Highly multiplexed single cell chromatin regulator and accessibility profiling elucidates chromatin dynamics in human B cell development and oncogenesis, and reveals an adverse prognostic gene expression signature in B lymphoblastic leukemias [patient]

Developing B cells undergo successive stages of chromatin reorganization which modulate DNA accessibility to control V(D)J recombination and gene transcription. These epigenetic shifts are mediated by histone modifications (e.g., H3K4me3, H3K27me3), histone-modifying enzymes (e.g., MLL1, LSD1), and chromatin remodelers (e.g., CTCF, DNMT1). We combined highly-multiplexed, multi-omic approaches to capture this choreographed dance – from single cell changes in chromatin modulators, to alterations in histone modifications, to genome-wide chromatin accessibility. This epigenetic map of normal human B cell differentiation enabled us to peer into the early origins of B cell leukemias and lymphomas – specifically, stage-specific chromatin accessibility at sites of recurrent chromosomal translocations and oncogenic transcription factors (TF). It further identified a chromatin state characterized by relative depletion of chromatin structure modulators and high leukemic TF accessibility, enriched in a small cohort of B lymphoblastic leukemias and associated with adverse prognosis.