The ontogeny of the natural, public IgM repertoire remains incompletely explored. Here, high-resolution immunogenetic analysis of B cells from (unrelated) fetal, child, and adult samples, shows that although fetal liver (FL) and bone marrow (FBM) IgM repertoires are equally diversified, FL is the main source of IgM natural immunity during the 2nd trimester. Strikingly, 0.25% of all prenatal clonotypes, comprising 18.7% of the expressed repertoire, are shared with the postnatal samples, consistent with persisting fetal IgM+ B cells being a source of natural IgM repertoire in adult life. Further, the origins of specific stereotypic IgM+ B cell receptors associated with chronic lymphocytic leukemia, can be traced back to fetal B cell lymphopoiesis, suggesting that persisting fetal B cells can be subject to malignant transformation late in life. Overall, these novel data provide unique insights into the ontogeny of physiological and malignant B lymphopoiesis that spans the human lifetime.

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Centre for Haematology Department of Medicine Imperial College London Imperial College Healthcare NHS Trust Hammersmith Hospital London UK

Centre for Haematology Department of Medicine Imperial College London Imperial College Healthcare NHS Trust Hammersmith Hospital London UK; RECAMO Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Paediatrics University of Oxford Brno Czech Republic

Department of Paediatrics University of Oxford Brno Czech Republic; Centro Ricerca Tettamanti Clinica Pediatrica Università di Milano Bicocca Ospedale San Gerardo Fondazione MBBM Monza Italy

Department of Paediatrics University of Oxford Brno Czech Republic; MRC Molecular Haematology Unit Weatherall Institute of Molecular Medicine University of Oxford and BRC Blood Theme NIHR Oxford Biomedical Centre Oxford UK

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