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Acute lymphoblastic leukemia

Profiling chromatin accessibility in pediatric acute lymphoblastic leukemia identifies subtype-specific chromatin landscapes and gene regulatory networks

Leukemia volume 35, pages 3078–3091 (2021)Cite this article

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Abstract

Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy comprised of molecular subtypes largely characterized by aneuploidy or recurring chromosomal rearrangements. Despite extensive information on the ALL transcriptome and methylome, there is limited understanding of the ALL chromatin landscape. We therefore mapped accessible chromatin in 24 primary ALL cell biospecimens comprising three common molecular subtypes (DUX4/ERG, ETV6-RUNX1 and hyperdiploid) from patients treated at St. Jude Children’s Research Hospital. Our findings highlight extensive chromatin reprogramming in ALL, including the identification ALL subtype-specific chromatin landscapes that are additionally modulated by genetic variation. Chromatin accessibility differences between ALL and normal B-cells implicate the activation of B-cell repressed chromatin domains and detail the disruption of normal B-cell development in ALL. Among ALL subtypes, we uncovered roles for basic helix-loop-helix, homeodomain and activator protein 1 transcription factors in promoting subtype-specific chromatin accessibility and distinct gene regulatory networks. In addition to chromatin subtype-specificity, we further identified over 3500 DNA sequence variants that alter the ALL chromatin landscape and contribute to inter-individual variability in chromatin accessibility. Collectively, our data suggest that subtype-specific chromatin landscapes and gene regulatory networks impact ALL biology and contribute to transcriptomic differences among ALL subtypes.

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Fig. 1: Extensive chromatin reprogramming between ALL and normal B-cells.
Fig. 2: Open chromatin heterogeneity among ALL molecular subtypes.
Fig. 3: Distinct TF footprints and TF activities among ALL molecular subtypes.
Fig. 4: Coordination between multiple levels of epigenetic and transcriptional control.
Fig. 5: Stronger gene regulatory network connectivity for subtype-specific up-regulated genes.
Fig. 6: DNA sequence variation impacts chromatin accessibility and related phenotypes.

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Acknowledgements

We would like to thank the Hartwell Center at St. Jude for ATAC-seq and RNA-seq library preparation and next-generation sequencing, and the Center for Advanced Genome Engineering (CAGE) at St. Jude for CRISPR/Cas9 genome editing in ALL cell lines. We would also like to thank Jeremy Hunt for technical support. This work was supported by the National Cancer Institute (R01CA234490, P30CA021765), the National Institute of General Medical Studies (P50GM115279) and the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jonathan D. Diedrich, Qian Dong, Daniel C. Ferguson, Brennan P. Bergeron, Robert J. Autry, Maoxiang Qian, Wenjian Yang, Colton Smith, Kristine R. Crews, Ching-Hon Pui, Jun J. Yang, Mary V. Relling, William E. Evans & Daniel Savic

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jonathan D. Diedrich, Qian Dong, Daniel C. Ferguson, Brennan P. Bergeron, Robert J. Autry, Maoxiang Qian, Wenjian Yang, Colton Smith, Kristine R. Crews, Jun J. Yang, Mary V. Relling, William E. Evans & Daniel Savic

  3. Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Brennan P. Bergeron

  4. Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA

    Robert J. Autry & Daniel Savic

  5. Department of Cell and Molecular biology and Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN, USA

    James B. Papizan, Jon P. Connelly & Shondra M. Pruett-Miller

  6. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Kohei Hagiwara

  7. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Ching-Hon Pui & Jun J. Yang

  8. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Ching-Hon Pui

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  1. Jonathan D. Diedrich
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Correspondence to Daniel Savic.

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Diedrich, J.D., Dong, Q., Ferguson, D.C. et al. Profiling chromatin accessibility in pediatric acute lymphoblastic leukemia identifies subtype-specific chromatin landscapes and gene regulatory networks. Leukemia 35, 3078–3091 (2021). https://doi.org/10.1038/s41375-021-01209-1

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