3D chromatin hubs as regulatory units of identity and survival in acute T-cell leukemia [scATAC-Seq]

Cancer progression is associated with genetic and epigenetic aberrations that affect chromatin 3D organization in the nucleus. Changes in loop extrusion or phase separation alter the relationships between enhancer and promoter elements, defining novel gene expression programs that are selected to promote growth and survival. Here, we provide an integrative approach based on chromatin conformation, accessibility and transcription, further validated by CRISPR interference screenings in order to identify chromatin topologies relevant to different subtypes of T-cell leukemia, namely T-ALL and ETP-ALL. By focusing on highly interconnected elements, we characterized 3D hubs as headquarters of leukemia progression and identity, demonstrating that oncogenes and disease markers are regulated by multiple cis-regulatory regions. Primary samples of T cell acute lymphoblastic leukemia (T-ALL) and early T cell precursor leukemia (ETP-ALL) were collected and analyzed by single-cell ATAC sequencing