Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity

Cell Stem Cell. 2018 Nov 1;23(5):714-726.e7. doi: 10.1016/j.stem.2018.08.018. Epub 2018 Sep 27.

Abstract

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.

Keywords: EZH2; IGF1; NOTCH1; T-ALL; acute leukemia; autocrine signaling; epigenetic silencing; fetal; leukemia stem cells; pediatric.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Cells / pathology
  • Epigenesis, Genetic / genetics*
  • Female
  • Insulin-Like Growth Factor I / genetics*
  • Insulin-Like Growth Factor I / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Signal Transduction / genetics*

Substances

  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I

Grant support