Uncovering the cis-regulatory program of early human B-cell commitment and its implications in the pathogenesis of B-cell acute lymphoblastic leukemia

Abstract

ABSTRACTThe early stages of the B-cell system are key for cellular immunity development, and alterations may lead to various disorders. Understanding the gene regulatory network (GRN) of this system is essential for studying healthy development and malignant transformations. To this end, we generated matched human data for chromatin accessibility and transcriptome in eight B-cell precursors, providing the first deep characterization of early B-cell differentiation, including the regulatory elements definition and the reconstruction of the GRN governing this process. Our data revealed ELK3 as a critical transcription factor (TF) in pro-B cells and uncovered their upstream regulators. We also identified MLXIP within the EBF1 regulators. Interestingly, modifications of enhancers preceding transcriptional changes were shown. Importantly, this resource helped uncover B-cell acute lymphoblastic leukemia (B-ALL) triggers, identifying pro-B and pre-B cells as inflection points of malignant transformation for some subgroups. The resource also explored the overlap of B-ALL susceptibility loci in the epigenomic profile. Overall, our study provides the most comprehensive atlas of early human B cell regulation (B-rex) athttps://brex.shinyapps.io/brex/, a resource for understanding B cell differentiation in health and disease.