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.
Martens
Joost H A
JH
Department of Molecular Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University, the Netherlands.
Brinkman
Arie B
AB
Simmer
Femke
F
Francoijs
Kees-Jan
KJ
Nebbioso
Angela
A
Ferrara
Felicetto
F
Altucci
Lucia
L
Stunnenberg
Hendrik G
HG
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