P210 Bcr-abl tyrosine kinase interaction with histone deacetylase 1 modifies histone H4 acetylation and chromatin structure of chronic myeloid leukaemia haematopoietic progenitors.
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.
Brusa
Gianluca
G
Istituto di Ematologia e Oncologia Medica Lorenzo e Ariosto Seràgnoli, Universita di Bologna, Bologna, Italy. gbrusa@alma.unibo.it
Zuffa
Elisa
E
Mancini
Manuela
M
Benvenuti
Michela
M
Calonghi
Natalia
N
Barbieri
Enza
E
Santucci
Maria Alessandra
MA
D000107:Acetylation; D018952:Antigens, CD34 / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry*; D003593:Cytoplasm / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
D018952:Antigens, CD34; D002843:Chromatin; D006657:Histones; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases