Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells

Cancer Res. 1999 Jun 15;59(12):2766-9.

Abstract

The (8;21) translocation, found in 12% of acute myeloid leukemia (AML), creates the chimeric fusion product, AML1-ETO. Previously, we demonstrated that the ETO moiety recruits a transcription repression complex that includes the histone deacetylase (HDAC1) enzyme. Here, we used inhibitors of HDAC1 to study the pathophysiology of AML1-ETO. Both the potent inhibitor, trichostatin (TSA), and the well-known but less specific inhibitor, phenylbutyrate (PB), could partially reverse ETO-mediated transcriptional repression. PB was also able to induce partial differentiation of the AML1-ETO cell line, Kasumi-1. With the intention of developing a clinically useful protocol, we combined PB with a number of other agents that induced differentiation and apoptosis of Kasumi-1 cells. In summary, transcriptional repression mediated by AML1-ETO appears to play a mechanistic role in the t(8;21) AML, and relief of repression using agents such as PB (alone or in combination) may prove to be therapeutically useful.

MeSH terms

  • 3T3 Cells
  • Acute Disease
  • Animals
  • Apoptosis / drug effects
  • Cell Differentiation / drug effects
  • Chromosomes, Human, Pair 21
  • Chromosomes, Human, Pair 8
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Leukemia, Myeloid / enzymology
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Mice
  • Neoplasm Proteins / genetics*
  • Phenylbutyrates / pharmacology
  • Proto-Oncogene Proteins*
  • RUNX1 Translocation Partner 1 Protein
  • Recombinant Fusion Proteins / metabolism
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics*
  • Transcription, Genetic / drug effects*
  • Translocation, Genetic
  • Tumor Cells, Cultured

Substances

  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Neoplasm Proteins
  • Phenylbutyrates
  • Proto-Oncogene Proteins
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • RUNX1T1 protein, human
  • Recombinant Fusion Proteins
  • Runx1 protein, mouse
  • Transcription Factors
  • trichostatin A