B-cell lymphoma

Follicular lymphomas (FL) are the second most common lymphomas after the aggressive Diffuse Large B-Cell Lymphoma (DLBCL) and are still considered incurable. Patients’ outcome is highly heterogeneous, ranging from rapid death for 10 to 15% of patients to survival exceeding 15 years for most patients. Biologically, FL are defined as a proliferation of malignant B cells arising from developmentally blocked germinal center (GC) B cells. A recent gene expression profile study conducted by our team in FL patients showed that the VPREB1 gene was overexpressed in a small group of patients at high risk for progression (Huet et al., 2018). This expression in FL cells is paradoxical since VPREB1 expression is normally limited to progenitor B cells, where it forms with λ5 the substitution light chain which associates with the µ chain to develop the pre-BCR.

The first part of this project will consist in exploring the expression of VPREB1 and potentially a complete pre-BCR in primary FL cells at diagnosis. One of our objectives will also be to confirm / expand the RNA-seq data and in particular the hypothesis of a stem cell-like signature using single cell RNA-seq experiments.

For the second part of the project, the role of VPREB1 in the proliferation and the survival of B cells will be studied using two in vitro models that we are currently developing. The first model is a cell line model in which we will express the VPREB1 gene in order to study its role. The second model is an organoid model that will allow us to study the reaction occurring within the GC (Purwada et al., 2019). We will also use another in vivo model recently developed in collaboration with Oncofactory based on the engraftment of lymph node cellular suspensions from FL patients into chicken embryos. This model also enables to administrate chemotherapy, and to measure its impact on tumoral growth. Moreover, to understand the molecular determinants of response to chemotherapy, we also collect the engrafted cells for integrative single cell RNA-seq. These projects are funded by ANR (FLINOVO project), the Ligue Nationale Contre le Cancer (LNCC) Equipe Labellisée LIGUE 2017, Roche Fundation and AstraZeneca.

Our work is also dedicated to study the functional role of somatic gene anomalies appearing during B-lymphomagenesis. In this context, we are studying the tumor suppressor gene BTG1 and its close relationship with lymphoma of the central nervous system. We show that BTG1 plays a key role during the course of this hemopathy by modulating the activity of the BCAR1 complex and thus, the migration capacities of these cells. We will continue the functional study of this gene in lymphomagenesis, by focusing on the very significant association of BTG1 mutations with activating mutations of MYD88. Having observed that inactivation of BTG1 leads to an increase in the number and functions of the mitochondria, we hypothesize that BTG1 has a role of metabolic "gatekeeper" of tumor transformation of B lymphocytes, following the perspective recently proposed by Markus Münschen. This work is funded by ARC and la Ligue Nationale Contre le Cancer.

The lymphoma incidence rate has more than doubled from 1970 until 2000, and has appeared stable over the last decade. Risk factors related to the development of lymphoma are only partially understood: genetic factors, chronic stimulation of the immune system, environmental exposures, and life style all appear to be contributing factors. We focus our work on the role of inherent single nucleotide polymorphisms (SNPs) studied at a genome-wide (GWAS) level to better understand the role of genetic factors for lymphoma susceptibility. These projects are conducted in the framework of INTERLYMPH consortium. We also investigated the role of germline SNPs associated with outcome of patients with lymphoma. In a first proof of concept GWAS for diffuse large B cell lymphoma (DLBCL) (Ghesquieres et al. J Clin Oncol 2015), an aggressive lymphoma, with cohorts of patients of the Lymphoma Study Association (LYSA) and Mayo Clinic (Rochester, MN, USA), we found for the first-time that genetic variants could predicted patient outcome independently of classical clinical and biological factors. One of top SNPs is localized in a long-non-coding RNA. We currently study the biological effect of this SNP in DLBCL pathogenesis. A new GWAS is ongoing to decipher the prognostic role of genetic variants for follicular lymphoma patients (INCa PRT-K grant).