Chromatin modifying activity of leukaemia associated fusion proteins.
The leukaemias, which are divided into chronic and acute forms, are malignant diseases of haematopoietic cells in which the proper balance between proliferation, differentiation and apoptosis is no longer operative. Genes, such as those of mixed-lineage leukaemia, AML1 and retinoic acid receptor alpha, have been found to be aberrantly fused to different partners, which often encode transcription factors or other chromatin modifying enzymes, in numerous types of acute lymphoid and myeloid leukaemias. These chimeric fusion oncoproteins, generated by reciprocal chromosomal translocations, are responsible for chromatin alterations on target genes whose expression is critical to stem cell development or lineage specification in haematopoiesis. Alterations in the 'histone code' or in the DNA methylation content occur as consequence of aberrant targeting of the corresponding enzymatic activities. Here, the author will review the most recent progress in the field, focusing on how fusion proteins generated by chromosomal translocation are responsible for chromatin alterations, gene deregulation and haematopoietic differentiation block and their implication for clinical treatment.
Di Croce
Luciano
L
ICREA and Centre de Regulació Genòmica (CRG), Passeig Maritim 37-49, 08003 Barcelona, Spain. luciano.dicroce@crg.es
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000378:metabolism*
D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C000607071:RARA protein, human; C493728:RUNX1 protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors