P210 Bcr-abl tyrosine kinase interaction with histone deacetylase 1 modifies histone H4 acetylation and chromatin structure of chronic myeloid leukaemia haematopoietic progenitors

Br J Haematol. 2006 Feb;132(3):359-69. doi: 10.1111/j.1365-2141.2005.05873.x.

Abstract

The BCR-ABL fusion gene, originating from the balanced (9;22) translocation, is the molecular hallmark and the causative event of chronic myeloid leukaemia (CML). The interactions of its p210 protein constitutively activated and improperly confined to the cytoplasm with multiple regulatory signals of cell cycle progression, apoptosis and self-renewal, induce the illegitimate enlargement of clonal haematopoiesis and genetic instability that drives its progression towards the fully transformed phenotype of blast crisis. However, its effects on the basic transcription machinery and chromatin remodelling are unknown. Our study underscored histone H4 hyperacetylation associated with p210 tyrosine kinase in vitro and in vivo and its role in BCR-ABL transcription. Histone H4 hyperacetylation proceeds, at least partly, from the 'loss of function' of histone deacetylase 1 protein, a critical component of Rb-mediated transcriptional repression, in consequence of its cytoplasmatic compartmentalisation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Antigens, CD34 / immunology
  • Cell Line
  • Cell Line, Tumor
  • Chromatin / chemistry*
  • Cytoplasm / metabolism
  • Fusion Proteins, bcr-abl
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / immunology
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / metabolism*
  • Histone Deacetylase 1
  • Histone Deacetylases / metabolism*
  • Histones / metabolism*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism

Substances

  • Antigens, CD34
  • Chromatin
  • Histones
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases