How well do we understand the link between fetal hematopoiesis and susceptibility to immune dysfunction?

Introduction: Layered hematopoiesis generates distinct, hematopoietic stem cell (HSC)-independent progenitor waves that establish long-lived immune compartments, profoundly influencing postnatal immunity and disease susceptibility. Areas covered: This article reviews the contribution of embryonic progenitors to resident immune populations, the impact of prenatal stressors (such as inflammation and maternal obesity) on immune programming, and the mechanisms by which fetal identity drives leukemogenesis and oncofetal reprogramming. We survey recent evidence examining how early environmental and genetic factors shape developmental hematopoietic trajectories and highlight resulting influences on postnatal disease. Expert opinion: While animal models provide valuable mechanistic insights in fetal hematopoiesis, translating findings to human biology remains challenging. Priorities include identifying persistent developmental signatures, employing single-cell multi-omics to track preleukemic clones, and advancing ontogeny-aware cell therapies and precision risk-stratification strategies.