| Literature DB >> 31383639 |
Sorcha O'Byrne1, Natalina Elliott1, Siobhan Rice2, Gemma Buck1,2, Nicholas Fordham2, Catherine Garnett2, Laura Godfrey2, Nicholas T Crump2, Gary Wright3, Sarah Inglott3, Peng Hua2,4, Bethan Psaila2, Benjamin Povinelli2, David J H F Knapp2, Antonio Agraz-Doblas5,6, Clara Bueno6, Ignacio Varela5, Phillip Bennett7, Hashem Koohy8, Suzanne M Watt4, Anastasios Karadimitris9, Adam J Mead2,10, Phillip Ancliff3, Paresh Vyas2,10, Pablo Menendez6,11,12, Thomas A Milne2,10, Irene Roberts1,2,10, Anindita Roy1.
Abstract
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.Entities:
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Year: 2019 PMID： 31383639 DOI： 10.1182/blood.2019001289
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 22.113