A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells

PLoS One. 2013;8(2):e55481. doi: 10.1371/journal.pone.0055481. Epub 2013 Feb 4.

Abstract

AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Apoptosis / drug effects*
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Gene Expression Regulation, Leukemic / drug effects*
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Inbred C57BL
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • RUNX1 Translocation Partner 1 Protein
  • Signal Transduction / drug effects
  • p300-CBP Transcription Factors / antagonists & inhibitors*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Enzyme Inhibitors
  • Histones
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-bcl-2
  • RUNX1 Translocation Partner 1 Protein
  • Granulocyte Colony-Stimulating Factor
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Proto-Oncogene Proteins c-kit

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81000221, No. 81171820, No. 90919044 and No. 30971297), the Beijing Natural Science Foundation (No. 7122169, No. 7112126), the Beijing New Stars Program of Science and Technology (No. 2010B075), the National Public Health Grand Research Foundation (No. 201202017) and the Capital Public Health Project (No. Z111107067311070). The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.