Acute leukemias are aggressive malignancies of developmentally arrested hematopoietic progenitors. We sought here to explore the possibility that changes in hematopoietic stem/progenitor cells during development might alter the biology of leukemias arising from this tissue compartment. Using a mouse model of acute T cell leukemia, we found that leukemias generated from fetal liver (FL) and adult bone marrow (BM) differed dramatically in their leukemia stem cell activity with FL leukemias showing markedly reduced serial transplantability as compared to BM leukemias. We present evidence that this difference is due to NOTCH1-driven autocrine IGF1 signaling, which is active in FL cells but restrained in BM cells by EZH2-dependent H3K27 trimethylation. Further, we confirmed this mechanism is operative in human disease and show that enforced IGF1 signaling effectively limits leukemia stem cell activity. These findings demonstrate that resurrecting dormant fetal programs in adult cells may represent an alternate therapeutic approach in human cancer. Display omitted •NOTCH1 leukemias derived from fetal liver are less transplantable than those from BM•NOTCH1 promotes auto/paracrine IGF1 signaling in fetal liver, but not BM progenitors•H3K27 methylation by EZH2 blocks NOTCH1 from accessing the IGF1 promoter in BM cells•Enforced IGF1 signaling depletes leukemia stem cells in both mouse and human T-ALL Giambra et al. show that NOTCH1 leukemias generated from fetal liver are less transplantable than those from adult bone marrow. NOTCH1 activates auto/paracrine IGF1 signaling in FL, but not BM cells, due to EZH2-dependent H3K27 trimethylation at the IGF1 promoter. This mechanism can be exploited to exhaust/deplete leukemia stem cells.