Epigenomic profiling of glucocorticoid responses identifies cis-regulatory disruptions impacting steroid resistance in childhood acute lymphoblastic leukemia [post]

Brennan Bergeron, Jonathan Diedrich, Yang Zhang, Kelly Barnett, Qian Dong, Daniel Ferguson, Robert Autry, Wenjian Yang, Baranda Hansen, Colton Smith, Kristine Crews, Yiping Fan (+7 others)
2022 unpublished
Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of childhood acute lymphoblastic leukemia (ALL), and resistance to GCs remains a major clinical concern. Resistance to GCs is predictive of ALL relapse and poor clinical outcome, and therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes implicated in GC resistance, there remains an insufficient understanding of the
more » ... of cis-regulatory disruptions in resistance. To address this, we mapped the gene regulatory response to GCs in two ALL cells using functional genomics and high-throughput reporter assays and identified thousands of GC-responsive changes to chromatin state, including the formation of over 250 GC-responsive super-enhancers and a depletion of AP-1 bound cis-regulatory elements implicated in cell proliferation and anti-apoptotic processes. By integrating our GC response maps with genetic and epigenetic datasets in primary ALL cells from patients, we further uncovered cis-regulatory disruptions at GC-responsive genes that impact GC resistance in childhood ALL. Overall, these data indicate that GCs initiate pervasive effects on the leukemia epigenome, and that alterations to the GC gene regulatory network contribute to GC resistance.
doi:10.21203/rs.3.rs-1617202/v1 fatcat:x5nvnqlgebfszfe6mzmbdq2r7e