3D Chromosome Remodeling in B-cell Development and Acute Lymphoblastic Leukemia.

UNLABELLED: The identification of molecular subgroups of pediatric B-cell acute lymphocytic leukemia (B-ALL) has proven to be a powerful tool in understanding disease pathogenesis and treatment stratification. Studies have suggested aberrant transcription factor function and epigenetic regulation can explain differences between B-ALL subtypes; however, the impact of 3D genome reorganization remains unclear. In this study, we used in situ Hi-C and RNA sequencing to profile the chromatin architectural landscape in healthy B-cell progenitors and B-ALL patient samples harboring prognostically relevant structural variations, including ETV6::RUNX1, KMT2A::AFF1, and BCR::ABL. We showed that B-ALLs undergo subtype-specific changes that, in part, reflect the differentiation stage of the disease and that they acquire aberrant chromatin configurations that allow the expression of oncogenic drivers. One such driver, ERG, displayed increased interactivity and expression in ETV6::RUNX1 B-ALL, and evidence suggests that it plays a role in regulating survival and differentiation. Overall, these results underscore the essential role of 3D nuclear organization in acute leukemia.

SIGNIFICANCE: Our integrative analyses of 3D chromatin architecture, accessibility, and gene expression in normal and malignant human B cells revealed an evolution of 3D genome architecture and associated transcription programs that may drive the differentiation of normal B cells as well as the transformation of B-ALL subtypes. See related commentary by Gruber, p. 509.