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

Abstract

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.

Mapping the developing human immune system across organs

“…For example, we found B cells along the entire developmental path from Pre-pro B cells to Small Pre B cells in thymus, spleen, lymph node, skin, gut and kidney. On the other hand, we only observed Pre-pro B cells in yolk sac, which is consistent with the literature that full B cell lymphopoiesis does not happen until later in embryonic life (34).…”

Marginal Zone B-Cell Populations and Their Regulatory Potential in the Context of HIV and Other Chronic Inflammatory Conditions

“…The first B-cell progenitors can be found as early as 7 weeks post conception in the fetal liver [ 8 ]. However, the B lymphoid progenitor compartment differs between fetal and postnatal life, and herein, we will only briefly focus on postnatal ontogeny, as these topics are beyond the scope of this article and have been thoroughly reviewed elsewhere [ 8 ].…”

“…The first B-cell progenitors can be found as early as 7 weeks post conception in the fetal liver [ 8 ]. However, the B lymphoid progenitor compartment differs between fetal and postnatal life, and herein, we will only briefly focus on postnatal ontogeny, as these topics are beyond the scope of this article and have been thoroughly reviewed elsewhere [ 8 ]. As depicted in Figure 1 , post-natal B-cell development originates in the bone marrow, first, with pluripotent hematopoietic stem cells and their differentiation into common lymphoid progenitors (CLP) [ 9 ].…”

Does lineage plasticity enable escape from CAR-T cell therapy? Lessons from MLL-r leukemia

“…Hematopoietic differentiation occurs through a continuum of fate restriction events, and some of the earliest-defined B-cell progenitor−enriched populations including common lymphocyte progenitors (CLPs) and lymphoid primed multipotent progenitors (LPMPs) retain myeloid potential [ 73 − 76 ]. Interestingly, murine fetal CLPs and LPMPs exhibit more robust myeloid priming or myeloid potential than their adult counterparts [ 77 , 78 ], a phenomenon shared with human fetal progenitors [ 79 ]. The molecular basis for B-cell commitment is understood best at the level of transcriptional antagonistic and feed-forward hierarchies featuring well-studied transcription factors such as E2A, EBF, and PAX5 [ 80 ].…”