Lin28b suppresses MLL-ENL–driven AML. (A-C) Lin28b, Hmga2 and Igf2bp2 were hyper-activated in MLL-ENL expressing neonatal, but not adult, HPCs. ***Adjusted P < .001. (D) Survival of Tet-OFF-MLL-ENL and Tet-OFF-MLL-ENL/Lin28b mice after neonatal transgene induction. Curves were compared by the log-rank test. (E-G) Spleen weight and HSC and HPC numbers in surviving Tet-OFF-MLL-ENL/Lin28b after they were euthanized at >1 year old. (H-I) Representative spleen histology and CD3 expression in control mice or Tet-OFF-MLL-ENL/Lin28b mice that became moribund. Scale bars indicate 100 μM (large panels) or 40 μM (insets). (J) MLL-ENL initiates AML most efficiently when it is induced during the neonatal stage of development. Lin28b might protect against AML initiation in utero. At later stages of development, MLL-ENL fails to activate target genes as efficiently as it does in neonates.