LRH‐1/NR5A2 interacts with the glucocorticoid receptor to regulate glucocorticoid resistance

Nuclear receptors are transcription factors with important functions in a variety of physiological and pathological processes. Targeting glucocorticoid receptor (GR) activity using glucocorticoids is a cornerstone in the treatment of patients with T cell acute lymphoblastic leukemia (T‐ALL), and resistance to GC‐induced cell death is associated with poor outcome and a high risk for relapse. Next to ligand‐binding, heterodimerization with other transcription factors presents an important mechanism for the regulation of GR activity. Here, we describe a GC‐induced direct association of the Liver Receptor Homolog‐1 (LRH‐1) with the GR in the nucleus, which results in reciprocal inhibition of transcriptional activity. Pharmacological and molecular interference with LRH‐1 impairs proliferation and survival in T‐ALL and causes a profound sensitization to GC‐induced cell death, even in GC‐resistant T‐ALL. Our data illustrate that direct interaction between GR and LRH‐1 critically regulates glucocorticoid sensitivity in T‐ALL opening up new perspectives for developing innovative therapeutic approaches to treat GC‐resistant T‐ALL.