Fetal context conveys heritable protection against MLL-rearranged AML that depends on MLL3.

MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and can transform fetal/neonatal progenitors with the help of only a few additional cooperating mutations. Despite the low threshold for transformation, infant leukemias are rare, and congenital leukemias, which arise before birth, are even less common. These observations raise the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. To test this possibility, we used a mouse model of temporally controlled MLL::ENL expression to show that fetal MLL::ENL exposure establishes a heritable, leukemia-resistant state within hematopoietic progenitors that persists after birth. When we induced MLL::ENL expression prior to birth and transplanted hematopoietic stem and progenitor cells, very few recipient mice developed acute myeloid leukemia (AML) despite robust engraftment. When we induced MLL::ENL expression shortly after birth, all recipient mice developed a highly penetrant AML. Fetal MLL::ENL expression imposed a negative selective pressure on hematopoietic progenitors before birth followed by loss of self-renewal gene expression and enhanced myeloid differentiation after birth that precluded transformation. These changes did not occur when MLL::ENL expression initiated shortly after birth. The fetal barrier to transformation was enforced by the histone methyltransferase MLL3, and it could be overcome by cooperating mutations, such as NrasG12D. Heritable fetal protection against leukemic transformation may contribute to the low incidence of congenital and infant leukemias in humans.