SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic...

Glucocorticoids are a mainstay in the treatment of B-cell acute lymphoblastic leukemia (B-ALL). The glucocorticoid receptor (GR), a ligand-activated transcription factor (TF), mediates their actions. Chromatin occupancy, chromatin-protein networks (chromatomes) and gene programmes of GR are regulated by SUMOylation, a post-translational modification with therapeutic implications in other hematomalignancies. To unravel the GR-SUMOylation crosstalk in B-ALL, we induced hypoSUMOylation in NALM6 B-ALL cells with a SUMOylation inhibitor (SUMOi, ML-792). Genome-wide profiling of GR and SUMO chromatin-binding and chromatin accessibility revealed that hypoSUMOylation augmented GR chromatin occupancy and altered chromatin openness. Association with transcriptome data indicated that the hypoSUMOylation-induced GR-binding sites predominantly repressed genes associated with cell cycle and DNA replication. Consistently, hypoSUMOylation potentiated glucocorticoid-induced cell cycle arrest and growth suppression. Moreover, our proteomic analyses revealed that the protein network of chromatin-bound GR is tightly intertwined with SUMO2/3 and that SUMOylation modulates the stability of the network. The chromatome contained several B-cell TFs with cognate binding motifs found on GR-adjacent chromatin sites, indicating their simultaneous occupancy on chromatin. In sum, our data imply potential for targeting SUMOylation to increase sensitivity to glucocorticoids in B-ALL, supported by ex vivo data of glucocorticoid and SUMOi TAK-981 combination-treated B-ALL patient samples.