Project description: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. To therefore better understand the role of gene regulatory alterations in GC resistance, we comprehensively mapped the GC gene regulatory network in two ALL cell lines using orthogonal functional genomic assays and identified tens of thousands of GREs in the ALL genome. A closer examination revealed binding profiles that were consistent with the long-range flexible billboard model of gene regulation. GCs also induced the formation of over 250 super-enhancers, and these GC-responsive super-enhancers control the expression of genes mediating GC resistance. By further integrating our results with genetic and epigenetic data in primary ALL cells from patient cohorts at St. Jude, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and validated an associated variant within the TLE1 gene locus. We also uncovered that 1929 accessible chromatin sites associated with ex vivo GC resistance were significantly enriched at GREs. A CRISPR interference screen of these elements validated their effects on GC resistance. Overall, these data suggest that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, while genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL.

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Tracking Therapy-Resistant Alterations in Childhood Acute Lymphoblastic Leukemia

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