Abstract:
: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 (RARalpha) at RA regulatory regions on RARbeta2, 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 RARbeta2 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, RARbeta2 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.
journal_name
Bloodjournal_title
Bloodauthors
Fazi F,Zardo G,Gelmetti V,Travaglini L,Ciolfi A,Di Croce L,Rosa A,Bozzoni I,Grignani F,Lo-Coco F,Pelicci PG,Nervi Cdoi
10.1182/blood-2006-09-045781subject
Has Abstractpub_date
2007-05-15 00:00:00pages
4432-40issue
10eissn
0006-4971issn
1528-0020pii
blood-2006-09-045781journal_volume
109pub_type
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