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

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.