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153. Abstract 4003: Comprehensive genomic profiling of Merkel cell carcinoma samples reveals bimodal distribution of tumor mutational burden and two mutually exclusive candidate mechanisms of malignant transformation

Author

Montesion, Meagan, primary, Sokol, Ethan S., additional, Knepper, Todd C., additional, Brohl, Andrew S., additional, Frampton, Garrett M., additional, Stephens, Phil J., additional, DeCaprio, James A., additional, Tsai, Kenneth Y., additional, and Albacker, Lee A., additional

Published
2018
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154. DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169

Author

Menon, Vijay R., primary, Ananthapadmanabhan, Varsha, additional, Swanson, Selene, additional, Saini, Siddharth, additional, Sesay, Fatmata, additional, Yakovlev, Vasily, additional, Florens, Laurence, additional, DeCaprio, James A., additional, Washburn, Michael P., additional, Dozmorov, Mikhail, additional, and Litovchick, Larisa, additional

Published
2018
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155. Comprehensive genomic profiling of advanced Merkel cell carcinoma to reveal insights into immunotherapy response.

Author

Knepper, Todd Cory, primary, Russell, Jeffery Scott, additional, Montesion, Meagan, additional, Sokol, Ethan, additional, Frampton, Garrett Michael, additional, Stephens, Phil, additional, Albacker, Lee A., additional, Schell, Michael J., additional, DeCaprio, James A, additional, Tsai, Kenneth Yee, additional, and Brohl, Andrew Scott, additional

Published
2018
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158. Cabozantinib in Patients with Advanced Merkel Cell Carcinoma

Author

Rabinowits, Guilherme, primary, Lezcano, Cecilia, additional, Catalano, Paul J., additional, McHugh, Patricia, additional, Becker, Hailey, additional, Reilly, Megan M., additional, Huang, Julian, additional, Tyagi, Ayushi, additional, Thakuria, Manisha, additional, Bresler, Scott C., additional, Sholl, Lynette M., additional, Shapiro, Geoffrey I., additional, Haddad, Robert, additional, and DeCaprio, James A., additional

Published
2018
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162. Binding of the Hippel-Lindau tumor suppressor protein to Elongin B and C

Author

Kibel, Adam, Iliopoulos, Othon, DeCaprio, James A., and Kaelin, Jr., William G.

Subjects
Carcinogenesis -- Genetic aspects -- Research, Tumor suppressor genes -- Research -- Genetic aspects, Science and technology, Genetic aspects, Research
Abstract

Germ-line mutations of the von Hippel-Lindau tumor supressor gene (VHL) predispose individuals to a variety of human tumors, and somatic mutations of this gene have been identified in sporadic renal cell carcinomas and cerebellar hemangioblastomas. Two transcriptional elongation factors, Elongin B and C, were shown to bind in vitro and in vivo to a short, colinear region of the VHL protein (pVHL) that is frequently mutated in human tumors. A peptide replica of this region inhibited binding of pVHL to Elongin B and C, whereas a point-mutant derivative, corresponding to a naturally occurring VHL missense mutation, had no effect. These results suggest that the tumor suppression function of pVHL may be linked to its ability to bind to Elongin B and C., Von Hippel-Lindau disease is a hereditary cancer syndrome characterized by the development of multiple tumors including renal cell carcinomas, retinal angiomas, cerebellar hemangioblastomas, and pheochromocytomas (1). The von Hippel-lindau susceptibility [...]

Published
1995

163. Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation

Author

Massachusetts Institute of Technology. Department of Chemical Engineering, Keibler, Mark Andrew, Berrios, Christian, Padi, Megha, Park, Donglim Esther, Molla, Vadim, Cheng, Jingwei, Lee, Soo Mi, Stephanopoulos, Gregory, Quackenbush, John, DeCaprio, James A., Massachusetts Institute of Technology. Department of Chemical Engineering, Keibler, Mark Andrew, Berrios, Christian, Padi, Megha, Park, Donglim Esther, Molla, Vadim, Cheng, Jingwei, Lee, Soo Mi, Stephanopoulos, Gregory, Quackenbush, John, and DeCaprio, James A.

Abstract

An accurate analytic model describing the microscopic mechanism of high-harmonic generation (HHG) in solids is derived. Extensive first-principles simulations within a time-dependent density-functional framework corroborate the conclusions of the model. Our results reveal that (i) the emitted HHG spectra are highly anisotropic and laser-polarization dependent even for cubic crystals; (ii) the harmonic emission is enhanced by the inhomogeneity of the electron-nuclei potential; the yield is increased for heavier atoms; and (iii) the cutoff photon energy is driver-wavelength independent. Moreover, we show that it is possible to predict the laser polarization for optimal HHG in bulk crystals solely from the knowledge of their electronic band structure. Our results pave the way to better control and optimize HHG in solids by engineering their band structure.

Published
2017

164. Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks

Author

Fischer, Martin, Grossmann, Patrick, Padi, Megha, DeCaprio, James A., Universität Leipzig, Dana-Farber Cancer Institute, and Harvard Medical School

Subjects
cell cycle, cancer, regulatory network, meta-analysis, ddc:610, Zellzyklus, Krebs, regulatorisches Netzwerk, Metaanalyse
Abstract

Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.

Published
2016

165. Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

Author

Becker, Jürgen C., primary, Stang, Andreas, additional, Hausen, Axel zur, additional, Fischer, Nicole, additional, DeCaprio, James A., additional, Tothill, Richard W., additional, Lyngaa, Rikke, additional, Hansen, Ulla Kring, additional, Ritter, Cathrin, additional, Nghiem, Paul, additional, Bichakjian, Christopher K., additional, Ugurel, Selma, additional, and Schrama, David, additional

Published
2017
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167. Merkel cell carcinoma

Author

Becker, Jürgen C., primary, Stang, Andreas, additional, DeCaprio, James A., additional, Cerroni, Lorenzo, additional, Lebbé, Celeste, additional, Veness, Michael, additional, and Nghiem, Paul, additional

Published
2017
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168. Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis

Author

Cheng, Jingwei, primary, Park, Donglim Esther, additional, Berrios, Christian, additional, White, Elizabeth A., additional, Arora, Reety, additional, Yoon, Rosa, additional, Branigan, Timothy, additional, Xiao, Tengfei, additional, Westerling, Thomas, additional, Federation, Alexander, additional, Zeid, Rhamy, additional, Strober, Benjamin, additional, Swanson, Selene K., additional, Florens, Laurence, additional, Bradner, James E., additional, Brown, Myles, additional, Howley, Peter M., additional, Padi, Megha, additional, Washburn, Michael P., additional, and DeCaprio, James A., additional

Published
2017
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170. Abstract 562: Oncovirus detection and integration analysis from human tumor samples using targeted massively parallel sequencing

Author

Burns, Robert T., primary, Hunter, Samuel S., additional, Ducar, Matthew D., additional, Thorner, Aaron R., additional, Decaprio, James A., additional, Hummelen, Paul Van, additional, Frieden, Alexander, additional, Nag, Anwesha, additional, Coleman, Haley A., additional, Slevin, Michael K., additional, Clapp, Andrea, additional, Drinan, Samantha D., additional, McShane, Suzanne R., additional, Thai, Edwin, additional, Shivdasani, Priyanka, additional, Bohannon, Joshua, additional, Hoeftberger, Johann, additional, Jacobs, Reuben, additional, Wollison, Bruce M., additional, Patel, Neil A., additional, Manam, Monica D., additional, Davineni, Phani, additional, Meyerson, Matthew, additional, and MacConaill, Laura E., additional

Published
2017
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171. Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma

Author

Starrett, Gabriel J., primary, Marcelus, Christina, additional, Cantalupo, Paul G., additional, Katz, Joshua P., additional, Cheng, Jingwei, additional, Akagi, Keiko, additional, Thakuria, Manisha, additional, Rabinowits, Guilherme, additional, Wang, Linda C., additional, Symer, David E., additional, Pipas, James M., additional, Harris, Reuben S., additional, and DeCaprio, James A., additional

Published
2017
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172. Telomerase maintains telomere structure in normal human cells

Author

Masutomi, Kenkichi, Yu, Evan Y., Khurts, Shilagardy, Ben-Porath, Ittai, Currier, Jennifer L., Metz, Geoffrey B., Brooks, Mary W., Kaneko, Shuichi, Murakami, Seishi, DeCaprio, James A., Weinberg, Robert A., Stewart, Sheila A., and Hahn, William C.

Subjects
Gene expression -- Physiological aspects, Cell proliferation -- Physiological aspects, Cell proliferation -- Genetic aspects, Cell division -- Genetic aspects, Cell division -- Physiological aspects, Cells -- Genetic aspects, Cells -- Physiological aspects, Telomeres -- Physiological aspects, Telomeres -- Genetic aspects, Cell research -- Analysis, Biological sciences
Abstract

Research has been conducted on telomerase and telomere structure. The authors suggest that this structure is dynamically regulated in normal human cells, and that it is unlikely that telomere length alone can trigger the entry into replicative senescence.

Published
2003

173. Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.

Author

Parka, Donglim Esther, Jingwei Cheng, Berrios, Christian, Montero, Joan, s-Crose, Marta Corté, Ferrettie, Stéphane, Arora, Reety, Tillgren, Michelle L., Gokhale, Prafulla C., and DeCaprio, James A.

Subjects
MERKEL cell carcinoma, CELL proliferation, POLYOMAVIRUSES, CANCER cells, RNA sequencing
Abstract

Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST-MYCL-EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1 α, an activator of MDM4, as target genes of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors. [ABSTRACT FROM AUTHOR]

Published
2019
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174. Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks

Author

Universität Leipzig, Dana-Farber Cancer Institute, Harvard Medical School, Fischer, Martin, Grossmann, Patrick, Padi, Megha, DeCaprio, James A., Universität Leipzig, Dana-Farber Cancer Institute, Harvard Medical School, Fischer, Martin, Grossmann, Patrick, Padi, Megha, and DeCaprio, James A.

Abstract

Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.

Published
2016

176. Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo

Author

Odajima, Junko, primary, Saini, Siddharth, additional, Jung, Piotr, additional, Ndassa-Colday, Yasmine, additional, Ficaro, Scott, additional, Geng, Yan, additional, Marco, Eugenio, additional, Michowski, Wojciech, additional, Wang, Yaoyu E., additional, DeCaprio, James A., additional, Litovchick, Larisa, additional, Marto, Jarrod, additional, and Sicinski, Piotr, additional

Published
2016
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177. Merkel Cell Carcinoma: A Population Analysis on Survival

Author

Sridharan, Vishwajith, primary, Muralidhar, Vinayak, additional, Margalit, Danielle N., additional, Tishler, Roy B., additional, DeCaprio, James A., additional, Thakuria, Manisha, additional, Rabinowits, Guilherme, additional, and Schoenfeld, Jonathan D., additional

Published
2016
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180. Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt

Author

Zhang, Jinfang, primary, Xu, Kai, additional, Liu, Pengda, additional, Geng, Yan, additional, Wang, Bin, additional, Gan, Wenjian, additional, Guo, Jianping, additional, Wu, Fei, additional, Chin, Y. Rebecca, additional, Berrios, Christian, additional, Lien, Evan C., additional, Toker, Alex, additional, DeCaprio, James A., additional, Sicinski, Piotr, additional, and Wei, Wenyi, additional

Published
2016
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181. Differences between gene mutation profile and outcome of Merkel cell polyomavirus (MCPyV) positive and negative Merkel cell carcinoma (MCC).

Author

Rabinowits, Guilherme, primary, Giobbie-Hurder, Anita, additional, Marcelus, Christina, additional, Cheng, Jingwei, additional, Thakuria, Manisha, additional, Schoenfeld, Jonathan Daniel, additional, Yoon, Charles H., additional, Sholl, Lynette M., additional, Becker, Hailey, additional, Ma, Laura, additional, LeBoeuf, Nicole R., additional, Haddad, Robert I., additional, and DeCaprio, James A, additional

Published
2016
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182. Contributors

Author

Abdel-Wahab, Omar, Abrahm, Janet L., Adams, Sharon, Adewoye, Adeboye H., Allen, Carl, Ambinder, Richard F., Anasetti, Claudio, Anastasi, John, Anderson, Julia A., Antin, Joseph H., Antony, Aśok C., Araten, David J., Armand, Philippe, Armstrong, Gillian, Armstrong, Scott A., Arnold, Donald M., Artz, Andrew S., Awan, Farrukh T., Baglin, Trevor P., Benson, Don M., Jr., Benz, Edward J., Jr., Berliner, Nancy, Bhagat, Govind, Bhardwaj, Nina, Bhatia, Ravi, Bhatia, Smita, Bhatt, Mihir D., Bhatt, Vijaya Raj, Bitan, Menachem, Blinderman, Craig D., Bollard, Catherine M., Braun, Benjamin S., Brenner, Malcolm K., Brittenham, Gary M., Brodsky, Robert A., Brown, Myles, Broxmeyer, Hal E., Brummel-Ziedins, Kathleen, Brunner, Andrew M., Buadi, Francis K., Burkhardt, Birgit, Burns, Melissa, Byrd, John C., Caimi, Paolo F., Caligiuri, Michael A., Canavan, Michelle, Cantor, Alan B., Carcao, Manuel, Carroll, Michael C., Carty, Shannon A., Castillo, Jorge J., Chan, Anthony K.C., Chapin, John, Chiu, April, Chute, John P., Clark, David B., Coates, Thomas D., Cogle, Christopher R., Connell, Nathan T., Cooke, Elizabeth, Cooley, Sarah, Corradini, Paolo, Creager, Mark A., Creger, Richard J., Cromwell, Caroline, Crowther, Mark A., Cushing, Melissa M., Cutler, Corey, Dang, Chi V., Danial, Nika N., Dave, Sandeep S., DeCaprio, James A., Dinauer, Mary C., Dinner, Shira, Diz-Küçükkaya, Reyhan, Dodd, Roger Y., Donato, Michele L., Dorshkind, Kenneth, Dotti, Gianpietro, Dror, Yigal, Dunleavy, Kieron, Dvorak, Christopher C., Ebert, Benjamin L., Eck, Michael J., Eikelboom, John W., Epperla, Narendranath, Ershler, William B., Evans, William E., Faderl, Stefan, Ferrara, James L.M., Filipovich, Alexandra Hult, Fischer, Martin, Fredenburgh, James C., Friedman, Kenneth D., Fuchs, Ephraim, Fuller, Stephen J., Gailani, David, Galipeau, Jacques, Gallagher, Patrick G., Ganapathi, Karthik A., Gardner, Lawrence B., Gee, Adrian P., Gerson, Stanton L., Gertz, Morie A., Giardina, Patricia J., Gibson, Christopher J., Golan, Karin, Golub, Todd R., Gonzales, Matthew J., Gotlib, Jason, Gottschalk, Stephen, Grant, Marianne A., Graubert, Timothy A., Gregg, Xylina T., Gribben, John G., Gross, Dawn M., Gruber, Tanja A., Guitart, Joan, Gurbuxani, Sandeep, Gur-Cohen, Shiri, Gutierrez, Alejandro, Hamadani, Mehdi, Hari, Parameswaran N., Hartwig, John H., Hayman, Suzanne R., Hayward, Catherine P.M., Hebbel, Robert P., Heslop, Helen E., Hillis, Christopher, Hillyer, Christopher D., Ho, Karin, Hockenbery, David M., Hoffman, Ronald, Hogg, Kerstin E., Holtan, Shernan G., Horny, Hans-Peter, Hsu, Yen-Michael S., Hunter, Zachary R., Huntington, James A., Iancu-Rubin, Camelia, Iqbal, Ali, Isenman, David E., Israels, Sara J., Italiano, Joseph E., Jr., Jaffe, Elaine S., Jaffer, Iqbal H., Jagannath, Sundar, Jäger, Ulrich, Jain, Nitin, James, Paula, Jeha, Sima, Jordan, Michael B., Josephson, Cassandra D., Jung, Moonjung, Kager, Leo, Kambayashi, Taku, Kanakry, Jennifer A., Kantarjian, Hagop M., Kaplan, Jason, Karafin, Matthew S., Karsan, Aly, Kaufman, Randal J., Kaufman, Richard M., Keller, Frank G., Kelly, Kara M., Kessler, Craig M., Key, Nigel S., Keyzner, Alla, Khandoga, Alexander G., Khanna-Gupta, Arati, Khatib-Massalha, Eman, Klein, Harvey G., Knoechel, Birgit, Kollet, Orit, Konkle, Barbara A., Kontoyiannis, Dimitrios P., Koreth, John, Koretzky, Gary A., Kotecha, Dipak, Kremyanskaya, Marina, Kumari, Anju, Kuzel, Timothy M., Küppers, Ralf, Lacy, Martha Q., Ladas, Elana, Landier, Wendy, Lapid, Kfir, Lapidot, Tsvee, Larson, Peter J., Levi, Marcel, Lewis, Russell E., Liebman, Howard A., Lillicrap, David, Lim, Wendy, Lin, Judith C., Lindblad, Robert, Lip, Gregory Y.H., Little, Jane A., Lohr, Jens G., López, José A., Luscinskas, Francis W., Maciejewski, Jaroslaw P., Majhail, Navneet S., Manches, Olivier, Mandle, Robert J., Mann, Kenneth G., Manno, Catherine S., Marcogliese, Andrea N., Mariani, Guglielmo, Marincola, Francesco M., Mascarenhas, John, Massberg, Steffen, McEver, Rodger P., McGrath, Emer, McKinney, Matthew S., Mehta, Rohtesh S., Mentzer, William C., Merlini, Giampaolo, Merryman, Reid, Michel, Marc, Migliaccio, Anna Rita, Miller, Jeffrey S., Mims, Martha P., Mondoro, Traci Heath, Moorehead, Paul, Muniz, Luciana R., Munshi, Nikhil C., Najfeld, Vesna, Nayak, Lalitha, Nazy, Ishac, Neff, Anne T., Ness, Paul M., Notarangelo, Luigi D., O'Brien, Sarah H., O'Connor, Owen A., O'Donnell, Martin, Olson, Amanda, Orkin, Stuart H., Pai, Menaka, Pai, Sung-Yun, Paidas, Michael, Panch, Sandhya R., Pande, Reena L., Papayannopoulou, Thalia, Parikh, Rahul, Petersdorf, Effie W., Peterson, Shane E., Pittaluga, Stefania, Ponce, Doris M., Popolo, Laura, Prchal, Josef T., Pui, Ching-Hon, Puigserver, Pere, Rak, Janusz, Ramos, Carlos A., Rand, Jacob H., Rand, Margaret L., Rao, Dinesh S., Ravandi, Farhad, Rawlings, David J., Reddy, Pavan, Reding, Mark T., Reiter, Andreas, Rice, Lawrence, Riese, Matthew J., Ritchey, Arthur Kim, Roberts, David J., Roman, Elizabeth, Rooney, Cliona M., Rosen, Steven T., Rosenthal, David S., Rossmann, Marlies P., Rot, Antal, Rowley, Scott D., Rubnitz, Jeffrey E., Rydz, Natalia, Salama, Mohamed E., Sauk, Steven, Saunthararajah, Yogen, Savage, William, Scadden, David, Schaefer, Kristen G., Schiffman, Fred, Schneidewend, Robert, Schrier, Stanley L., Schuchman, Edward H., Scullion, Bridget Fowler, Selvaggi, Kathy J., Senoo, Keitaro, Shaheen, Montaser, Shaz, Beth H., Shelburne, Samuel A., Shpall, Elizabeth J., Shurin, Susan B., Siegal, Deborah, Silberstein, Leslie E., Silberstein, Lev, Silverstein, Roy L., Sloan, Steven R., Smith, Franklin O., Smith, James W., Smith, Katy, Steensma, David P., Steinberg, Martin H., Stock, Wendy, Storry, Jill R., Stramer, Susan L., Strauss, Ronald G., Stroncek, David F., Taylor, Justin, Thota, Swapna, Treon, Steven P., Tulpule, Anil, Valdes, Roberto Ferro, Valent, Peter, Vedantham, Suresh, Vercellotti, Gregory M., Verneris, Michael R., Vichinsky, Elliott P., von Andrian, Ulrich H., Vose, Julie M., Wagner, Andrew J., Wang, Ena, Wang, Jia-huai, Warkentin, Theodore E., Wasserstein, Melissa P., Webster, Ann, Weisdorf, Daniel J., Weitz, Jeffrey I., Westhoff, Connie M., Wheeler, Allison P., Widick, Page, Wiley, James S., William, Basem M., Williams, David A., Wilson, Wyndham H., Wolfe, Joanne, Wolgast, Lucia R., Wood, Deborah, Wu, Jennifer, Yahalom, Joachim, Yee, Donald L., Younes, Anas, Young, Neal S., and Zeller, Michelle P.

Published
2018
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183. Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC.

Author

Becker, Jürgen C., Stang, Andreas, Hausen, Axel zur, Fischer, Nicole, DeCaprio, James A., Tothill, Richard W., Lyngaa, Rikke, Hansen, Ulla Kring, Ritter, Cathrin, Nghiem, Paul, Bichakjian, Christopher K., Ugurel, Selma, and Schrama, David

Subjects
MERKEL cell carcinoma, EPIDEMIOLOGY, IMMUNOREGULATION, PUBLIC health, IMMUNOTHERAPY, THERAPEUTICS
Abstract

Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project ‘Immune Modulating strategies for treatment of Merkel Cell Carcinoma’, which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC. [ABSTRACT FROM AUTHOR]

Published
2018
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184. Cyclin D–CDK4 relieves cooperative repression of proliferation and cell cycle gene expression by DREAM and RB

Author

Schade, Amy E., Oser, Matthew G., Nicholson, Hilary E., and DeCaprio, James A.

Abstract

The retinoblastoma protein (RB) restricts cell cycle gene expression and entry into the cell cycle. The RB-related protein p130 forms the DREAM (DP, RB-like, E2F, and MuvB) complex and contributes to repression of cell cycle-dependent genes during quiescence. Although both RB and DREAM bind and repress an overlapping set of E2F-dependent gene promoters, it remains unclear whether they cooperate to restrict cell cycle entry. To test the specific contributions of RB and DREAM, we generated RB and p130 knockout cells in primary human fibroblasts. Knockout of both p130 and RB yielded higher levels of cell cycle gene expression in G0 and G1 cells compared to cells with knockout of RB alone, indicating a role for DREAM and RB in repression of cell cycle genes. We observed that RB had a dominant role in E2F-dependent gene repression during mid to late G1 while DREAM activity was more prominent during G0 and early G1. Cyclin D–Cyclin-Dependent Kinase 4 (CDK4)-dependent phosphorylation of p130 occurred during early G1, and led to the release of p130 and MuvB from E2F4 and decreased p130 and MuvB binding to cell cycle promoters. Specific inhibition of CDK4 activity by palbociclib blocked DREAM complex disassembly during cell cycle entry. In addition, sensitivity to CDK4 inhibition was dependent on RB and an intact DREAM complex in both normal cells as well as in palbociclib-sensitive cancer cell lines. Although RB knockout cells were partially resistant to CDK4 inhibition, RB and p130 double knockout cells were significantly more resistant to palbociclib treatment. These results indicate that DREAM cooperates with RB in repressing E2F-dependent gene expression and cell cycle entry and supports a role for DREAM as a therapeutic target in cancer.

Published
2019
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185. The biology and treatment of Merkel cell carcinoma: current understanding and research priorities

Author

Harms, Paul W., Harms, Kelly L., Moore, Patrick S., DeCaprio, James A., Nghiem, Paul, Wong, Michael K. K., and Brownell, Isaac

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)–programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.

Published
2018
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190. Merkel cell polyomavirus and Merkel cell carcinoma.

Author

DeCaprio, James A.

Subjects
*MERKEL cell carcinoma, *POLYOMAVIRUS diseases, *MERKEL cells, *ETIOLOGY of cancer, *IMMUNOCOMPROMISED patients
Abstract

Merkel cell polyomavirus (MCPyV) causes the highly aggressive and relatively rare skin cancer known as Merkel cell carcinoma (MCC). MCPyV also causes a lifelong yet relatively innocuous infection and is one of 14 distinct human polyomaviruses species. Although polyomaviruses typically do not cause illness in healthy individuals, several can cause catastrophic diseases in immunocompromised hosts. MCPyV is the only polyomavirus clearly associated with human cancer. How MCPyV causes MCC and what oncogenic events must transpire to enable this virus to cause MCC is the focus of this essay. [ABSTRACT FROM AUTHOR]

Published
2017
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191. Transcriptional landscape of the human cell cycle.

Author

Yin Liu, Sujun Chen, Su Wang, Soares, Fraser, Fischer, Martin, Feilong Meng, Zhou Du, Lin, Charles, Meyer, Clifford, DeCaprio, James A., Brown, Myles, Liu, X. Shirley, and Housheng Hansen He

Subjects
GENE regulatory networks, HUMAN cell cycle, CELL cycle, MAMMALIAN cell cycle, BREAST cancer
Abstract

Steady-state gene expression across the cell cycle has been studied extensively. However, transcriptional gene regulation and the dynamics of histone modification at different cell-cycle stages are largely unknown. By applying a combination of global nuclear run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and histonemodification Chip sequencing (ChIP-seq), we depicted a comprehensive transcriptional landscape at the G0/G1, G1/S, and M phases of breast cancer MCF-7 cells. Importantly, GRO-seq and RNA-seq analysis identified different cell-cycle–regulated genes, suggesting a lag between transcription and steady-state expression during the cell cycle. Interestingly, we identified genes actively transcribed at earlyMphase that are longer in length and have low expression and are accompanied by a global increase in active histone 3 lysine 4 methylation (H3K4me2) and histone 3 lysine 27 acetylation (H3K27ac) modifications. In addition, we identified 2,440 cell-cycle–regulated enhancer RNAs (eRNAs) that are strongly associated with differential active transcription but not with stable expression levels across the cell cycle. Motif analysis of dynamic eRNAs predicted Kruppel-like factor 4 (KLF4) as a key regulator of G1/S transition, and this identification was validated experimentally. Taken together, our combined analysis characterized the transcriptional and histone-modification profile of the human cell cycle and identified dynamic transcriptional signatures across the cell cycle. [ABSTRACT FROM AUTHOR]

Published
2017
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196. Loss of the Mammalian DREAM Complex Deregulates Chondrocyte Proliferation

Author

Forristal, Chantal, primary, Henley, Shauna A., additional, MacDonald, James I., additional, Bush, Jason R., additional, Ort, Carley, additional, Passos, Daniel T., additional, Talluri, Srikanth, additional, Ishak, Charles A., additional, Thwaites, Michael J., additional, Norley, Chris J., additional, Litovchick, Larisa, additional, DeCaprio, James A., additional, DiMattia, Gabriel, additional, Holdsworth, David W., additional, Beier, Frank, additional, and Dick, Frederick A., additional

Published
2014
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197. Viral perturbations of host networks reflect disease etiology.

Author

Gulbahce, Natali, Yan, Han, Dricot, Amélie, Padi, Megha, Byrdsong, Danielle, Franchi, Rachel, Lee, Deok-Sun, Rozenblatt-Rosen, Orit, Mar, Jessica C, Calderwood, Michael A, Baldwin, Amy, Zhao, Bo, Santhanam, Balaji, Braun, Pascal, Simonis, Nicolas, Huh, Kyung-Won, Hellner, Karin, Grace, Miranda, Chen, Alyce, Rubio, Renee, Marto, Jarrod A, Christakis, Nicholas A, Kieff, Elliott, Roth, Frederick P, Roecklein-Canfield, Jennifer, Decaprio, James A, Cusick, Michael E, Quackenbush, John, Hill, David E, Münger, Karl, Vidal, Marc, Barabási, Albert-László, Gulbahce, Natali, Yan, Han, Dricot, Amélie, Padi, Megha, Byrdsong, Danielle, Franchi, Rachel, Lee, Deok-Sun, Rozenblatt-Rosen, Orit, Mar, Jessica C, Calderwood, Michael A, Baldwin, Amy, Zhao, Bo, Santhanam, Balaji, Braun, Pascal, Simonis, Nicolas, Huh, Kyung-Won, Hellner, Karin, Grace, Miranda, Chen, Alyce, Rubio, Renee, Marto, Jarrod A, Christakis, Nicholas A, Kieff, Elliott, Roth, Frederick P, Roecklein-Canfield, Jennifer, Decaprio, James A, Cusick, Michael E, Quackenbush, John, Hill, David E, Münger, Karl, Vidal, Marc, and Barabási, Albert-László

Abstract

Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2012

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