The Origin of B-cells: Human Fetal B Cell Development and Implications for the Pathogenesis of Childhood Acute Lymphoblastic Leukemia

Human B-lymphopoiesis is a dynamic life-long process that starts in utero by around six post-conception weeks. A detailed understanding of human fetal B-lymphopoiesis and how it changes in postnatal life is vital for building a complete picture of normal B-lymphoid development through ontogeny, and its relevance in disease. B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common cancers in children, with many of the leukemia-initiating events originating in utero. It is likely that the biology of B-ALL, including leukemia initiation, maintenance and progression depends on the developmental stage and type of B-lymphoid cell in which it originates. This is particularly important for early life leukemias, where specific characteristics of fetal B-cells might be key to determining how the disease behaves, including response to treatment. These cellular, molecular and/or epigenetic features are likely to change with age in a cell intrinsic and/or microenvironment directed manner. Most of our understanding of fetal B-lymphopoiesis has been based on murine data, but many recent studies have focussed on characterizing human fetal B-cell development, including functional and molecular assays at a single cell level. In this mini-review we will give a short overview of the recent advances in the understanding of human fetal B-lymphopoiesis, including its relevance to infant/childhood leukemia, and highlight future questions in the field.