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 (<10-fold lower than infant leukemias, which are themselves rare). These observations raise the question of whether mechanisms exist to suppress AML initiation during embryogenesis. Using relevant mouse models, we have shown that fetal blood progenitors do indeed actively resist transformation when confronted with recurrent leukemogenic mutations. For example, the MLL::ENL fusion protein reprograms fetal progenitors to create an AML-resistant state that persists even after birth. This protection depends on MLL3, a myeloid tumor suppressor gene that often harbors inherited deleterious variants infant leukemia patients. Inherited variants may therefore mitigate fetal leukemia suppression. As a second example, we have found that NUP98 fusion proteins (e.g., NUP98::HOXA9) convey resistance to AML before birth. NUP98 fusion proteins reprogram the fetal hematopoietic hierarchy to favor non-leukemic erythroid differentiation in situ. This protective developmental reprogramming does not occur in juvenile progenitors, which readily transform. These data illustrate how fetal blood progenitors are hard-wired to differentiate, rather than transform, when they express a fusion oncoprotein. Thus, fusion oncoproteins convey a negative, rather than positive selective pressure. When fusion protein-driven leukemias do arise in utero or in infants, premalignant cells must overcome developmentally restricted failsafe mechanisms so that the fusion protein becomes tolerable at these early ages. Citation Format: Jeff Magee. Fetal barriers to fusion protein-driven leukemogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr IA005.