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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4432-4440. Prepublished online as a Blood First Edition Paper on January 23, 2007; DOI 10.1182/blood-2006-09-045781.
NEOPLASIA Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia1 San Raffaele Bio-medical Park Foundation, Rome, Italy; 2 Departments of Histology and Medical Embryology and 3 Cellular Biotechnologies and Hematology, University La Sapienza, Rome, Italy; 4 Department of Experimental Oncology, European Institute of Oncology, Milan Italy, 5 Institute Pasteur Cenci-Bolognetti and Department of Genetics and Molecular Biology, University La Sapienza, Rome, Italy; 6 Department of Clinical and Experimental Medicine, University of Perugia, Italy; 7 Department of Biopathology, University Tor Vergata, Rome, Italy
Alteration of lineage-specific transcriptional programs for hematopoiesis causes differentiation block and promotes leukemia development. Here, we show that AML1/ETO, the most common translocation fusion product in acute myeloid leukemia (AML), counteracts the activity of retinoic acid (RA), a transcriptional regulator of myelopoiesis. AML1/ETO participates in a protein complex with the RA receptor alpha (RAR
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
) at RA regulatory regions on RARß2, which is a key RA target gene mediating RA activity/resistance in cells. At these sites, AML1/ETO recruits histone deacetylase, DNA methyltransferase, and DNA-methyl-CpG binding activities that promote a repressed chromatin conformation. The link among AML1/ETO, heterochromatic RARß2 repression, RA resistance, and myeloid differentiation block is indicated by the ability of either siRNA-AML1/ETO or the DNA methylation inhibitor 5-azacytidine to revert these epigenetic alterations and to restore RA differentiation response in AML1/ETO blasts. Finally, RARß2 is commonly silenced by hypermethylation in primary AML blasts but not in normal hematopoietic precursors, thus suggesting a role for the epigenetic repression of the RA signaling pathway in myeloid leukemogenesis. 
