Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML

Exp Hematol. 2016 Aug;44(8):713-726.e14. doi: 10.1016/j.exphem.2016.05.004. Epub 2016 May 20.


Epigenetic changes can contribute to development of acute myeloid leukemia (AML), a malignant disease of the bone marrow. A single-nucleotide polymorphism of transcription factor growth factor independence 1 (GFI1) generates a protein with an asparagine at position 36 (GFI1(36N)) instead of a serine at position 36 (GFI1(36S)), which is associated with de novo AML in humans. However, how GFI1(36N) predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI1(36N) or GFI1(36S). Presence of GFI1(36N) shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI1(36N) induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI1(36N)-expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI1(36N)-induced AML can be targeted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Bone Marrow / pathology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Transformation, Neoplastic / genetics
  • Codon
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Disease Progression
  • Epigenesis, Genetic* / drug effects
  • Gene Expression Regulation, Leukemic
  • Genetic Predisposition to Disease
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism
  • Humans
  • Immunophenotyping
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Mutation*
  • Myelodysplastic Syndromes / drug therapy
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / mortality
  • Transcription Factors / genetics*


  • Codon
  • DNA-Binding Proteins
  • GFI1 protein, human
  • Histone Deacetylase Inhibitors
  • Transcription Factors
  • Histone Deacetylases