PML-RARalpha/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia.
Many different molecular mechanisms have been associated with PML-RARalpha-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARalpha binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARalpha with RXR to the vast majority of these binding regions. Genome-wide epigenetic studies revealed that treatment with pharmacological doses of all-trans retinoic acid induces changes in H3 acetylation, but not H3K27me3, H3K9me3, or DNA methylation at the PML-RARalpha/RXR binding sites or at nearby target genes. Our results suggest that PML-RARalpha/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for hematopoietic differentiation, RAR signaling, and epigenetic control is crucial to its transforming potential.
Department of Molecular Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University, the Netherlands.
Joost H A
JH
Martens
Arie B
AB
Brinkman
Femke
F
Simmer
Kees-Jan
KJ
Francoijs
Angela
A
Nebbioso
Felicetto
F
Ferrara
Lucia
L
Altucci
Hendrik G
HG
Stunnenberg
D000107:Acetylation; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D047488:Retinoid X Receptors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D006657:Histones; D015514:Oncogene Proteins, Fusion; D047488:Retinoid X Receptors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D006655:Histone Deacetylases