Abstract
Integration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. We use single-cell transcriptomics/proteomics to identify differentially expressed gene networks across B cell development and correlate these networks with subtypes of B cell leukemia. Here we show unique transcriptional signatures that refine the pre-B cell expansion stages into pre-BCR-dependent and pre-BCR-independent proliferative phases. These changes correlate with reciprocal changes in expression of the transcription factor EBF1 and the RNA binding protein YBX3, that are defining features of the pre-BCR-dependent stage. Using pseudotime analysis, we further characterize the expression kinetics of different biological modalities across B cell development, including transcription factors, cytokines, chemokines, and their associated receptors. Our findings demonstrate the underlying heterogeneity of developing B cells and characterise developmental nodes linked to B cell transformation.
Highlights
Integration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells
Comparisons of various human B-cell acute lymphoblastic leukemia (B-ALL) transcriptomes to those of different stages of B-cell development highlight the developmental nodes that associate with varying subtypes of B-ALL and how they correlate with prognosis
Cell cycle status was determined by measuring the average expression of gene sets representing canonical S and G2M phases and a recently described postmitotic G1 phase (G1PM) that is associated with rapidly cycling cells that contain carryover G2M transcripts[16,17]
Summary
Integration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. Distinct stages of B-cell development have been delineated using flow cytometry and a variety of surface[1,2] and intracellular markers[3,4] The use of such markers in combination with distinct gene knockout mice has greatly expanded our understanding of specific B-lymphoid transcription factors[5,6,7], cytokines[8,9,10], and signaling pathways that entrain B cell development. Our analysis discovered several stages of pre-B-cell differentiation— including a pre-BCR-dependent and two pre-BCR-independent stages that exhibited distinct modalities of proliferation This process of pre-B-cell differentiation was characterized by oscillatory regulation of the transcription factor EBF1, with reciprocal changes in the RNA-binding protein YBX3. Comparisons of various human B-ALL transcriptomes to those of different stages of B-cell development highlight the developmental nodes that associate with varying subtypes of B-ALL and how they correlate with prognosis
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