The deacetylase inhibitor LAQ824 induces notch signalling in haematopoietic progenitor cells

Leuk Res. 2011 Jan;35(1):119-25. doi: 10.1016/j.leukres.2010.06.024. Epub 2010 Jul 31.

Abstract

AML progenitor cells (AML-PC) undergo significant apoptosis in response to the deacetylase inhibitor (DACi) LAQ824 and lose the replating capacity which was not observed with the DACi valproic acid. Treatment of normal hematopoietic progenitor cells (HPC) with LAQ824 resulted in (i) inhibition of differentiation, (ii) an G2/M cell cycle arrest exclusively in multipotent CD34(+) HPC and (iii) induction of apoptosis predominantly in committed CD34(-) HPC. Gene expression analysis showed induction of coactivator and target genes of the notch pathway as well as cell cycle arrest-inducing genes in the most primitive CD34(+) CD38(-) HPC population which may in part be responsible for the considerable, but reversible haematotoxicity of this drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Receptors, Notch / metabolism*
  • Signal Transduction / drug effects*

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • LAQ824
  • Receptors, Notch