Many different molecular mechanisms have been associated with PML-RARa-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARa binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARa 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-RARa/RXR binding sites or at nearby target genes. Our results suggest that PML-RARa/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.
PML-RARalpha/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia
NEBBIOSO, Angela;ALTUCCI, Lucia;
2010
Abstract
Many different molecular mechanisms have been associated with PML-RARa-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARa binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARa 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-RARa/RXR binding sites or at nearby target genes. Our results suggest that PML-RARa/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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
