PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia

Joost H.A. Martens; Arie B. Brinkman; Femke Simmer; Kees Jan Francoijs; Angela Nebbioso; Felicetto Ferrara; Lucia Altucci; Hendrik G. Stunnenberg

doi:10.1016/j.ccr.2009.12.042

PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia

Joost H.A. Martens, Arie B. Brinkman, Femke Simmer, Kees Jan Francoijs, Angela Nebbioso, Felicetto Ferrara, Lucia Altucci, Hendrik G. Stunnenberg

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259 Citations (Scopus)

Abstract

Many different molecular mechanisms have been associated with PML-RARα-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARα binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARα 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-RARα/RXR binding sites or at nearby target genes. Our results suggest that PML-RARα/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.

Original language	English
Pages (from-to)	173-185
Number of pages	13
Journal	Cancer Cell
Volume	17
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2009.12.042
Publication status	Published - 17 Feb 2010
Externally published	Yes

Keywords

CELLCYCLE

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title = "PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia",

abstract = "Many different molecular mechanisms have been associated with PML-RARα-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARα binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARα 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-RARα/RXR binding sites or at nearby target genes. Our results suggest that PML-RARα/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.",

keywords = "CELLCYCLE",

author = "Martens, {Joost H.A.} and Brinkman, {Arie B.} and Femke Simmer and Francoijs, {Kees Jan} and Angela Nebbioso and Felicetto Ferrara and Lucia Altucci and Stunnenberg, {Hendrik G.}",

note = "Funding Information: We thank E. Megens for technical assistance. H3K27me3 and H3K9me3 were a kind gift of T. Jenuwein. This work was supported by the Netherlands Bioinformatics Centre, the European Union (LSHC-CT-2005-518417 “ Epitron ”; HEALTH-F2-2007-200620 “ CancerDip ”), the Dutch Cancer Foundation (KWF KUN 2008-4130), and l'Associazione Italiana per la Ricerca Contro il Cancro. ",

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doi = "10.1016/j.ccr.2009.12.042",

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AU - Martens, Joost H.A.

AU - Brinkman, Arie B.

AU - Simmer, Femke

AU - Francoijs, Kees Jan

AU - Nebbioso, Angela

AU - Ferrara, Felicetto

AU - Altucci, Lucia

AU - Stunnenberg, Hendrik G.

N1 - Funding Information: We thank E. Megens for technical assistance. H3K27me3 and H3K9me3 were a kind gift of T. Jenuwein. This work was supported by the Netherlands Bioinformatics Centre, the European Union (LSHC-CT-2005-518417 “ Epitron ”; HEALTH-F2-2007-200620 “ CancerDip ”), the Dutch Cancer Foundation (KWF KUN 2008-4130), and l'Associazione Italiana per la Ricerca Contro il Cancro.

PY - 2010/2/17

Y1 - 2010/2/17

N2 - Many different molecular mechanisms have been associated with PML-RARα-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARα binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARα 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-RARα/RXR binding sites or at nearby target genes. Our results suggest that PML-RARα/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.

AB - Many different molecular mechanisms have been associated with PML-RARα-dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARα binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARα 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-RARα/RXR binding sites or at nearby target genes. Our results suggest that PML-RARα/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.

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PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia

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