Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators

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

doi:10.1016/j.xgen.2023.100442

Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators

Cell Genom. 2023 Nov 20;3(12):100442. doi: 10.1016/j.xgen.2023.100442. eCollection 2023 Dec 13.

Authors

Kelly R Barnett^{1

2}, Robert J Mobley^{1

2}, Jonathan D Diedrich^{1

2}, Brennan P Bergeron^{1

2

3}, Kashi Raj Bhattarai^{1

2}, Alexander C Monovich⁴, Shilpa Narina⁵, Wenjian Yang^{1

2}, Kristine R Crews^{1

2}, Christopher S Manring⁶, Elias Jabbour⁷, Elisabeth Paietta⁸, Mark R Litzow⁹, Steven M Kornblau⁷, Wendy Stock¹⁰, Hiroto Inaba^{1

11}, Sima Jeha^{1

11}, Ching-Hon Pui^{1

11}, Charles G Mullighan^{1

12}, Mary V Relling^{1

2}, Shondra M Pruett-Miller^{5

13}, Russell J H Ryan⁴, Jun J Yang^{1

2

3

14}, William E Evans^{1

2}, Daniel Savic^{1

2

3

14}

Affiliations

¹ Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
² Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
³ Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁴ Department of Pathology, University of Michigan-Ann Arbor, Rogel Cancer Center, Ann Arbor, MI 48109, USA.
⁵ Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁶ Alliance Hematologic Malignancy Biorepository, Clara D. Bloomfield Center for Leukemia Outcomes Research, Columbus, OH 43210, USA.
⁷ Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Oncology, Montefiore Medical Center, Bronx, NY 10467, USA.
⁹ Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
¹⁰ University of Chicago Comprehensive Cancer Center, Chicago, IL 60637, USA.
¹¹ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹² Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹³ Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹⁴ Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38105, USA.

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

Abstract

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