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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2498.
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NEOPLASIA
Comment on Hoemme et al, page 2887
Epigenomic repression by APL oncoprotein
Filippa Pettersson, and
Wilson H. Miller, Jr
SEGAL CANCER CENTRE OF THE SIR MORTIMER B DAVIES JEWISH GENERAL HOSPITAL
In recent years, powerful technologies to globally examine epigenetic targets of transcription factors and directly link these to changes in gene expression have emerged. Acute leukemias are characterized by translocations leading to the production of chimeric transcription factors, which are perfect targets for such analyses.
In acute promyelocytic leukemia (APL), a t(15;17) translocation leads to the production of PML-RAR , the fusion oncoprotein responsible for the vast majority of APL cases. Expression of PML-RAR leads to transcriptional repression of RAR target genes and a differentiation block at the promyelocytic stage, but also to a unique responsiveness to treatment with all-trans retinoic acid (ATRA).
In this issue of Blood, Hoemme and colleagues present a comprehensive study using chromatin precipitation (ChIP)–chip as well as microarrays to analyze changes that occur with induced expression of PML-RAR in a promonocytic cell line. The authors used different antibodies to correlate PML-RAR binding to gene promoters with epigenetic modifications, including histone acetylation and methylation. Their data show a strong trend for promoters bound by PML-RAR to display lower levels of histone H3 acetylation, confirming that PML-RAR acts as a global repressor of gene transcription. Interestingly, a significant correlation between PML-RAR binding and increased levels of tri-methylated H3 lysine-9 is also evident, suggesting that a major effect of PML-RAR binding may be recruitment of the histone methyltransferase SUV39H1 to target promoters.1
The study identified binding of PML-RAR to 372 genomic locations. Most were found close to the transcriptional start site of genes, but only about 40% of the targets contained bona fide retinoic acid receptor response elements, a finding that is in line with previous studies showing much more "relaxed" DNA binding requirements for PML-RAR compared with wildtype RAR.2 Microarray analyses were performed to assess global changes in gene expression associated with induced PML-RAR, and the resulting data show quite convincingly that PML-RAR binding, and the resulting chromatin changes, correlate with a global repression of transcription.
Pathway analysis of genes repressed by PML-RAR identified genes regulating many important cellular functions. Further analysis of these genes and their de-repression by ATRA in APL may shed important light on the molecular mechanisms of APL pathogenesis. In fact, 2 of the 3 most strongly repressed genes identified in the study, RGS2 and S100P, are previously identified regulators of myeloid differentiation, and RGS2 has been shown by the authors to be induced during ATRA treatment of the APL cell line NB4.3 Additional information about ATRA regulation of the identified epigenetic and genetic targets will be valuable, especially in light of other studies that have shown reversal of epigenetic silencing by ATRA4 and our recent data showing that ATRA can induce chromatin changes associated with transcriptional activation via binding to either PML-RAR or wild-type RAR.5
Understanding the mechanisms of deregulated transcription by leukemia fusion onco-proteins is critical for the design of tailored antileukemic strategies aimed at re-establishing the differentiation program. The use of global epigenetic and genetic analysis tools to identify targets of different leukemia-associated oncoproteins will likely prove increasingly important in this quest.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Carbone R, Botrugno OA, Ronzoni S, et al. Recruitment of the histone methyltransferase SUV39H1 and its role in the oncogenic properties of the leukemia-associated PML-retinoic acid receptor fusion protein. Mol Cell Biol 2006; 26:1288–1296.[Abstract/Free Full Text]
- Kamashev D, Vitoux D, de Thé H. PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J Exp Med 2004; 199:1163–1174.[Abstract/Free Full Text]
- Schwable J, Choudhary C, Thiede C, et al. RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation. Blood 2005; 105:2107–2114.[Abstract/Free Full Text]
- Di Croce L, Raker VA, Corsaro M, et al. Methyl-transferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002; 295:1079–1082.[Abstract/Free Full Text]
- Witcher M, Pettersson F, Dupere-Richer D, et al. Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoter. Nucl Acids Res 2008; 36:435–443.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Chromatin modifications induced by PML-RAR repress critical targets in leukemogenesis as analyzed by ChIP-Chip
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Blood 2008 111: 2887-2895.
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