3D Chromatin Remodeling in B-cell Development and B-cell Acute Lymphoblastic Leukemia [Hi-C]

The identification of molecular subgroups of B-cell progenitor acute lymphocytic leukemia (B-ALL) have proven to be a powerful tool in understanding the derivation of ALL while also providing essential prognostic information. Several studies have also shown changes in epigenetic landscape including differences across B-ALL subtypes. However, the state of the 3D genome across subtypes and how they compare to healthy B-cell progenitors remains unexplored. Here we use Hi-C and RNA-seq to profile early B-cell progenitors from healthy donors and a number of B-ALL samples harboring the most frequent and prognostic structural variations, including KMT2A::AFF1 and BCR::ABL. We show that B-ALLs undergo subtype-specific changes in 3D genome organization that indicate the differentiation stage of the disease. Additional analysis shows B-ALLs acquire aberrant chromatin configurations and expression of oncogenic drivers compared to normal progenitors. We also find that the TF ERG is aberrantly activated in ETV6::RUNX1 B-ALL, and it aids in the establishment of a differentiation block. Overall, the findings from our study show the impact of altered chromatin folding on the leukemogenic state of B-ALL.