Mapping the cellular origin and early evolution of leukemia in Down syndrome

Science. 2021 Jul 9;373(6551):eabf6202. doi: 10.1126/science.abf6202.

Abstract

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / analysis
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Lineage
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomes, Human, Pair 21 / genetics
  • Chromosomes, Human, Pair 21 / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Down Syndrome / complications
  • Down Syndrome / genetics*
  • Female
  • GATA1 Transcription Factor / genetics*
  • GATA1 Transcription Factor / metabolism
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / physiology*
  • Heterografts
  • Humans
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Liver / embryology
  • Male
  • Megakaryocytes / physiology
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Mutation
  • Preleukemia / genetics*
  • Preleukemia / metabolism
  • Preleukemia / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-kit / analysis
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors

Substances

  • Antigens, CD34
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • MicroRNAs
  • Protein Kinase Inhibitors
  • STAG2 protein, human
  • cohesins
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit