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Target epigenetic modifiers in Multiple Myeloma to develop lethal combinations and overcome drug resistance

Mardi 5 septembre 2017 11:00 - Duree : 1 heure
Lieu : Salle de Conférence de l’IAB - Rond Point de La Chantourne, 38700 La Tronche (arrêt de tram Grand Sablon, ligne B)

Orateur : Jérôme MOREAUX (CHU Montpellier)

Multiple Myeloma (MM) is a neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance. Using a microarray-based genome-wide screen for genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 DNA helicase among the most downregulated genes. RECQ1 is significantly overexpressed in MM cells and RECQ1 knockdown inhibits cells growth, induces apoptosis and promotes the development of DNA double-strand breaks. In contrast, RECQ1 overexpression protects MMCs from melphalan and bortezomib cytotoxicity. RECQ1 interacts with PARP1 in MMCs exposed to treatment and RECQ1 depletion sensitizes MMCs to PARP inhibitor. DNMT inhibitor treatment results in RECQ1 downregulation through miR203 deregulation in MMC. Altogether, these data suggest that association of DNA damaging agents and/or PARP inhibitors with DNMT inhibitors may represent a therapeutic approach in patients with high RECQ1 expression, associated with a poor prognosis. We also investigated the epigenetic genes differentially expressed between normal plasma cells and MM plasma cells from patients. Among all the epigenetic actors, we identified that MM cells significantly overexpressed predominantly histone methyltransferases in association with a poor prognosis including EZH2. Specific EZH2 inhibition by EPZ-6438 leads to the growth inhibition of a subgroup of myeloma cell lines and primary MM cells of patients. Using RNA-seq and ChIP-seq data, we establish a gene expression-based EZ-score allowing to identify poor prognosis patients that could benefit from EZH2 inhibitor treatment. We also demonstrate a synergistic effect of EPZ-6438 and Lenalidomide, a conventional drug used for MM treatment. Furthermore, pretreatment with EPZ-6438 significantly re-sensitizes drug-resistant MMCs to Lenalidomide. These data suggest that the association of EZH2 inhibitors with IMiDs may represent a therapeutic approach in patients with high EZ-score associated with a poor prognosis. The aim of our projects is to increase our knowledge of MM development, progression and drug resistance, as well as, develop new therapeutic strategies in order to improve the treatment of patients with MM.

Contact : karin.sadoul@univ-grenoble-alpes.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (IAB)
Nature évènement : (Séminaire)
Evènement répétitif : (Mardis de l’IAB)
Site de l'évènement : Pôle Santé / La Tronche

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