Abstract IA005: Fetal barriers to fusion protein-driven leukemogenesis

Abstract One of the most fascinating aspects of developmental biology is that single-cell blastocysts can expand exponentially to become trillion celled organisms with near-perfect fidelity. In addition to having functional organs and normal appendages, most newborn infants escape neoplasia despite having traversed a stage of life typified by rapidly expanding, highly-stimulated developmental fields. Each cell division cycle creates opportunities for replication errors to occur and propagate, and high proliferation rates magnify this risk. Yet congenital malignancies are exceedingly rare. This raises a fundamental question: What protects the developing fetus from malignancy? Acute myeloid leukemia (AML) illustrates this paradox nicely. A majority of infant and early childhood AML are driven by fusion oncoproteins, expressed as a consequence of translocation mutations that often occur before birth. Infant AML tend to have few additional mutations, implying a low genetic threshold for transformation. Rapid proliferation of hematopoietic stem cells (HSCs) and other progenitors during fetal stages of ontogeny should therefore afford ample opportunity for mutant clones to expand and transform, yet congenital leukemias are exceedingly rare (