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

Sorcha O'Byrne, Natalina Elliott, Siobhan Rice, Gemma Buck, Nicholas Fordham, Catherine Garnett, Laura Godfrey, Nicholas T. Crump, Gary Wright, Sarah Inglott, Peng Hua, Beth Psaila, Benjamin Povinelli, David J.H.F. Knapp, Antonio Agraz-Doblas, Clara Bueno, Ignacio Varela, Phillip Bennett, Hashem Koohy, Suzanne M. Watt, Anastasios Karadimitris, Adam J. Mead, Phillip Ancliff, Paresh Vyas, Pablo Menendez, Thomas A. Milne, Irene Roberts and Anindita Roy

Key Points

  • CD10-ve PreProB-progenitors are the earliest fetal B-lymphoid restricted progenitors and are enriched in fetal bone marrow

  • Fetal PreProB-progenitors have a unique ontogeny-related developmental gene expression program distinct from their rare adult counterparts


Human lymphopoiesis is a dynamic life-long process that starts in utero 6 weeks post-conception. Fetal B-lymphopoiesis remains poorly defined and yet 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 two 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- and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal BM, where together they form >40% of the total HSC/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors while, by contrast, PreProB-progenitors are almost undetectable (0.53{plus minus}0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB- upstream of ProB-progenitors, identifying them as the first B-lymphoid restricted progenitor in human fetal life. Fetal BM PreProB- and ProB-progenitors both give rise solely to B-lineage cells yet they are transcriptionally distinct. Like 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 which is not seen in adult PreProB-progenitors; and 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.

  • Submitted November 29, 2018.
  • Revision received August 1, 2019.
  • Accepted July 5, 2019.