primary event in the aggressive transformation of GC B-cells. Key points- REL provides a long-term competitive advantage allowing for GC B-cell persistence and continuous recirculation of AID-imprinted B-cells - AID-imprinted B-cells overexpressing REL can occasionally transform into aggressive B-cell lymphomas Explanation of the noveltyBy showing in a new dual-color mouse model that dysregulation of REL in a very limited pool of AID-imprinted B-cells confers a strong long-term competitive advantage in the context of repeated immune responses and may occasionally lead to transformation into an aggressive B- cell lymphoma, we provide for the first time experimental evidence supporting the fact that that REL is most likely a primary event in the aggressive transformation of germinal center B-cells.

cancer biology↗

bioRxiv2020

Splice switching oligonucleotide mediated gene knockdown in B cells and plasma cells

The need to identify new therapeutic approaches to the treatment of cancers of the B lymphoid lineage is crucial. Unlike CRISPR/Cas technology, antisense strategies result in transient modifications of gene expression and lack mutagenic effects at the DNA level. Here, we provide evidence for efficient knockdown of c-REL and RELA expression after treatment with splice switching antisense oligonucleotides (SSO) inducing exon skipping and reading frameshifts. We also developed a tool to facilitate the choice of exons for on purpose inhibition of mouse and human gene expression. Interestingly, treatments with morpholino SSO targeting the c-REL exon 2 donor splice site or RELA exon 5 acceptor splice site elicited very efficient knockdown in diffuse large B cell lymphoma (DLBCL) cell lines and antibody-secreting cells derived from primary human B cells. Consistent with the clinical relevance of c-REL activation in DLBCLs, treatment with c-REL SSO induced major alterations in NF-{kappa}B and TNF signalling pathways and strongly decreased cell viability. Altogether, SSO-mediated knockdown is a powerful approach to transiently inhibit the expression of given genes in B-lineage cells that should pave the way for cancer treatments, provided optimized ligand-conjugations for in vivo delivery. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/302984v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@170de4forg.highwire.dtl.DTLVardef@113229corg.highwire.dtl.DTLVardef@145377forg.highwire.dtl.DTLVardef@13e8c1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

B-cell enforced expression of the mouse ortholog of MYD88L265P is responsible for Waldenstrom-like B-cell lymphoma.

Here, we created a conditional transgenic mouse model with insertion of a sequence coding for both MYD88L252P and the Yellow Fluorescent Protein (YFP) into the rosa26-locus. B-cell specific induction of the transgene constantly led to spleen enlargement with expansion of YFP positive B-cells in 8-12 month-old mice, with a moderate B-cell proliferation increase. Being clonal or oligoclonal, these B-cells exhibited a marked morphological and immunophenotypic lymphoplasmocytic aspect with a plasma cell transcriptomic signature and a serum immunoglobulin M peak. Therefore, continuous activation of MYD88 in mice can lead on its own to a lymphoma close to Waldenstrom Macroglobulinemia.\n\nKey pointB-cell specific enforced expression of MYD88L252P leads to a clonal indolent lymphoplasmocytic B-cell lymphoma with a serum IgM peak.

cancer biology↗

bioRxiv2018

Pre-Clinical Blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma.

Escape from immune control must be important in the natural course of B-cell lymphomas, especially for those with activation of NF-{kappa}B. The pre-clinical L.CD40 transgenic mouse model is characterized by B-cell specific CD40 signaling responsible for NF-{kappa}B continuous activation with a spleen monoclonal B-cell tumor after one year in 60% of cases. L.CD40 tumors B-cells expressed high levels of PD-L1. This expression was dependent on activation of either NF-{kappa}B, JAK1/JAK2 or BTK pathways since ex vivo treatment with the inhibitory molecules PHA-408, ruxolitinib and ibrutinib led to decrease of its expression. Treatment of L.CD40 lymphomatous mice with an anti-PD-L1 monoclonal antibody induced tumor regression with decreased spleen content, activation and proliferation rate of B-cells as well as a marked increase in T cell activation, as assessed by CD62L and CD44 expression. These results highlight the interest of therapies targeting the PD-1/PD-L1 axis in activated lymphomas with PD-L1 expression, with possible synergies with tyrosine kinase inhibitors.

cancer biology↗

bioRxiv2018

Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice.

Transformation of an indolent B-cell lymphoma is associated with a more aggressive clinical course and poor survival. The role of immune surveillance in the transformation of a B-cell indolent lymphoma towards a more aggressive form is poorly documented. To experimentally address this question, we used the L.CD40 mouse model, which is characterized by B-cell specific continuous CD40 signaling, responsible for spleen indolent clonal or oligoclonal B-cell lymphoma after one year in 60% cases. Immunosuppression was obtained either by T/NK cell depletion or by treatment with the T-cell immunosuppressive drug cyclosporin A. Immunosuppressed L.CD40 mice had larger splenomegaly with increased numbers of B-cells in both spleen and peripheral blood. High-throughput sequencing of immunoglobulin variable segments revealed that clonal expansion was increased in immunosuppressed L.CD40 mice. Tumor B cells of immunosuppressed mice were larger with an immunoblastic aspect, both on blood smears and spleen tissue sections, with increased proliferation rate and increased numbers of activated B-cells. Collectively, these features suggest that immune suppression induced a shift from indolent lymphomas into aggressive ones. Thus, as a preclinical model, immunosuppressed L.CD40 mice reproduce aggressive transformation of an indolent B-cell tumor and highlight the role of the immune surveillance in its clinical course, opening new perspective for immune restoration therapies.\n\nSummary statementHighlighting the role of immune surveillance, transformation of indolent B-cell lymphoma into an aggressive malignancy is experimentally reproduced after T-cell immune suppression in the L.CD40 preclinical mouse model.

cancer biology↗