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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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NEOPLASIA

Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia

Francesco Fazi1,2, Giuseppe Zardo1,3, Vania Gelmetti1,2, Lorena Travaglini1,2, Alberto Ciolfi1,2, Luciano Di Croce4, Alessandro Rosa5, Irene Bozzoni5, Francesco Grignani6, Francesco Lo-Coco7, Pier Giuseppe Pelicci4, and Clara Nervi1,2

1 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{alpha}) 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.


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AML1/ETO, a promiscuous fusion oncoprotein
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Blood 2007 109: 4109-4110. [Full Text] [PDF]



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