3D chromosome remodeling in B-cell development and acute lymphoblastic leukemia [HiChIP]

The identification of molecular subgroups of pediatric B-cell acute lymphocytic leukemia (B-ALL) has proven to be a powerful tool in both understanding disease pathogenesis and treatment stratification. Several studies have suggested that aberrant transcription factor (TF) function and epigenetic regulation can explain the differences between distinct B-ALL subtypes. However, the organization of the 3D genome across leukemia subtypes and comparison with healthy B-cell progenitors remains unclear. Here we use in situ Hi-C and RNA-seq to profile early human B-cell progenitors from healthy bone marrow donors and B-ALL patient samples harboring prognostically relevant structural variations, including ETV6::RUNX1, KMT2A::AFF1 and BCR::ABL. We show that B-ALLs undergo subtype-specific changes in 3D genome organization that in part reflect the differentiation stage of the disease. We demonstrate that B-ALL blasts also acquire distinct aberrant chromatin configurations that allow expression of oncogenic drivers compared to normal progenitors. One such driver, the transcription factor ERG, displays increased interactivity and expression in ETV6::RUNX1 B-ALL, and directly regulates B-cell progenitor survival and differentiation. Overall, these results underscore the essential role of 3D nuclear organization in human acute leukemia.