Epigenomic Mapping Reveals Distinct B Cell Acute Lymphoblastic Leukemia Chromatin Architectures and Regulators

Authors

Kelly R Barnett
Robert J Mobley
Jonathan D Diedrich
Brennan P Bergeron
Kashi Raj Bhattarai
Alexander C Monovich
Shilpa Narina
Wenjian Yang
Kristine R Crews
Christopher S Manring
Elias Jabbour
Elisabeth Paietta
Mark R Litzow
Steven M Kornblau
Wendy Stock
Hiroto Inaba
Sima Jeha
Ching-Hon Pui
Charles G Mullighan
Mary V Relling
Shondra M Pruett-Miller
Russell J H Ryan
Jun J Yang
William E Evans
Daniel Savic

Publication Date

12-13-2023

Journal

Cell Genemics

Abstract

B cell lineage acute lymphoblastic leukemia (B-ALL) is composed of diverse molecular subtypes, and while transcriptional and DNA methylation profiling has been extensively examined, the chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq in primary B-ALL cells from 156 patients spanning ten molecular subtypes and present this dataset as a resource. Differential chromatin accessibility and transcription factor (TF) footprint profiling were employed and identified B-ALL cell of origin, TF-target gene interactions enriched in B-ALL, and key TFs associated with accessible chromatin sites preferentially active in B-ALL. We further identified over 20% of accessible chromatin sites exhibiting strong subtype enrichment and candidate TFs that maintain subtype-specific chromatin architectures. Over 9,000 genetic variants were uncovered, contributing to variability in chromatin accessibility among patient samples. Our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants that promote unique gene-regulatory networks.

Keywords

acute lymphoblastic leukemia, ATAC-seq, chromatin accessibility, gene regulation, gene-regulatory network, transcription factor, transcription factor footprints, genetic variation, ATAC-QTLs

Comments

Supplementary Materials

PMID: 38116118