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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    • "Specifically, Top2b is required for normal neural development (Yang et al., 2000;Nur-E-Kamal et al., 2007;Lyu et al., 2006;Tiwari et al., 2012) and TOP2B has been demonstrated to be recruited to certain hormone responsive promoters upon ligand treatment (Haffner et al., 2010;Ju et al., 2006;Wong et al., 2009;Perillo et al., 2008). TOP2B negatively regulates the expression of RARα following exposure to retinoic acid (McNamara et al., 2008) and was isolated as a component of the Groucho/TLE repressor complex, along with PARP1 (Ju et al., 2004). The extracellular ligands appear to trigger a molecular switch/change of chromatin state via TOP2B. "
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    ABSTRACT: We report the whole genome ChIP seq for human TOP2B from MCF7 cells. Using three different peak calling methods, regions of binding were identified in the presence or absence of the nuclear hormone estradiol, as TOP2B has been reported to play a role in ligand-induced transcription. TOP2B peaks were found across the whole genome, 50% of the peaks fell either within a gene or within 5 kb of a transcription start site. TOP2B peaks coincident with gene promoters were less frequently associated with epigenetic features marking active promoters in estradiol treated than in untreated cells. Significantly enriched transcription factor motifs within the DNA sequences underlying the peaks were identified. These included SP1, KLF4, TFAP2A, MYF, REST, CTCF, ESR1 and ESR2. Gene ontology analysis of genes associated with TOP2B peaks found neuronal development terms including axonogenesis and axon guidance were significantly enriched. In the absence of functional TOP2B there are errors in axon guidance in the zebrafish eye. Specific heparin sulphate structures are involved in retinal axon targeting. The glycosaminoglycan biosynthesis-heparin sulphate/heparin pathway is significantly enriched in the TOP2B gene ontology analysis, suggesting changes in this pathway in the absence of TOP2B may cause the axon guidance faults.
    Full-text · Article · Oct 2015 · Biology Open
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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
    Full-text · Article · Sep 2014 · British Journal of Cancer
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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.
    Full-text · Article · Feb 2014 · Genes Chromosomes and Cancer
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