Oncoproteins, heterochromatin silencing and microRNAs: a new link for leukemogenesis.
The pathogenesis of acute myeloid leukemias involves complex molecular events triggered by diverse alterations of genomic DNA. A limited number of initiating lesions, such as chromosomal translocations generating fusion genes, are constantly identified in specific forms of leukemia and are critical to leukemogenesis. Leukemia fusion proteins derived from chromosomal translocations can mediate epigenetic silencing of gene expression. Epigenetic deregulation of the DNA methylation status and of the chromatin "histone code" at specific gene sites cooperate in the pathogenesis of leukemias. The neutralization of these crucial oncogenic events can revert the leukemia phenotype. Thus, their identification and the study of their molecular and biological consequences is essential for the development of novel and specific therapeutic strategies. In this context, we recently reported a link between the differentiation block of leukemia and the epigenetic silencing of the microRNA-223 gene by the AML1/ETO oncoprotein, the product of the t(8;21) the commonest AML-associated chromosomal translocation. This finding indicates microRNAs as additional epigenetic targets for leukemogenesis and for therapeutic intervention in leukemias.
Nervi
Clara
C
Department of Histology and Medical Embryology; University La Sapienza & San Raffaele Bio-medical Park Foundation; Rome, Italy. clara.nervi@uniroma1.it
Fazi
Francesco
F
Grignani
Francesco
F
D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D019175:DNA Methylation; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006570:Heterochromatin / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics*; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D006570:Heterochromatin; D035683:MicroRNAs; D015513:Oncogene Proteins; C493728:RUNX1 protein, human