Mutual antagonism between glucocorticoid and canonical Wnt signaling pathways impacts steroid resistance in acute lymphoblastic leukemia [CUT&RUN]

Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. In this work (which is a follow-up of our recent study- Bergeron et al. Leukemia 2022), we uncovered the genomic mechanism linking disruptions to the Wnt repressor gene TLE1 with glucocorticoid (GC) drug resistance in acute lymphoblastic leukemia. In this process we uncovered extensive crosstalk and mutual antagonism between GC signaling and canonical Wnt signaling in ALL cells at the DNA sequence, transcriptome and proteome levels. CUT&RUN was performed in Nalm6 cells with or without prednisolone treatment. Cells grown in standard culture conditions were treated with prednisolone (5uM for Nalm6 cells) for 24 hours. Half a million cells were collected for each replicate from independent experiments. 1ul of LEF1 antibody or 0.5ug of IgG was used for each replicate.