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Título: | Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs |
Autor: | 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 CSIC ORCID; Bennett, Phillip; Koohy, Hashem; Watt, Suzanne M.; Karadimitris, Anastasios; Mead, Adam J.; Ancliff, Phillip; Vyas, Paresh; Menéndez, Pablo; Milne, Thomas A.; Roberts, Irene; Roy, Anindita | Palabras clave: | Fetus Neprilysin b-lymphocytes Growth Lymphopoiesis cd19 antigens |
Fecha de publicación: | 26-sep-2019 | Editor: | American Society of Hematology | Citación: | Blood 134(13): 1059-1071 (2019) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.1182/blood.2019001289 | URI: | http://hdl.handle.net/10261/204396 | DOI: | 10.1182/blood.2019001289 | ISSN: | 0006-4971 | E-ISSN: | 1528-0020 |
Aparece en las colecciones: | (IBBTEC) Artículos |
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