Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia.
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.
Fazi
Francesco
F
San Raffaele Bio-medical Park Foundation, Rome, Italy.
Zardo
Giuseppe
G
Gelmetti
Vania
V
Travaglini
Lorena
L
Ciolfi
Alberto
A
Di Croce
Luciano
L
Rosa
Alessandro
A
Bozzoni
Irene
I
Grignani
Francesco
F
Lo-Coco
Francesco
F
Pelicci
Pier Giuseppe
PG
Nervi
Clara
C
D000208:Acute Disease; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing; D006570:Heterochromatin / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D000075142:RUNX1 Translocation Partner 1 Protein; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D020298:U937 Cells
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D006570:Heterochromatin; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014212:Tretinoin