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, Clara Nervi

Research output: Contribution to journalArticle

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 (RARα) at RA regulatory regions on RARβ2, 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 RARβ2 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, RARβ2 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.

Original languageEnglish
Pages (from-to)4432-4440
Number of pages9
JournalBlood
Volume109
Issue number10
DOIs
Publication statusPublished - May 15 2007

ASJC Scopus subject areas

  • Hematology

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    Fazi, F., Zardo, G., Gelmetti, V., Travaglini, L., Ciolfi, A., Di Croce, L., Rosa, A., Bozzoni, I., Grignani, F., Lo-Coco, F., Pelicci, P. G., & Nervi, C. (2007). Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia. Blood, 109(10), 4432-4440. https://doi.org/10.1182/blood-2006-09-045781