Deregulation of Hck expression is associated with histone H3 hypoacetylation induced by AML1-ETO fusion protein

摘要

The AML1-ETO fusion protein, which is present in 10-15% of cases of acute myeloid leukemia (AML), is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. By focusing on the hematopoietic cell kinase (Hck) gene, we found that AMLl-ETO-expressing cell lines displayed low level of the Hck gene. Chromatin immunoprecipitation assays demonstrated that Hck was direct transcriptional target of AML1-ETO. The universal binding of AML1-ETO to genomic DNA resulted in reduction of histone H3 acetylation, indicating that AML1-ETO induced heterochromatic silencing of Hck. This can be reversed by exposing cells to a histone deacetylase tributyrin. Our results suggested that the aberrant transcription factor AML1-ETO epigenetically silenced the function of Hck by inducing repressed chromatin configurations at its promoter through histone modification. These data indicate that Hck may have tumor suppressor properties in AML1-ETO positive leukemia.