Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia

Sonali Narang, Yohana Ghebrechristos, Nikki A. Evensen, Nina Murrell, Sylwia Jasinski, Talia H. Ostrow, David T. Teachey, Elizabeth A. Raetz, Timothee Lionnet, Matthew Witkowski, Iannis Aifantis (), Aristotelis Tsirigos () and William L. Carroll ()
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Sonali Narang: NYU Langone Health
Yohana Ghebrechristos: NYU Langone Health
Nikki A. Evensen: NYU Langone Health
Nina Murrell: NYU Langone Health
Sylwia Jasinski: NYU Langone Health
Talia H. Ostrow: NYU Langone Health
David T. Teachey: Children’s Hospital of Philadelphia
Elizabeth A. Raetz: NYU Langone Health
Timothee Lionnet: NYU Langone Health
Matthew Witkowski: University of Colorado Anschutz Medical Campus
Iannis Aifantis: NYU Langone Health
Aristotelis Tsirigos: NYU Langone Health
William L. Carroll: NYU Langone Health

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions.

Date: 2024
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DOI: 10.1038/s41467-024-51492-6

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