Fabienne Desmots (research engineer), Céline Pangault (assistant professor), Cédric Pastoret (medical doctor), Thierry Lamy (PU-PH), Marie-Laure Boulland (research engineer), Francisco Llamas Guiterrez (PH)
Follicular Lymphoma’s addiction to epigenetic alterations, with lesions in epigenetic modifiers occurring in nearly all patients is nowadays well established. For example, the loss-of-function mutations in the histone acetyltransferase domain of CREBBP gene in found in about 60% of FL and 30% in DLBCL. These mutations are drivers in lymphomagenesis by impairing the acetylation of non-histone proteins p53 and BCL6, which lead to a constitutive repression of target gene that could explain part of the FL blockade. Moreover, some clinical trial indicates a benefit of HDACi treatment with long term durable response in FL but with a high heterogeneity in the response. In the case of DLBCL, patients are resistant to the treatment but this could be circumvented by combination with other therapeutics. Given the potential benefit of HDACi treatment in lymphoma, but the high heterogeneity in the response, there is a need to identify patients most likely to respond to HDACi. Besides genes inactivation by mutations, it has been shown that expression of lncRNA and miRNA could be involved in the differentiation blockade and drug resistance of FL/ DLBCL. Their mode of action through chromatin modifications makes them perfect targets for epidrugs treatment.
In other lymphoproliferations, chromatin modifications are observed, in particular in methylation status. In our group, we are here focusing on chronic lymphoprofiferative disorders of NK cells (CLPD-NK) with DNA hypermethylation linked to TET2 and DNMT3A mutations.
This project aims to decipher epigenetic mechanisms leading to tumor development with the final objective to improve the diagnosis and/or the treatment of patients with lymphoma
- To investigate the functional modification of FL B cells after treatment with epigenetic-modifier drugs in order to identify responder patient profile, using in vitro model with conditioned supportive stroma.
- To determine the non-coding RNA (lncRNA and miRNA) implicated in epigenetic regulation of FL.
- To identify and characterize FL and DLBCL non-coding driver mutations.
- To investigate plasma biomarkers (LncRNA and cfDNA) in FL and DLBCL.
- To decipher molecular landscape of CLPD-NK (linking DNA methylation pattern to transcriptomic and mutational profile of CLPD-NK