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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.
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Submitted September 7, 2006
Accepted January 14, 2007
Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia
Francesco Fazi, Giuseppe Zardo, Vania Gelmetti, Lorena Travaglini, Alberto Ciolfi, Luciano Di Croce, Alessandro Rosa, Irene Bozzoni, Francesco Grignani, Francesco Lo-Coco, Pier Giuseppe Pelicci, and Clara Nervi*
San Raffaele Bio-medical Park Foundation, Rome, Italy
Depts of Cellular Biotechnologies & Hematology, University La Sapienza, Rome, Italy
Depts of Histology and Medical Embryology, University La Sapienza, Rome, Italy
Dept of Experimental Oncology, European Institute of Oncology, Milan, Italy
Institute Pasteur Cenci-Bolognetti, & Department of Genetics and Molecular Biology and IBPM, University La Sapienza, Rome, Italy
Dept of Clinical & Experimental Medicine, University of Perugia, Italy
Dept of Biopathology, University Tor Vergata, Rome, Italy
* Corresponding author; email: clara.nervi{at}uniroma1.it.
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 myelopoyesis. AML1/ETO participates in a protein complex with the RA-receptor alpha (RAR ) at RA-regulatory regions on RAR 2, 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 RAR2 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, RAR2 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
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