Biology subjects

Crews, K. R.

Publications and source records attributed to Crews, K. R..

3 recordsLinked to original sources

bioRxiv2026

Glucocorticoid receptor activation reorganizes Wnt/LEF1 regulatory circuitry associated with therapeutic response in B-cell acute lymphoblastic leukemia

Glucocorticoids (GCs) are foundational to B-cell acute lymphoblastic leukemia (B-ALL) therapy, yet how glucocorticoid receptor (GR) activation interacts with lineage regulatory circuitry to shape therapeutic response remains incompletely understood. Using LEF1 to interrogate canonical Wnt regulatory circuitry, we show that GR activation reorganizes GR+LEF1 elements into recruitment, retention, and dissociation states. LEF1 dissociates from Wnt-responsive regulatory elements while being recruited to GRE-rich GR-associated elements that progressively acquire chromatin accessibility, H3K27ac, BRD4 and BRG1. RUNX1 and AP-1 show class-dependent redistribution across LEF1-defined states, extending organization beyond LEF1. GR+LEF1 reorganization is observed in patient-derived B-ALL. GR+LEF1 elements lose accessibility in GC-resistant B-ALL and during diagnosis-to-relapse evolution, with recruitment elements enriched for remodeling. Perturbation of resistance-associated GR+LEF1 elements at BIM and BMF alters GC-induced apoptotic signaling. Together, these findings identify Wnt/LEF1 circuitry as an interface through which therapeutic GR activation reorganizes the B-ALL regulatory landscape into states associated with glucocorticoid response and resistance.

cancer biology↗

bioRxiv2023

Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures

B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated cis-regulatory rewiring in B-ALL. Cis-regulatory rewiring promoted B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. We also identified that over 20% of B-ALL accessible chromatin sites exhibit strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that maintain subtype-specific chromatin architectures. Over 9000 inherited genetic variants were further uncovered that contribute to variability in chromatin accessibility among individual patient samples. Overall, our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks that contribute to transcriptional differences among B-ALL subtypes. HIGHLIGHTSO_LIPro-B progenitor cells as the most common cell-of-origin for B-ALL C_LIO_LIAP-1 TF-associated cis-regulatory rewiring in B-ALL C_LIO_LISubtype-specific accessible chromatin signatures representing 20% of all B-ALL sites C_LIO_LIRole for distinct TFs in promoting subtype-specific chromatin architectures C_LIO_LIThousands of inherited genetic variants identified impacting chromatin state C_LI

cancer biology↗

bioRxiv2020

Effects of NT5C2 germline variants on 6-mecaptopurine metabolism in children with acute lymphoblastic leukemia

6-mercaptopurine (6-MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide metabolites (TGN). Recent genome-wide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6-MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6-MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms (SNPs) nominally associated with erythrocyte TGN during 6-MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6-MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6-MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in-cis. Our results indicated that NT5C2 germline variation significantly contributes to inter-patient variability in thiopurine drug disposition.

genetics↗