Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs

• Published in: Blood 2019-09, Vol.134 (13), p.1059-1071
• Main Authors: O'Byrne, Sorcha, Elliott, Natalina, Rice, Siobhan, Buck, Gemma, Fordham, Nicholas, Garnett, Catherine, Godfrey, Laura, Crump, Nicholas T., Wright, Gary, Inglott, Sarah, Hua, Peng, Psaila, Bethan, Povinelli, Benjamin, Knapp, David J.H.F., Agraz-Doblas, Antonio, Bueno, Clara, Varela, Ignacio, Bennett, Phillip, Koohy, Hashem, Watt, Suzanne M., Karadimitris, Anastasios, Mead, Adam J., Ancliff, Phillip, Vyas, Paresh, Menendez, Pablo, Milne, Thomas A., Roberts, Irene, Roy, Anindita
• Format: Article
• Language: English
• Subjects: Adult; Bone Marrow - embryology; Bone Marrow - metabolism; Cells, Cultured; Fetus - cytology; Fetus - embryology; Fetus - metabolism; Gene Expression Regulation, Developmental; Humans; Liver - embryology; Liver - metabolism; Lymphopoiesis; Neprilysin - analysis; Neprilysin - genetics; Precursor Cells, B-Lymphoid - cytology; Precursor Cells, B-Lymphoid - metabolism; Transcriptome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019001289

Human lymphopoiesis is a dynamic lifelong process that starts in utero 6 weeks postconception. Although fetal B-lymphopoiesis remains poorly defined, it is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of 2 distinct CD19+ B-progenitors, an adult-type CD10+ve ProB-progenitor and a new CD10-ve PreProB-progenitor, and describe their molecular and functional characteristics. PreProB-progenitors and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal bone marrow (BM), where together they form >40% of the total hematopoietic stem cell/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors, whereas, by contrast, PreProB-progenitors are almost undetectable (0.53% ± 0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB-progenitors upstream of ProB-progenitors, identifying them as the first B-lymphoid–restricted progenitor in human fetal life. Although fetal BM PreProB-progenitors and ProB-progenitors both give rise solely to B-lineage cells, they are transcriptionally distinct. As with their fetal counterparts, adult BM PreProB-progenitors give rise only to B-lineage cells in vitro and express the expected B-lineage gene expression program. However, fetal PreProB-progenitors display a distinct, ontogeny-related gene expression pattern that is not seen in adult PreProB-progenitors, and they share transcriptomic signatures with CD10-ve B-progenitor infant acute lymphoblastic leukemia blast cells. These data identify PreProB-progenitors as the earliest B-lymphoid–restricted progenitor in human fetal life and suggest that this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukemia initiation. •CD10-ve PreProB-progenitors are the earliest fetal B-lymphoid–restricted progenitors and are enriched in fetal BM.•Fetal PreProB-progenitors have a unique ontogeny-related developmental gene expression program distinct from their rare adult counterparts. [Display omitted]