bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B53: Selective BET bromodomains epigenetic signaling inhibition as a therapeutic strategy in primary bone tumors
Authors: Lamoureux Francois , Baud'huin Marc , Rodriguez Lidia , Jacques Camille , Berreur Martine , Rédini Francoise , Bradner James E. , Heymann Dominique , Ory Benjamin 
Published: August 2014

Abstract
Osteosarcoma is the most frequent primary bone tumor that develops mainly in young adults. Despite recent improvements of the therapeutic advances, the survival rate at 5 years is below 30% for patients with poor response to treatment or with metastasis.
The histones modifications are of critical importance in maintaining of the transcription program of both normal and tumor cells. The bromodomain and extra-terminal domain (BET) protein family is an important class of “histone reading protein” capable to recognize the N-acetylation of lysine residues on histone tails. BET bromain proteins have recently been described as regulators of MYC expression in various tumors. In this study, we present the therapeutic opportunity to pharmacologically target the BET bromodomain family in primary bone tumors.
The consequence of this pharmacologic inhibition of bromodomains is a wide gene expression alteration, but it is believed to selectively target malignant cells by disrupting transcription at intense activity, most notably MYC and Runx2 in our model. Considering MYC and Runx2 are of particular importance for the oncogenic potential of primary bone tumors, a therapeutic strategy targeting those networks might be extremely relevant and potent.
In osteosarcoma tumor cell lines, BET inhibitor reduced cell growth in a dose-dependent manner and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. These biological events were accompanied by decreased expression and activity of both MYC and Runx-2, and by an expression modulation of their target genes. Moreover, BET inhibitor affects bone remodeling process by disrupting both osteoclast and osteoblast differenciation. In vivo, BET inhibitor (IP; 50mg/kg) significantly inhibits tumor growth by 70% and prolongs survival in both POS-1 syngenic and HOS xenograft models compared to control. Additionnally, these results were accompanied by a decrease of associated bone lesions.
These findings demonstrate that dual pharmacologic inhibition of MYC and Runx-2 is achievable through targeting BET bromodomains to treat osteosarcoma.
Note: This abstract was not presented at the conference.
Citation Format: Francois Lamoureux, Marc Baud'huin, Lidia Rodriguez, Camille Jacques, Martine Berreur, Francoise Rédini, James E. Bradner, Dominique Heymann, Benjamin Ory. Selective BET bromodomains epigenetic signaling inhibition as a therapeutic strategy in primary bone tumors. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B53.
Abstract B58: Implementation of a synthetic reagent to mimic chromatin provides a chromatin immunoprecipitation quantitative control
Authors: Rosenfeld John M. , Li Zirong , Taganov Konstantin , Cooke Tracy , Thyagarajan Bhaskar , Solache Alejandra 
Published: August 2014

Abstract
Chromatin immunoprecipitation (ChIP) is an analytical method used to investigate interaction of proteins with specific genomic DNA regions in vivo to provide a better understanding of mechanisms of gene regulation, DNA replication and DNA repair. However, variations in the efficiency of immunoprecipitation, background signals from carryover in immunoprecipitation, variability between chromatin preps, and loss of material during immunoprecipitation and purification of the ChIP DNA are sources of variability that restrict the use of ChIP as a quantitative tool. To address these limitations, we have developed a simple spike-in control that enables labs to generate results that are more consistent and more quantitative. The approach we have developed uses a synthetic peptide-DNA reagent that is spiked into chromatin immunoprecipitation reactions. Because this reagent mimics the behavior of cross-linked chromatin and can be quantitatively recovered by immunoprecipitation, it can be readily incorporated in to virtually any ChIP protocol. To utilize this internal control, a fixed amount of the synthetic peptide-DNA complex is spiked into the chromatin and co-ChIPed simultaneously with the antibody of interest. The recovered synthetic DNA is then used to normalize the results obtained with the antibody of interest. This spike-in control can be designed using a peptide specific to the ChIP antibody of interest and recovered using a single antibody. Alternatively, a universal spike-in control can be designed using a peptide that is recognized by an epitope tag antibody. This universal spike-in control and epitope tagged antibody are used along with the antibody of interest in a standard ChIP reaction. Our data show that the inclusion of our internal control significantly reduces variability between ChIP assays, thus increasing the accuracy of the ChIP data. Because of the universal feature, this method can also be used to compare ChIP data between different antibodies or to normalize data variations that often result between users and multiple experiments. Furthermore, experiments are underway to confirm that such a spike in control can be incorporated upstream of chromatin preparation, and is capable of being adapted for NGS library construction to aid in normalization between chromatin NGS experiments.
Citation Format: John M. Rosenfeld, Zirong Li, Konstantin Taganov, Tracy Cooke, Bhaskar Thyagarajan, Alejandra Solache. Implementation of a synthetic reagent to mimic chromatin provides a chromatin immunoprecipitation quantitative control. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B58.
Abstract IA04: ATRX mutations in human carcinogenesis
Authors: Papadopoulos Nickolas E. 
Published: August 2014

Abstract
The recent years, genome-wide analyses identified the genetic landscapes of many different tumor types. One of the most frequent class of genes found to be mutated were genes whose products regulate epigenetic mechanisms, like chromatin modification and remodeling, providing a link between genetic alterations and epigenetic changes in cancer. One of these genes is ATRX. This gene has been studied in the context of alpha thalassemia-mental retardation X-linked syndrome. In human sporadic solid tumors, it was first shown to be mutated in pancreatic neuroendocrine tumors (PanNETs). Approximately, 50% of PanNETs had mutations in either ATRX or DAXX. The proteins of these two genes form a complex that deposits H3.3 at heterochromatin and telomeres. ATRX, but not DAXX, has also been found to be mutated in certain types of central nervous system tumors. The prevalence of mutations in ATRX is different for the different types of gliomas. It is mutated more frequently in astrocytomas and oligoastrocytomas, but rarely in primary glioblastomas. Recently, we identified mutations in the promoter of TERT in the same set of glioma samples. TERT mutations were more prevalent in primary glioblastomas and oligodendrogliomas. Overall, mutations in ATRX and TERT were mutually exclusive, suggesting that these two genetic mechanisms result in equivalent growth advantages. Mutations in ATRX have almost perfect correlation with Alternative Lengthening of Telomeres (ALT) phenotype in PanNETs, CNS tumors and other cases with ATRX mutations, thus, TERT activation and ALT phenotype are mutually exclusive. This has implications for understanding the relationship between telomeres and tumorigenesis. These studies, in addition to providing clues about the underlying genetic changes that drive tumorigenesis, they also have clinical implications. Mutations in ATRX or DAXX in PanNETs associate with better prognosis. Mutations of ATRX and TERT aid in the classification and prognostication of brain tumors. Further understanding of the role of ATRX in tumorigenesis should help in uncovering new ways for therapeutic targeting of tumors with mutations in this gene.
Citation Format: Nickolas E. Papadopoulos. ATRX mutations in human carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA04.
Abstract IA06: Epigenetic regulation and heterogeneity in cancer
Authors: Bernstein Bradley E. 
Published: August 2014

Abstract
We are using emerging technologies to characterize chromatin state and regulation in human cells. Chromatin maps for diverse normal tissues and cells reveal the locations and cell type-specificities of distal regulatory elements and facilitate the interpretation of genetic variants associated with complex human diseases. Analogous studies of malignant tumors reveal regulatory programs that drive proliferation, while also emphasizing the importance of epigenetic heterogeneity in cancer biology and therapeutic resistance. I will highlight representative studies in these areas and touch on new technological approaches for the study of tumor heterogeneity.
Citation Format: Bradley E. Bernstein. Epigenetic regulation and heterogeneity in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA06.
Abstract IA25: Linking genetic features of human cancers and histone-modifying enzymes for future cancer therapies
Authors: Schreiber Stuart L. 
Published: August 2014

Abstract
Small-molecular therapeutics targeting chromatin-modifying enzymes offer promise for future treatment of cancers, but the most suitable ways to use such agents is still largely unknown. This lecture will explore several avenues of research aimed at advancing chromatin-based therapeutics, including the identification of cancer genetic dependencies involving chromatin, the creation of new cancer dependencies by altering cell states through chromatin modifications, and the discovery of novel small molecules that alter chromatin states.
Citation Format: Stuart L. Schreiber. Linking genetic features of human cancers and histone-modifying enzymes for future cancer therapies. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA25.
Abstract PR04: Genomic and epigenomic interactions of an Ewing sarcoma-specific long noncoding RNA
Authors: Mitra Sheetal A. , Mitra Anirban P. , Buckley Jonathan D. , May William A. , Kapranov Philipp , Arceci Robert A. , Triche Timothy J. 
Published: August 2014

Abstract
Ewing sarcoma is a highly invasive pediatric bone malignancy with a 30% 5-year survival rate for patients with metastatic disease. The EWS-FLI1 fusion gene is detected in 90% of these cases, and functions as a transcription factor that regulates oncogenesis-related gene expression. The functions of EWS-FLI1 and other oncogenes have been explored in the past to detect potential therapeutic targets.
Here we report the functions and interactions of a long intergenic non-coding RNA (lincRNA) that is unique to Ewing sarcoma. Gene expression profiling studies identified a significant association of lincRNA, AK057037, with Ewing sarcoma. Chromatin immunoprecipitation (ChIP) and functional studies with EWS-FLI1 detected direct regulation of this multi-exonic, multivariant lincRNA by EWS-FLI1. Comparative RNA-seq analysis on primary and metastatic tumor cell lines showed increased transcriptional activity in the metastatic cell line. In vitro and in vivo functional studies with the lincRNA confirmed its role as an oncogene in promoting anchorage independence and metastasis of the Ewing sarcoma cell lines and xenograft models, respectively. Further, ChIP studies showed that AK057037 was bound to Ezh2, a methyltransferase in the polycomb repressor complex 2 (PRC2). ChIP-seq using histone antibodies showed changes in methylation pattern in promoter regions of genes affected by the lincRNA knockdown.
In conclusion, the lincRNA AK057037 behaves as an oncogene in Ewing sarcoma. Its association with the PRC2 complex allows for chromatin remodeling such that it promotes metastasis by perturbing transcription of genes involved in migration in this malignancy.
This abstract is also presented as Poster A33.
Citation Format: Sheetal A. Mitra, Anirban P. Mitra, Jonathan D. Buckley, William A. May, Philipp Kapranov, Robert A. Arceci, Timothy J. Triche. Genomic and epigenomic interactions of an Ewing sarcoma-specific long noncoding RNA. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR04.
Abstract PR06: CARM1 methylates BAF155 and perturbs chromatin remodeling machinery to enhance tumor progression
Authors: Wang Lu , Zhao Zibo , Meyer Mark , Pike Wesley J. , Xu Wei 
Published: August 2014

Abstract
CARM1 belongs to the type I protein arginine (R) methyltransferase (PRMT) family and asymmetrically di-methylates proteins on arginines. Because CARM1 is highly expressed in high grade breast tumors and was shown to transactivate cancer-relevant transcription factors including ERα, NF-κB, p53 and E2F1, it has been strongly implicated in tumorigenesis. To fully characterize functions of CARM1 in breast cancer, we knocked-out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology. Western blot using an asymmetric di-methylated R antibody revealed striking differences between CARM1 KO and parental MCF7 cell lysates, indicating that CARM1 methylates a significant number of substrates in breast cancer cells. BAF155, a core subunit of SWI/SNF chromatin remodeling complex, was identified as a CARM1 substrate by mass spectrometry. Further biochemical analyses validated that BAF155 was methylated by CARM1 in vivo and in vitro and methylation was mapped to a single site, R1064. We next generated BAF155R1064K knock-in MCF7 and MDA-mb-231 cells and showed that methylation of BAF155 is essential for breast cancer cell growth, colony formation and migration. Further, we developed an antibody that selectively recognized methylated form of BAF155 (me-BAF155) and observed strong nuclear me-BAF155 staining in invasive ductal carcinoma but not in the normal breast tissue. Importantly, me-BAF155 immunostaining positively correlates with tumor stage and metastasis. To understand the molecular mechanism by which BAF155 methylation affects tumorigenesis, we performed ChIP-seq using ChIP-validated BAF155 antibody in the BAF155WT or BAF155R1064K knock-in MCF7 cells. Interestingly, C-Myc pathway genes were only identified in WT but not mutant BAF155 regulated categories. Individual ChIP assays validated differential binding of BAF155WT or BAF155R1064K to specific target genes and importantly, the mRNA levels of these genes were affected correspondingly. This result suggests that BAF155 methylation affects gene expression by altering genomic association of BAF155, and perhaps the SWI/SNF complex, to chromatin regions. Collectively, our study revealed novel mechanisms by which CARM1 perturbs the chromatin remodeling machinery to enhance tumor progression.
This work is supported by DOD ERA of HOPE Scholar Award and Shaw Scientist Award to W.X.
This abstract is also presented as Poster A37.
Citation Format: Lu Wang, Zibo Zhao, Mark Meyer, Wesley J. Pike, Wei Xu. CARM1 methylates BAF155 and perturbs chromatin remodeling machinery to enhance tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR06.
Abstract PR10: Modulation of chromatin structure and transcription by the SWI/SNF complex in acute lymphoblastic leukemia
Authors: Wu Jennifer , Pinello Luca , Yissachar Elinor , Yuan Guo-Cheng , Roberts Charles 
Published: August 2014

Abstract
SWI/SNF chromatin remodelers act as tumor suppressors in a wide variety of tissue types and cancers. Recent reports describe that as many as 20% of human cancers harbor mutations in one or more subunits of this multi-protein complex. Intriguingly, mutations in the SWI/SNF complex are rarely found in leukemias. However, it has long been understood that SWI/SNF is a key component of glucocorticoid-mediated transcription. Diminished expression of SWI/SNF subunits has also been linked to altered sensitivity to glucocorticoid-induced cell death in acute lymphoblastic leukemias (ALL). Glucocorticoid-induced cell death is a critical component of successful ALL therapy. We therefore use the glucocorticoid-mediated transcriptional program in a human ALL cell line to interrogate the genome-wide chromatin changes and contributions to transcription mediated by an intact SWI/SNF complex. We begin by elucidating the dynamic relationships between glucocorticoid receptor binding to chromatin and recruitment of SWI/SNF using ChIP-Seq. We further relate these glucocorticoid-inducible binding events to changes in position of modified histones, changes in chromatin accessibility by DNase-seq, and changes in gene expression. By better understanding the mechanisms by which SWI/SNF modifies the chromatin landscape within a specific transcriptional program, we will facilitate additional studies of how disruption of the SWI/SNF complex affects ALL responses to steroid therapy. Furthermore, we will contribute to future studies of how mutations in the SWI/SNF complex functionally affect chromatin structure and contribute to oncogenesis.
This abstract is also presented as Poster B07.
Citation Format: Jennifer Wu, Luca Pinello, Elinor Yissachar, Guo-Cheng Yuan, Charles Roberts. Modulation of chromatin structure and transcription by the SWI/SNF complex in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR10.
Abstract A27: Mapping of chemical-genetic interactions in breast cancer reveals a mechanism of resistance to PI3K inhibitors
Authors: Muellner Markus K. , Uras Iris Z. , Gapp Bianca , Nijman Sebastian M. 
Published: August 2014

Abstract
Linking the molecular aberrations of cancer to drug responses allows directing the choice of treatment and to explore new therapeutic applications. We set out to systematically map drug-gene interactions in breast cancer and established a multiplexed assay to study the cellular fitness of a panel of engineered isogenic cells in response to a collection of drugs. This approach so far revealed several synthetic-lethal interactions and drug-resistance mechanisms, including previously discovered interactions from other model systems. Among the novel interactions NOTCH pathway activation, which occurs frequently in breast cancer, unexpectedly conferred resistance to phosphoinositide 3-kinase (PI3K) inhibitors, which are currently undergoing clinical trials in breast cancer patients. NOTCH1 and downstream induction of c-MYC over-rode the dependency of cells on the PI3K-mTOR pathway for proliferation. These data reveal a new mechanism of resistance to PI3K inhibitors with direct clinical implications.
Citation Format: Markus K. Muellner, Iris Z. Uras, Bianca Gapp, Sebastian M. Nijman. Mapping of chemical-genetic interactions in breast cancer reveals a mechanism of resistance to PI3K inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A27.
Abstract IA19: Small-molecule modulators of the Hedgehog signaling pathway
Authors: Chen James K. 
Published: August 2014

Abstract
The Hedgehog (Hh) signaling pathway plays critical roles in embryonic patterning and tissue homeostasis, and its inappropriate activation can lead to basal cell carcinoma, medulloblastoma, and other cancers. Small molecules that modulate Hh signaling proteins can therefore be valuable probes of Hh pathway-dependent physiology and targeted therapies for Hh pathway-related diseases. While high-throughput screening campaigns in academia and industry have yielded several Hh pathway modulators that potently and selectively target the transmembrane protein Smoothened (Smo), there is a growing need for compounds that inhibit Hh target gene expression through other mechanisms. Such small molecules could provide new insights into the cellular processes that regulate Gli transcription factor function and possibly prevent or overcome the emergence of tumors that are resistant to Smo antagonists. Toward this goal, we have completed large-scale screens for Hh pathway inhibitors that act downstream of Smo, revealing several compounds that inhibit Gli-dependent transcription through distinct mechanisms of action. We have successfully determined the cellular target of one inhibitor from our screens, and mechanistic studies of other Gli antagonists are currently underway.
Citation Format: James K. Chen. Small-molecule modulators of the Hedgehog signaling pathway [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA19.
Abstract IA5: Designing synthetic regulatory RNAs: New tools for temporal and spatial control in biological systems
Authors: Smolke Christina D. 
Published: August 2014

Abstract
Advances in synthetic biology are transforming our ability to design and build synthetic biological systems. While progress has been made in the design of complex genetic circuits, capabilities for constructing large genetic systems currently surpass our ability to design such systems. This growing “design gap” has highlighted the need to develop methods that support the generation of new functional biological components and scalable design strategies for complex genetic circuits that will lay the foundation for integrated biological devices and systems.
As examples of functional RNA molecules playing key roles in the behavior of natural biological systems have grown over the past decade, there has been growing interest in the design and implementation of synthetic counterparts. Researchers are taking advantage of the relative ease with which RNA molecules can be modeled and designed to engineer functional RNA molecules that act as diverse components including sensors, regulators, controllers (ligand-responsive RNA regulators), and scaffolds. These synthetic regulatory RNAs are providing new tools for temporal and spatial control in biological systems. I will describe recent work in the design of RNA controllers and advances in addressing challenges faced in their broad implementation as user-programmed control systems in living cells. In particular, I will describe the development of high-throughput cell-based screens for rapidly generating synthetic regulatory RNAs with specified quantitative properties. I will also discuss how the application of synthetic regulatory RNAs as controllers in different biological pathways are leading to the elucidation of integrated systems design strategies and new capabilities for programming genetic systems.
Citation Format: Christina D. Smolke. Designing synthetic regulatory RNAs: New tools for temporal and spatial control in biological systems [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA5.