The bcr-abl fusion gene originated from the balanced (9;22) translocation is the molecular hallmark and the causative event of chronic myeloid leukemia (CML). Constitutive activation and improper localization to the cytosol of p210 protein of bcr-abl induce enlargement of clonal hematopoiesis over its normal counterpart and consequently genetic instability that drives leukemic progenitor progression towards the fully transformed phenotype of blast crisis.
To define a role to tyrosine kinase p210bcr-abl, we considered its impact on histone H4 acetylation status, focusing on the proceeding of enzyme HDAC1 (histone deacetylase1) during progression of the pathology. We performed molecular analysis in vitro in 32D cell clone expressing a temperature-sensitive (ts) bcr-abl mutant and in vivo in CD34+ from patients affected by CML.
We observed that HDAC1 has several effects on gene expression in different phases of CML. In particular p210bcr-abl tyrosine kinase binds HDAC1, resulting in its cytoplasmic compartimentalization and consequently loss of function of HDAC1 itself: this event may be prominent in early chronic phase of the disease, when bcr-abl is the only genetic lesion and its transcription is essential for clonal hematopoiesis to proliferate and survive. It may also contribute to the disease progression by promoting clonal progenitor genomic instability driving the accumulation of additional genetic aberrations. Deregulation of transcription of genes controlling differentiation, apoptosis and growth arrest resulting from HDAC1 compartimentalization in the cytoplasm may be protagonist of more advanced stages of CML, when a fully transformed, drug-resistant phenotype emerges
