Topoisomerase II Negatively Modulates Retinoic Acid Receptor Function: a Novel Mechanism of Retinoic Acid Resistance

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Segal Cancer Center, 3755 Chemin de la Côte-Ste-Catherine, Montreal, Quebec, Canada.
Molecular and Cellular Biology (Impact Factor: 4.78). 04/2008; 28(6):2066-77. DOI: 10.1128/MCB.01576-07
Source: PubMed


Interactions between retinoic acid (RA) receptor α (RARα) and coregulators play a key role in coordinating gene transcription
and myeloid differentiation. In patients with acute promyelocytic leukemia (APL), the RARα gene is fused with the promyelocytic
leukemia (PML) gene via the t(15;17) translocation, resulting in the expression of a PML/RARα fusion protein. Here, we report
that topoisomerase II beta (TopoIIβ) associates with and negatively modulates RARα transcriptional activity and that increased
levels of and association with TopoIIβ cause resistance to RA in APL cell lines. Knockdown of TopoIIβ was able to overcome
resistance by permitting RA-induced differentiation and increased RA gene expression. Overexpression of TopoIIβ in clones
from an RA-sensitive cell line conferred resistance by a reduction in RA-induced expression of target genes and differentiation.
Chromatin immunoprecipitation assays indicated that TopoIIβ is bound to an RA response element and that inhibition of TopoIIβ
causes hyperacetylation of histone 3 at lysine 9 and activation of transcription. Our results identify a novel mechanism of
resistance in APL and provide further insight to the role of TopoIIβ in gene regulation and differentiation.

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    • "Point mutations within the PML–RARalpha ligand-binding domain (LBD) have been found and account for B40% of ATRA-resistant APL (Gallagher et al, 2012). Given the central role of epigenetic reprogramming underlying ATRA response, another major resistant mechanism, which may also apply to the variant PLZF–RARalpha fusion, is due to the formation of aberrant repression complexes that cannot be easily dissociated by ATRA treatment (McNamara et al, 2008). "
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    ABSTRACT: Transcriptional deregulation plays a key role in a large array of cancers, and successful targeting of oncogenic transcription factors that sustain diseases has been a holy grail in the field. Acute promyelocytic leukaemia (APL) driven by chimeric transcription factors encoding retinoic acid receptor alpha fusions is the paradigm of targeted cancer therapy, in which the application of all-trans retinoic acid (ATRA) treatments have markedly transformed this highly fatal cancer to a highly manageable disease. The extremely high complete remission rate resulted from targeted therapies using ATRA in combination with arsenic trioxide will likely be able to minimise or even totally eliminate the use of highly toxic chemotherapeutic agents in APL. In this article, we will review the molecular basis and the upcoming challenges of these targeted therapies in APL, and discuss the recent advance in our understanding of epigenetics underlying ATRA response and their potential use to further improve treatment response and overcome resistance.British Journal of Cancer advance online publication, 23 September 2014; doi:10.1038/bjc.2014.374
    British Journal of Cancer 09/2014; 112(3). DOI:10.1038/bjc.2014.374 · 4.84 Impact Factor
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    • "Human cells contain two TOP2 isozymes; alpha (TOP2A) and beta (TOP2B). TOP2A is involved in chromosome condensation and segregation and TOP2B has been implicated in transcription (Lyu et al., 2006; Tiwari et al., 2012), including modulation of transcription by nuclear hormones, such as estradiol, androgen, and retinoic acid (Ju et al., 2006; McNamara et al., 2008; Perillo et al., 2008; Haffner et al., 2010; Williamson and Lees-Miller, 2011). Approximately, 20–30% of therapy-related hematologic disease cases contain balanced chromosome translocations (Rowley and Olney, 2002). "
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    ABSTRACT: Rearrangements involving the RUNX1 gene account for approximately 15% of balanced translocations in therapy-related acute myeloid leukemia (t-AML) patients and are one of the most common genetic abnormalities observed in t-AML. Drugs targeting the topoisomerase II (TOP2) enzyme are implicated in t-AML; however, the mechanism is not well understood and to date a single RUNX1-RUNX1T1 t-AML breakpoint junction sequence has been published. Here we report an additional five breakpoint junction sequences from t-AML patients with the RUNX1- RUNX1T1 translocation. Using a leukemia cell line model, we show that TOP2 beta (TOP2B) is required for induction of RUNX1 chromosomal breaks by the TOP2 poison etoposide and that, while TOP2 alpha (TOP2A) and TOP2B proteins are both present on RUNX1 and RUNX1T1 chromatin, only the TOP2B enrichment reached significance following etoposide exposure at a region on RUNX1 where translocations occur. Furthermore, we demonstrate that TOP2B influences the separation between RUNX1 and two translocation partners (RUNX1T1 and EVI) in the nucleus of lymphoid cells. Specifically, we identified a TOP2B-dependent increase in the number of nuclei displaying juxtaposed RUNX1 and RUNX1T1 loci following etoposide treatment. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 02/2014; 53(2):117-28. DOI:10.1002/gcc.22124 · 4.04 Impact Factor
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    • "Topo IIβ physically interacts with developmentally controlled genes and up- or downregulates their transcription (34,35). Topo IIβ induces the activation of gene promoters regulated by nuclear hormone receptors (36), inhibits the transcription of genes regulated by the retinoic acid receptor alpha (37) and modulates the expression of genes involved in neuronal survival (38). Thus far, the molecular mechanisms by which topo IIβ regulates transcription are poorly understood. "
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    ABSTRACT: Eukaryotic topoisomerase II (topo II) is the essential decatenase of newly replicated chromosomes and the main relaxase of nucleosomal DNA. Apart from these general tasks, topo II participates in more specialized functions. In mammals, topo IIα interacts with specific RNA polymerases and chromatin-remodeling complexes, whereas topo IIβ regulates developmental genes in conjunction with chromatin remodeling and heterochromatin transitions. Here we show that in budding yeast, topo II regulates the expression of specific gene subsets. To uncover this, we carried out a genomic transcription run-on shortly after the thermal inactivation of topo II. We identified a modest number of genes not involved in the general stress response but strictly dependent on topo II. These genes present distinctive functional and structural traits in comparison with the genome average. Yeast topo II is a positive regulator of genes with well-defined promoter architecture that associates to chromatin remodeling complexes; it is a negative regulator of genes extremely hypo-acetylated with complex promoters and undefined nucleosome positioning, many of which are involved in polyamine transport. These findings indicate that yeast topo II operates on singular chromatin architectures to activate or repress DNA transcription and that this activity produces functional responses to ensure chromatin stability.
    Nucleic Acids Research 08/2013; 41(20). DOI:10.1093/nar/gkt707 · 9.11 Impact Factor
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