Epigenomic profiling of glucocorticoid responses identifies cis-regulatory disruptions impacting steroid resistance in childhood acute lymphoblastic leukemia.
Brennan P BergeronJonathan D DiedrichYang ZhangKelly R BarnettQian DongDaniel C FergusonRobert J AutryWenjian YangBaranda S HansenColton SmithKristine R CrewsYiping FanChing-Hong PuiShondra M Pruett-MillerMary V RellingJun J YangChunliang LiWilliams E EvansDaniel SavicPublished in: Leukemia (2022)
Glucocorticoids (GCs) are a mainstay of contemporary, multidrug 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 impact of cis-regulatory disruptions in resistance. To address this, we mapped the gene regulatory response to GCs in two ALL cell lines 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.
Keyphrases
- acute lymphoblastic leukemia
- transcription factor
- genome wide
- high throughput
- gas chromatography
- cell proliferation
- dna methylation
- gene expression
- single cell
- cell death
- bone marrow
- machine learning
- cancer therapy
- cell cycle
- newly diagnosed
- oxidative stress
- acute myeloid leukemia
- radiation therapy
- squamous cell carcinoma
- allogeneic hematopoietic stem cell transplantation
- copy number
- signaling pathway
- patient reported outcomes
- early life
- rna seq
- free survival
- combination therapy
- patient reported
- artificial intelligence
- simultaneous determination
- pi k akt
- rectal cancer
- anti inflammatory