Heritable fetal protection against MLL::ENL-driven leukemogenesis depends on MLL3 [scRNA-seq]

MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and require very few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life. Here, we show that in mice, fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors that persists after birth to suppress transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in that context. The fetal barrier to transformation is enforced by MLL3. It can be bypassed by cooperating mutations or inactivation of MLL3. Heritable, fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.