MODULATING G9A / GLP POST-TRANSLATIONAL MODIFICATIONS FOR SENSITIZING B-ACUTE LYMPHOBLASTIC LEUKEMIA TO GLUCOCORTICOID THERAPY

Orateur : Coralie POULARD (CRCL, Lyon)

Glucocorticoids (GCs) are used in combination chemotherapies as front-line treatment for B-cell acute lymphoblastic leukemia (B-ALL). Although effective, many patients relapse and become resistant to chemotherapy, and GCs in particular. Why these patients relapse is not clear. We took a comprehensive, functional genomics approach to identify sources of GC resistance. A genome-wide shRNA screen identified the transcriptional coactivators G9a, GLP, and HP1gas important contributors to GC-induced cell death. This complex selectively supports GC-induced expression of genes contributing to cell death. A meta-analysis of gene expression data from B-ALL patient specimens revealed that Aurora kinase B (AURKB), which restrains GC signaling by phosphorylating G9a and GLP, is over-expressed in relapsed B-ALL, suggesting it as a potential contributor to relapse. Inhibition of AURKB enhanced GC-induced expression of cell death genes, resulting in potentiation of GC cytotoxicity in cell lines and relapsed B-ALL patient samples. Since G9a and GLP coactivator activity depends on their self-methylation, another way to increase sensitivity of B-ALL cells to GC is to increase G9a methylation. Lysine methylation is regulated by more than 20 lysine demethylases (KDMs). To identify a category of KDMs involved in G9a demethylation, we used KDM inhibitors. We found a demethylase inhibitor specific for a subfamily of JmjC KDMs that increased G9a methylation and enhanced cell death in a B-ALL cell line by increasing expression of G9a-HP1γ-dependent GR target genes. In vitro G9a demethylation assay were also used to identify G9a demethylases.

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