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1. Immunotherapy Bridge 2017 and Melanoma Bridge 2017: meeting abstracts

Author

David Carbone, Michael Sharpnack, Kai He, Lisa H. Butterfield, Alexander M. M. Eggermont, Maria Gonzalez-Cao, Niki Karachaliou, Guillermo Crespo, Erika Aldeguer, Ana Drozdowskyj, Ana Giménez-Capitán, Cristina Teixidó, Miguel Angel Molina-Vila, Santiago Viteri Ramírez, Salvador Martin Algarra, Elisabeth Pérez-Ruiz, Iván Márquez-Rodas, Delvys Rodriguez-Abreu, Remei Blanco, Teresa Puértolas, Maria Angeles Royo, Rafael Rosell, Maria Libera Ascierto, Svetlana Hamm, Tanja Wulff, Kerstin Kronthaler, Sabine Schrepfer, Ulrike Parnitzke, Anne Catherine Bretz, Roland Baumgartner, Veronica Ferrucci, Francesco Paolo Pennino, Luisa Dassi, Fatemeh Asadzadeh, Roberto Siciliano, Marianeve Carotenuto, Daniela Spano, Cristina Maria Chiarolla, Adelaide Greco, Monica Cantile, Maurizio Di Bonito, Gerardo Botti, Vandenbussche Jonathan, Gevaert Kris, Massimo Zollo, Teresa Amaral, Ioanna Tampouri, Ulrike Keim, Thomas Eigentler, Claus Garbe, Andrea Forschner, Alessandra Cesano, Sarah Warren, Duane Moogk, Kaitao Li, Zhou Yuan, Shi Zhong, Zhiya Yu, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Navin Varadarajan, Nicholas P. Restifo, Alan Frey, Cheng Zhu, Michelle Krogsgaard, Claire Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Cristiana Lo Nigro, Alexander Renziehausen, Andreas G. Tzakos, Hexiao Wang, Bhavya Rao, Rubeta Matin, Catherine Harwood, Daniela Vivenza, Federica Tonissi, Marcella Occelli, Lynda Weir, Su Li, Van Ren Sim, Kevin O’Neill, Alan Evans, Alastair Thompson, Peter Szlosarek, Colin Fleming, Charlotte Proby, Nelofer Syed, Marco Merlano, Tim Crook, Robert Ferguson, Danny Simpson, Carlos Martinez, Matjaz Vogelsang, Esther Kazlow, Melissa Wilson, Anna Pavlick, Jeffrey Weber, Ryan Sullivan, Keith Flaherty, Antoni Ribas, Tomas Kirchhoff, Antonio D’Avino, Licia Guida, Augusto Cosacco, Roberta D’Aniello, Piera Maiolino, Teresa Tramontano, Maria R. Sarno, Ida Palazzo, Angela Di Napoli, Gianclaudio Acunzo, Mariarosanna De Fina, Antonia Silvestri, Monica Specchia, Michela Musacchio, Gianfranco Giglio, Francesco Carrozza, Liberato Di Lullo, Gian Marco De Maddi, Adele Venturelli, Elisabetta Gambale, Alessia Gatta, Davide Brocco, Consiglia Carella, Michele De Tursi, Thomas F. Gajewski, Costanza M. Cristiani, Rossana Tallerico, Valeria Ventura, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Eliska Selinger, Cinzia Garofalo, Elina Staaf, Ester Simeone, Antonio M. Grimaldi, Genny del Zotto, Elio Gulletta, Gennaro Ciliberto, Alessandro Moretta, Paolo A. Ascierto, Ennio Carbone, Susan Costantini, Angela Sorice, Francesca Capone, Alfredo Budillon, Carolina Cauchi, Grazia Sciancalepore, Michela Rovera, Chiara Varamo, Zelda Seia, Stefania Palazzini, Fabiana Errico, Davide Basso, Laura Quaranta, Giuseppe Forte, Fulvio Lavagna, Silvia Violante, Paolo Bosio, Laura Lattanzio, Marco C Merlano, Mike Gowen, Jeremy Tchack, Hua Zhou, Keith Giles, Scott Paschke, Una Moran, David Fenyo, Aris Tsirigos, Michael Pacold, Silvana Morello, Claudia Sorrentino, Diana Giannarelli, Aldo Pinto, Federica Fratangelo, Rosaria Falcone, Vito Vanella, Dirk Schadendorf, Karl Lewis, Michele Maio, Lev Demidov, Mario Mandalà, Igor Bondarenko, Christopher Herbert, Andrzej Mackiewicz, Piotr Rutkowski, Alexander Guminski, Grant Goodman, Brian Simmons, Chenglin Ye, Gregory Hooper, Matthew J. Wongchenko, Yibing Yan, Frank Hermann, Astrid Ammendola, René Bartz, Bulotta Alessandra, Colombo Letizia, Mirabile Aurora, Lazzari Chiara, Mercuri Santo Raffaele, Parolini Danilo, Rizzo Nathalie, Martella Stefano, Modorati Giulio, Brianti Pina, Cestone Enza, Bellinzona Federica, Miserocchi Elisabetta, Gianni Luca, Gregorc Vanesa, Sanjiv Agarwala, B. Mark Smithers, Axel Haushild, Eric Watcher, Luigi Fattore, Ciro Francesco Ruggiero, Domenico Liguoro, Andrea Cerri, Maria Elena Pisanu, and Rita Mancini

Subjects
Medicine
Published
2018
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2. Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets

Author

Alan B. Frey, Ivan Liadi, William Rittase, Nicholas P. Restifo, Iman Osman, Zhiya Yu, Michelle Krogsgaard, Duane Moogk, Cheng Zhu, Navin Varadarajan, Arianne Perez-Garcia, Shi Zhong, Janna Dougherty, and Victoria Fang

Subjects
Cytotoxicity, Immunologic, 0301 basic medicine, T cell, Blotting, Western, Immunology, chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Biology, Lymphocyte Activation, Polymerase Chain Reaction, Time-Lapse Imaging, Article, Mice, 03 medical and health sciences, T-Lymphocyte Subsets, medicine, Animals, Humans, Immunology and Allergy, Cytotoxic T cell, Effector, T-cell receptor, hemic and immune systems, Flow Cytometry, Markov Chains, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Immunologic Memory, Memory T cell, Tyrosine kinase, CD8, Proto-oncogene tyrosine-protein kinase Src
Abstract

CD8+ T cells develop increased sensitivity following Ag experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that >50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with

Published
2016
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3. Immunotherapy Bridge 2016 and Melanoma Bridge 2016: meeting abstracts

Author

Vera Hirsh, Sandro Pignata, Melissa Bersanelli, Letizia Gnetti, Cinzia Azzoni, Lorena Bottarelli, Donatello Gasparro, Francesco Leonardi, Enrico Maria Silini, Sebastiano Buti, Erik Wennerberg, Aranzazu Mediero, Bruce Cronstein, Silvia Formenti, Sandra Demaria, Claire Vanpouille-Box, Karsten Pilones, Nils Rudqvist, Julie Diamond, Zachary S. Morris, Emily I. Guy, David M. Francis, Monica M. Gressett, Eric A. Armstrong, Shyhmin Huang, Stephen D. Gilles, Alan J. Korman, Jacquelyn A. Hank, Anna Hoefges, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Yared Hailemichael, Willem W. Overwijk, Per thor Straten, Alessandro Lugli, Heather Dawson, Annika Blank, Inti Zlobec, Luigi Fattore, Susan Costantini, Mario Acunzo, Giulia Romano, Giovanni Nigita, Alessandro Laganà, Debora Malpicci, Ciro Francesco Ruggiero, Maria Elena Pisanu, Alessia Noto, Claudia De Vitis, Carlo Maria Croce, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto, Michael Postow, Jason Luke, David Stroncek, Luciano Castiello, Wenjing Chen, Ping Jin, Jiaqiang Ren, Marianna Sabatino, Soldano Ferrone, Connie PM Duong, Marie Vetizou, Laurence Zitvogel, Marcella Occelli, Carolina Cauchi, Grazia Sciancalepore, Cristiana Lo Nigro, Michela Rovera, Chiara Varamo, Daniela Vivenza, Zelda Seia, Stefania Palazzini, Fabiana Errico, Davide Basso, Laura Quaranta, Giuseppe Forte, Fulvio Lavagna, Silvia Violante, Paolo Bosio, Laura Lattanzio, Marco Carlo Merlano, Duane Moogk, Shi Zhong, Zhiya Yu, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Nicholas P. Restifo, Alan Frey, Michelle Krogsgaard, Timea Balatoni, Anita Moho, Timea Sebestyén, Anita Varga, Judit Oláh, Zsuzsanna Lengyel, Gabriella Emri, Gabriella Liszkay, Andrea Ladányi, Beatrice Polini, Stefano Fogli, Sara Carpi, Barbara Pardini, Alessio Naccarati, Nevio Dubbini, Maria Cristina Breschi, Antonella Romanini, Paola Nieri, Francesca Morgese, Davide Soldato, Silvia Pagliaretta, Riccardo Giampieri, Donatella Brancorsini, Silvia Rinaldi, Mariangela Torniai, Anna Campanati, Giulia Ganzetti, Annamaria Offidani, Alfredo Giacchetti, Giuseppe Ricotti, Agnese Savini, Azzurra Onofri, Francesca Bianchi, Rossana Berardi, Giovanna Galdo, Gianfranco Orlandino, Salvatore Serio, Domenico Massariello, Tommaso Fabrizio, Valentina Montagnani, Matteo Benelli, Alessandro Apollo, Chiara Pescucci, Danilo Licastro, Carmelo Urso, Gianni Gerlini, Lorenzo Borgognoni, Lucio Luzzatto, Barbara Stecca, Elisabetta Gambale, Camilla Tinari, Alberto Quinzii, Alessio Cortellini, Consiglia Carella, Michele De Tursi, Adele Emanuela De Francesco, Mariarosanna De Fina, Maria Cristina Zito, Maria Dezia Bisceglia, Stefania Esposito, Giuseppina Fersini, Silvana Morello, Claudia Sorrentino, Aldo Pinto, Antonella Di Sarno, Antonella Bianco, Carmine D’Aniello, Francesca Andreozzi, Lucia Festina, Vito Vanella, Vincenzo Montesarchio, Beatrix Kotlan, Maria Godeny, Farkas Emil, Laszlo Toth, Szabolcs Horvath, Klara Eles, Akos Savolt, Andras Szollar, Miklós Kasler, Daniel Yiu, Fabio Grizzi, Federica Patrinicola, Maurizio Chiriva-Internati, Stefania Motta, Marcello Monti, Lavinia Benini, Stefano Ugel, Sara Cingarlini, Alessandra Fiore, Elisabetta Grego, Giampaolo Tortora, Vincenzo Bronte, Luca Tondulli, Gianluca Di Monta, Corrado Caracò, Ugo Marone, Lucia Festino, and Nicola Mozzillo

Subjects
0301 basic medicine, Medicine(all), business.industry, Biochemistry, Genetics and Molecular Biology(all), General Medicine, Bridge (interpersonal), Meeting Abstracts, General Biochemistry, Genetics and Molecular Biology, Construction engineering, 03 medical and health sciences, 030104 developmental biology, Medicine, business
Published
2017

4. Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia

Author

Martin S. Tallman, Jacob M. Rowe, Valeria Tosello, Mireia Castillo, Andrea Califano, Elisabeth Paietta, Jiyang Yu, Adolfo A. Ferrando, Erich Piovan, Justin R. Cross, Marta Sanchez-Martin, Stefano Indraccolo, Giuseppe Basso, Elisa de Stanchina, Isaura Rigo, Daniel Herranz, Janis Racevskis, Arianne Perez-Garcia, Alberto Ambesi-Impiombato, Jules P.P. Meijerink, Carlos Cordon-Cardo, and Ana Carolina Da Silva

Subjects
Cancer Research, glucocorticoid resistance, acute T-cell lymphoblastic leukemia, AKT inhibition, Active Transport, Cell Nucleus, AKT1, Chromosomal translocation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Dexamethasone, Article, Mice, Glucocorticoid receptor, Receptors, Glucocorticoid, PTEN, Animals, Humans, Phosphorylation, Protein kinase B, biology, Kinase, PTEN Phosphohydrolase, Cell Biology, Oncology, Apoptosis, Drug Resistance, Neoplasm, biology.protein, Cancer research, Heterocyclic Compounds, 3-Ring, Proto-Oncogene Proteins c-akt, hormones, hormone substitutes, and hormone antagonists
Abstract

Summary Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.

Published
2013
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5. Kinetics of the CTLA-4 isoforms expression after T-lymphocyte activation and role of the promoter polymorphisms on CTLA-4 gene transcription

Author

Anna Bosch-Vizcaya, Nazly Santos, E Tuset, Rosa Coll, Arianne Perez-Garcia, Rocío Rodríguez, Gemma Osca, Nichollas Kelleher, Josep Maria Roncero, Natalia Lloveras, Yolanda González, Maite Serrando, and David Gallardo

Subjects
Gene isoform, Genotype, T-Lymphocytes, Immunology, Enzyme-Linked Immunosorbent Assay, Stimulation, Biology, Lymphocyte Activation, Inhibitory postsynaptic potential, Transcription (biology), Humans, Protein Isoforms, Immunology and Allergy, CTLA-4 Antigen, Transgenes, Cloning, Molecular, Allele, Promoter Regions, Genetic, Cells, Cultured, Polymorphism, Genetic, General Medicine, Molecular biology, Gene Expression Regulation, Spain, CTLA-4, CTLA4 Gene
Abstract

Cytotoxic T lymphocyte antigen 4 (CTLA-4) plays a key inhibitory role during T lymphocyte activation. The CTLA4 gene is translated into two proteic isoforms: a full-length protein (flCTLA-4) and a soluble counterpart. We explored the expression of both isoforms on healthy subjects. Whereas in non-stimulated cells the flCTLA-4 isoform is predominant, after stimulation the expression of the soluble form rapidly increases, reaching its maximum 24h after and falling again to the basal levels 72 h after stimulation. In contrast, the flCTLA-4 mRNA levels increase is slower, reaching the maximum level 72 h after stimulation. The presence of the T allele in the promoter positions -1722 and -318 is associated with an increased transcriptional activity and this effect seems to be synergic. We conclude that the kinetics of CTLA-4 isoform expression are sequential, and that the promoter polymorphisms -1722(C/T) and -318(C/T) are involved in the control of the CTLA4 transcription.

Published
2013
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6. The Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability

Author

Panagiotis Ntziachristos, Junwei Shi, Luyao Xu, Christopher R. Vakoc, Beatriz Aranda-Orgilles, Steven S. Shen, Arianne Perez-Garcia, Iannis Aifantis, Bryan King, Thomas Trimarchi, Peter Sandy, Adolfo A. Ferrando, Linsey Reavie, and Jasper Mullenders

Subjects
F-Box-WD Repeat-Containing Protein 7, Somatic cell, Ubiquitin-Protein Ligases, Mutant, Mutation, Missense, Cell Cycle Proteins, medicine.disease_cause, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Mice, 0302 clinical medicine, Ubiquitin, medicine, Animals, Humans, Receptor, Notch1, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Mutation, biology, Oncogene, Biochemistry, Genetics and Molecular Biology(all), F-Box Proteins, Ubiquitination, Hematopoietic stem cell, medicine.disease, Hematopoietic Stem Cells, Ubiquitin ligase, Leukemia, Disease Models, Animal, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Tumor Suppressor Protein p53
Abstract

SummarySequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.

Published
2013
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7. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Author

Martin S. Tallman, Elisabeth Paietta, Gannie Tzoneva, Renate Kirschner-Schwabe, Adolfo A. Ferrando, Jacob M. Rowe, Arianne Perez-Garcia, Valeria Tosello, Maddalena Paganin, Giuseppe Basso, Hossein Khiabanian, Zachary Carpenter, Teresa Palomero, Maddalena Allegretta, Jana Hof, Raul Rabadan, and Janis Racevskis

Subjects
Nucleotidase activity, medicine.medical_treatment, Antineoplastic Agents, Drug resistance, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Malignant transformation, 5'-nucleotidase, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Nucleotidase, medicine, Humans, Thioguanine, 5'-Nucleotidase, 030304 developmental biology, 0303 health sciences, Chemotherapy, Base Sequence, Mercaptopurine, leukemia, Cancer, General Medicine, Sequence Analysis, DNA, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, 3. Good health, Leukemia, HEK293 Cells, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Immunology, Mutation, Cancer research, Arabinonucleosides
Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

Published
2013

8. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016
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9. Early Hematopoietic Microchimerism Predicts Clinical Outcome After Kidney Transplantation

Author

David Gallardo, Salvador Gil-Vernet, Josep M. Grinyó, Maite Encuentra, Pilar Hernandez, Josep-Maria Pujal, Mariona Mestre, Arianne Perez-Garcia, and A Caldés

Subjects
Time Factors, medicine.medical_treatment, Polymerase Chain Reaction, HLA Antigens, medicine, Humans, Treatment Failure, Kidney transplantation, Transplantation Chimera, Transplantation, Kidney, business.industry, Histocompatibility Testing, Microchimerism, Immunosuppression, Odds ratio, Hematopoietic Stem Cells, medicine.disease, Kidney Transplantation, Calcineurin, Kinetics, Tolerance induction, Treatment Outcome, medicine.anatomical_structure, Immunology, business, Follow-Up Studies
Abstract

Background. The presence of a few circulating donor cells in recipient's blood was first thought to be only an epiphenomenon of solid organ transplantation, also called microchimerism, but several authors have suggested that these circulating cells may contribute to tolerance induction. This study aims to assess the rate of microchimerism after kidney transplantation and determine its influence on acute rejection in a 4-year follow-up. Methods. A total of 84 single-kidney recipients were included for microchimerism detection and quantification 2, 6, 12, and 18 months after transplantation by specific detection of non-shared STR, VNTR, human leukocyte antigen-A, -B, -DRB1, and SRY alleles. Kinetic establishment of microchimerism was monitored in a double kidney transplanted recipient for 150 min after declamping and after 7 days. Results. Microchimerism was detected in 56.2% of kidney recipients 2 months after transplantation (M2): this fell to 30.1% at 12 months. In renal calcineurin inhibitor-based immunosuppression cohort (n=73), the microchimerism-negative group (n=32) showed 37.9% biopsy-proven acute rejection (BPAR), whereas in the microchimerism-positive group (n=41), no recipient did (P

Published
2007
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10. CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors

Author

Alvaro Urbano-Ispizua, Jose Roman-Gomez, Javier de la Rubia, Josep M. Ribera, Montserrat Hoyos, Arianne Perez-Garcia, David P. Serrano, Jose B Nieto, Carlos Solano, Salut Brunet, Arturo Iriondo, Josep M. Pujal, Ildefonso Espigado, Marcos González, Rafael de la Cámara, David Gallardo, Antonio Jiménez-Velasco, and Maite Encuentra

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Genotype, medicine.medical_treatment, Immunology, Graft vs Host Disease, Human leukocyte antigen, Hematopoietic stem cell transplantation, Biology, Biochemistry, Antigen, Antigens, CD, HLA Antigens, Internal medicine, medicine, Humans, Transplantation, Homologous, Cytotoxic T cell, CTLA-4 Antigen, Child, Polymorphism, Genetic, Hematology, Siblings, Hazard ratio, Hematopoietic Stem Cell Transplantation, Infant, Cell Biology, Middle Aged, Antigens, Differentiation, Survival Rate, Transplantation, Treatment Outcome, Child, Preschool, Histocompatibility, Female, Stem cell
Abstract

CTLA-4 is an inhibitory molecule that down-regulates T-cell activation. Although polymorphisms at CTLA-4 have been correlated with autoimmune diseases their association with clinical outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has yet to be explored. A total of 5 CTLA-4 single-nucleotide polymorphisms were genotyped on 536 HLA-identical sibling donors of allo-HSC transplants. Genotypes were tested for an association with patients' posttransplantation outcomes. The effect of the polymorphisms on cytotoxic T-lymphocyte antigen 4 (CTLA-4) mRNA and protein production were determined in 60 healthy control participants. We observed a reduction in the mRNA expression of the soluble CTLA-4 isoform in the presence of a G allele at CT60 and +49. Patients receiving stem cells from a donor with at least 1 G allele in position CT60 had worse overall survival (56.2% vs 69.8% at 5 years; P = .001; hazard ratio [HR], 3.80; 95% confidence interval [CI], 1.75-8.22), due to a higher risk of relapse (P = .049; HR, 1.71; 95% CI, 1.00-2.93). Acute graft-versus-host disease (aGVHD) was more frequent in patients receiving CT60 AA stem cells (P = .033; HR, 1.54; 95% CI, 1.03-2.29). This is the first study to report an association between polymorphisms at CTLA-4 and clinical outcome after allo-HSCT. The CT60 genotype influences relapse and aGVHD, probably due to its action on CTLA-4 alternative splicing.

Published
2007
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11. Clinical outcome after sex-mismatched allogeneic stem cell transplantation from human lymphocyte antigen-identical sibling donors: influence of stem cell source

Author

Alvaro Urbano-Ispizua, Josep-Maria Ribera, D Caballero, Salut Brunet, R de la Cámara, David Gallardo, Cristina Barrenetxea, Arturo Iriondo, Carlos Vallejo, Antonio Jiménez-Velasco, D Serrano, Arianne Perez-Garcia, Antoni Torres, I Espigado, Maite Encuentra, and J de la Rubia

Subjects
Adult, Male, Cancer Research, Adolescent, Graft vs Host Disease, Disease, Granulocyte, Humans, Transplantation, Homologous, Medicine, Cumulative incidence, Child, Prospective cohort study, Aged, business.industry, Histocompatibility Testing, Siblings, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, Infant, Hematology, Middle Aged, Tissue Donors, Transplantation, surgical procedures, operative, medicine.anatomical_structure, Oncology, Child, Preschool, Immunology, Female, Bone marrow, Stem cell, business
Abstract

Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) is increasingly selected as a source of stem cells for allogeneic transplantation.1 The shift from using bone marrow (BM) to PB stem cells is based on the faster haematological recovery and lower transplant-related mortality (TRM) in patients with advanced disease observed after transplantation with PB.2 However, it remains unclear whether the use of PB is associated with an increased incidence of acute graft-versus-host disease (GvHD). Several retrospective and randomized prospective studies comparing BM and PB found a similar incidence of acute GvHD,2, 3 except the European Group for Blood and Marrow Transplantation (EBMT) study, which seems to indicate that PB transplants are associated with an increased cumulative incidence of acute GvHD.4 This association was recently confirmed by a meta-analysis of nine randomized trials.5 Nevertheless, it seems clear that PB transplants have an increased risk of chronic GvHD.2, 3, 4, 5

Published
2006
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12. Genetic loss of SH2B3 in acute lymphoblastic leukemia

Author

Maddalena Paganin, Michael Hadler, Chaim Jalas, Alberto Ambesi-Impiombato, Elisabeth Paietta, Wei Tong, Janis Racevskis, Giuseppe Basso, Kara M. Kelly, Martin S. Tallman, Arianne Perez-Garcia, Jacob M. Rowe, Charles A. LeDuc, Isaura Rigo, Adolfo A. Ferrando, and Wendy K. Chung

Subjects
Male, Genotype, Somatic cell, Developmental Disabilities, Immunology, Blotting, Western, DNA Mutational Analysis, Molecular Sequence Data, Biology, Biochemistry, Germline, Autoimmune Diseases, Pathogenesis, Mice, Germline mutation, medicine, Genetic predisposition, Animals, Humans, Child, Germ-Line Mutation, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, Base Sequence, Siblings, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Infant, Proteins, Cell Biology, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Pedigree, Mice, Inbred C57BL, Leukemia, Haematopoiesis, Child, Preschool, Cancer research, Female, Stem cell
Abstract

The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.

Published
2013

13. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas

Author

Teresa Palomero, Lucile Couronné, Hossein Khiabanian, Mi-Yeon Kim, Alberto Ambesi-Impiombato, Arianne Perez-Garcia, Zachary Carpenter, Francesco Abate, Maddalena Allegretta, J Erika Haydu, Xiaoyu Jiang, Izidore S Lossos, Concha Nicolas, Milagros Balbin, Christian Bastard, Govind Bhagat, Miguel A Piris, Elias Campo, Olivier A Bernard, Raul Rabadan, and Adolfo A Ferrando

Subjects
RHOA, DNA damage, Molecular Sequence Data, Mutation, Missense, Fluorescent Antibody Technique, Ataxia Telangiectasia Mutated Proteins, Biology, medicine.disease_cause, Proto-Oncogene Proteins c-fyn, Deep sequencing, Article, DNA Methyltransferase 3A, Dioxygenases, Epigenesis, Genetic, FYN, Proto-Oncogene Proteins, Genetics, medicine, Escherichia coli, Humans, Exome, Epigenetics, DNA (Cytosine-5-)-Methyltransferases, Exome sequencing, Mutation, Base Sequence, Sequence Analysis, RNA, Computational Biology, High-Throughput Nucleotide Sequencing, Lymphoma, T-Cell, Peripheral, CD58 Antigens, Molecular biology, Isocitrate Dehydrogenase, 3. Good health, DNA-Binding Proteins, HEK293 Cells, Cancer research, biology.protein, rhoA GTP-Binding Protein, Proto-oncogene tyrosine-protein kinase Src
Abstract

Peripheral T cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non-Hodgkin lymphomas. Here we combined whole-exome sequencing of 12 tumor-normal DNA pairs, RNA sequencing analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p.Gly17Val alteration present in 22 of 35 (67%) angioimmunoblastic T cell lymphoma (AITL) samples and in 8 of 44 (18%) PTCL, not otherwise specified (PTCL-NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated guanine-exchange factor (GEF) proteins. In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.

Published
2013

14. Mutational Landscape, Clonal Evolution Patterns and Role of RAS Mutations in Relapsed Acute Lymphoblastic Leukemia

Author

Mignon L. Loh, Giuseppe Basso, Adolfo A. Ferrando, Katsuyoshi Koh, Renate Kirschner-Schwabe, Motohiro Kato, Francesco Abate, Teresa Palomero, Arianne Perez-Garcia, Concepcion Nicolas, Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Gannie Tzoneva, Koichi Oshima, Meenakshi Devidas, Julie M. Gastier-Foster, Maddalena Paganin, Zachary Carpenter, Milagros Balbín, Raul Rabadan, Hossein Khiabanian, Maria Luisa Sulis, Cornelia Eckert, Alex Penson, and Ana C. da Silva-Almeida

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Vincristine, Immunology, Biology, medicine.disease_cause, Biochemistry, Somatic evolution in cancer, Clonal Evolution, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Acute lymphocytic leukemia, medicine, Humans, Childhood Acute Lymphoblastic Leukemia, Multidisciplinary, Base Sequence, Wild type, Combination chemotherapy, Cell Biology, Hematology, Biological Sciences, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Virology, PTPN11, Leukemia, Genes, ras, Methotrexate, 030104 developmental biology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, Cancer research, KRAS, medicine.drug
Abstract

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children. Altogether 90% of pediatric ALL patients achieve a complete hematologic remission with current high dose combination chemotherapy and 80% of them remain leukemia free. However, the outcome for patients showing refractory disease or those whose leukemia relapses after an initial transient response remains disappointingly poor with cure rates of less than 40%. To investigate genetic drivers of relapse and resistance and explore the specific roles of clonal evolution in disease progression and relapse here we performed whole-exome sequence analysis of matched diagnosis, germline (remission) and relapse DNA samples in a panel of 55 pediatric ALL patients including 33 T-cell ALLs and 22 B-cell precursor ALLs. These analyses identified an average of 9 mutations present in diagnostic samples and 17 mutations in relapsed leukemia DNAs. Phylogenetic tree analysis for each of the 48 cases with optimal variant call parameters analyzing their clonal evolution dynamics during disease progression, combined with whole genome sequencing of targeted samples with low exonic mutation input, showed that branched evolution in which relapse clones contain some, but not all genetic lesions present in the major clone at diagnosis as the primary mechanism driving tumor progression and relapse present in 45/48 (94%) cases. In addition, and consistent with previous reports we identified the presence of chemotherapy associated mutations in NT5C2 (10/55), TP53 (3/55), CREBBP (4/55) and the NR3C1 glucocorticoid receptor gene (2/55). However, and most strikingly, 23/27 (85%) recurrently mutated genes in this series with mutations preferentially selected or retained at the time of relapse (mutation never lost in the relapse clone) were not implicated in relapse ALL before (HTR3A, MED12, USP9X, CACNA1H, ODZ3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3 and EYS). A branched pattern of genetic evolution and the presence of recurrent mutations selected at relapse support that chemotherapy imposes a strong Darwinian genetic selection in leukemic cell populations. In this context it is worth noting that RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, while in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Most notably, and in agreement with this hypothesis, inducible expression of mutant KRAS in human ALL lines demonstrate that oncogenic KRAS G12D induces methotrexate resistance, but also improves leukemia response to vincristine; a phenotype perfectly recapitulated in a isogenic ALL leukemia model generated from a conditional inducible Kras G12D knockin mice. Mechanistically, KRAS G12 expression induces MAPK dependent abrogation of methotrexate induced apoptosis. Moreover, Kras mutant tumors show enhanced G2/M cell cycle arrest and apoptosis upon spindle poisoning with vincristine, a phenotype linked with increased PLK phosphorylation and transcriptional down-regulation of mitotic genes. Finally clonal competition assays demonstrate that the differential response to methotrexate and vincristine in isogenic Kras wild type and Kras mutant ALL cells results in clonal dominance of Kras G12D populations in cultures treated with methotrexate, while Kras wild type cells are selected the context of vincristine treatment. In all these results show novel insight on the genetics and mechanisms of clonal selection, disease progression and relapse in ALL and demonstrate a previously unrecognized dual role of RAS mutations in chemotherapy response. Disclosures Loh: Abbvie: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Published
2016
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15. Constitutive LcK activity drives sensitivity differences between CD8+ memory T cell subsets

Author

Michelle Krogsgaard, Duane Moogk, Shi Zhong, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Nicholas P Restifo, and Alan B Frey

Subjects
Immunology, Immunology and Allergy
Abstract

CD8+ T cells develop increased sensitivity following antigen experience, and differences in sensitivity exist between T cell memory subsets. How differential T cell receptor (TCR) signaling between memory subsets contributes to sensitivity differences is unclear. We show that constitutive activity of lymphocyte-specific protein tyrosine kinase (Lck) is greater in effector memory T cells (TEM) compared with central memory T cells (TCM), leading to enhanced activation signaling, including Zeta-chain-associated protein kinase 70 (Zap-70) phosphorylation and intracellular calcium influx, and resulting in increased cytotoxic effector function in TEM. We provide evidence that the differences in Lck activity between CD8+ TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase (Csk). Together, this work demonstrates a role for constitutive Lck activity in controlling antigen sensitivity, and suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM.

Published
2016
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16. Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL

Author

Janis Racevskis, Luyao Xu, Jacob M. Rowe, Alberto Ambesi-Impiombato, Arianne Perez-Garcia, Jules P.P. Meijerink, Mukesh Bansal, Elisabeth Paietta, Andrea Califano, Kim De Keersmaecker, Xavier Solé, Peter H. Wiernik, Giusy Della Gatta, Teresa Palomero, Adolfo A. Ferrando, Zachary Carpenter, and Pediatrics

Subjects
Oncogens, Protein Conformation, Systems biology, T cell, T-Cell Transformation, Gene regulatory network, Computational biology, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mediator, hemic and lymphatic diseases, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Humans, Gene Regulatory Networks, Transcription factor, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, Homeodomain Proteins, 0303 health sciences, Leukemia, Tumor Suppressor Proteins, Leucèmia, General Medicine, Oncogenes, medicine.disease, medicine.anatomical_structure, Cell Transformation, Neoplastic, RUNX1, chemistry, 030220 oncology & carcinogenesis, Core Binding Factor Alpha 2 Subunit, Mutation, Cancer research
Abstract

The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL)(1,2). Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL.

Published
2011

17. ETV6 mutations in early immature human T cell leukemias

Author

Isaura Rigo, Jacob M. Rowe, Pieter Van Vlierberghe, Giusy Della Gatta, Alberto Ambesi-Impiombato, Elisabeth Paietta, Selina M. Luger, Michael Hadler, Peter H. Wiernik, Adolfo A. Ferrando, Arianne Perez-Garcia, Valeria Tosello, J. Erika Haydu, Montserrat Rué, and Janis Racevskis

Subjects
Male, Neuroblastoma RAS viral oncogene homolog, Myeloid, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease_cause, 0302 clinical medicine, NOTCH1, hemic and lymphatic diseases, Immunology and Allergy, Genes, Tumor Suppressor, TUMOR-SUPPRESSOR, CLASS DISCOVERY, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Mutation, Gene Expression Regulation, Leukemic, 3. Good health, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, SURVIVAL, Female, REGULATOR, Adult, EXPRESSION, IDH1, Immunology, ACUTE MYELOID-LEUKEMIA, Biology, IDH2, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, HEMATOPOIETIC STEM-CELLS, 030304 developmental biology, ACUTE LYMPHOBLASTIC-LEUKEMIA, Proto-Oncogene Proteins c-ets, Gene Expression Profiling, Brief Definitive Report, Infant, Biology and Life Sciences, medicine.disease, GENE, Repressor Proteins, Gene expression profiling, ETV6, Cancer research
Abstract

A substantial proportion of adult T-ALL samples display gene expression and mutation characteristics of both T cell and acute myeloid leukemias; mutations in ETV6 are found exclusively within this new molecular subgroup of adult T-ALL patients., Early immature T cell acute lymphoblastic leukemias (T-ALLs) account for ∼5–10% of pediatric T-ALLs and are associated with poor prognosis. However, the genetic defects that drive the biology of these tumors remain largely unknown. In this study, analysis of microarray gene expression signatures in adult T-ALL demonstrated a high prevalence of early immature leukemias and revealed a close relationship between these tumors and myeloid leukemias. Many adult immature T-ALLs harbored mutations in myeloid-specific oncogenes and tumor suppressors including IDH1, IDH2, DNMT3A, FLT3, and NRAS. Moreover, we identified ETV6 mutations as a novel genetic lesion uniquely present in immature adult T-ALL. Our results demonstrate that early immature adult T-ALL represents a heterogeneous category of leukemias characterized by the presence of overlapping myeloid and T-ALL characteristics, and highlight the potential role of ETV6 mutations in these tumors.

Published
2011

18. Retroviral Transduction of T-cell Receptors in Mouse T-cells

Author

Arianne Perez-Garcia, Shi Zhong, Karolina Malecek, and Michelle Krogsgaard

Subjects
Adoptive cell transfer, Mouse, T-Lymphocytes, T cell, medicine.medical_treatment, General Chemical Engineering, Immunology, Receptors, Antigen, T-Cell, Epitopes, T-Lymphocyte, chemical and pharmacologic phenomena, Biology, Transfection, General Biochemistry, Genetics and Molecular Biology, Transduction, Mice, 03 medical and health sciences, Transduction (genetics), 0302 clinical medicine, Immune system, T-cell, Antigen, Transduction, Genetic, medicine, Animals, Humans, T-cell receptor, Antigen-presenting cell, 030304 developmental biology, Issue 44, 0303 health sciences, Retrovirus, General Immunology and Microbiology, General Neuroscience, hemic and immune systems, Immunotherapy, 3. Good health, Cell biology, Retroviridae, medicine.anatomical_structure, Models, Animal, Spleen, 030217 neurology & neurosurgery
Abstract

T-cell receptors (TCRs) play a central role in the immune system. TCRs on T-cell surfaces can specifically recognize peptide antigens presented by antigen presenting cells (APCs)1. This recognition leads to the activation of T-cells and a series of functional outcomes (e.g. cytokine production, killing of the target cells). Understanding the functional role of TCRs is critical to harness the power of the immune system to treat a variety of immunology related diseases (e.g. cancer or autoimmunity). It is convenient to study TCRs in mouse models, which can be accomplished in several ways. Making TCR transgenic mouse models is costly and time-consuming and currently there are only a limited number of them available2-4. Alternatively, mice with antigen-specific T-cells can be generated by bone marrow chimera. This method also takes several weeks and requires expertise5. Retroviral transduction of TCRs into in vitro activated mouse T-cells is a quick and relatively easy method to obtain T-cells of desired peptide-MHC specificity. Antigen-specific T-cells can be generated in one week and used in any downstream applications. Studying transduced T-cells also has direct application to human immunotherapy, as adoptive transfer of human T-cells transduced with antigen-specific TCRs is an emerging strategy for cancer treatment6. Here we present a protocol to retrovirally transduce TCRs into in vitro activated mouse T-cells. Both human and mouse TCR genes can be used. Retroviruses carrying specific TCR genes are generated and used to infect mouse T-cells activated with anti-CD3 and anti-CD28 antibodies. After in vitro expansion, transduced T-cells are analyzed by flow cytometry.

Published
2010
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19. Immune Reconstitution Of Regulatory T-Cells Following Autologous Hematopoietic Stem Cell Transplantation

Author

S. Lopez, Montserrat Arnan, Arianne Perez-Garcia, Rafael F. Duarte, E. Cabezudo, P. Ramos-Oliva, M. Mestre, J. Odriozola, Isabel Marugán, Javier López-Jiménez, T Peralta, Carlos Solano, and Isabel Benet

Subjects
Transplantation, Immune system, business.industry, medicine.medical_treatment, medicine, Cancer research, Hematopoietic stem cell transplantation, Hematology, business, CXCR4
Published
2009
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20. Association of melanoma expression of matrix metalloproteinase-23 with blunted tumor immunity and poor responses to immunotherapy

Author

Tianqi Li, Michelle W. Ma, Paul J. Christos, Duane Moogk, Ines Pires da Silva, Anna C. Pavlick, Erica B. Friedman, Michelle Krogsgaard, Nina Bhardwaj, Arianne Perez-Garcia, Iman Osman, Patrick Scanlon, Eleazar Vega-Saenz de Miera, Farbod Darvishian, and Chelsea Wei Ting Lee

Subjects
Cancer Research, business.industry, medicine.medical_treatment, T cell, Melanoma, Tumor immunity, Immunotherapy, Matrix (biology), Matrix metalloproteinase, medicine.disease, Potassium channel, medicine.anatomical_structure, Oncology, Cancer research, Medicine, business
Abstract

e20057 Background: Matrix metalloproteinase-23 (MMP-23) can inhibit T cell activation by selectively blocking the voltage-gated potassium channel Kv1.3, and may also alter T cell activity and pheno...

Published
2015
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21. Matrix metalloproteinase-23 as a new immunotherapeutic checkpoint target in melanoma

Author

Duane Moogk, Eleazar Vega-Saenz de Miera, Paul J. Christos, Anna C. Pavlick, Ines Pires da Silva, Arianne Perez-Garcia, Patrick Scanlon, Michelle Krogsgaard, Michelle W. Ma, Iman Osman, Nina Bhardwaj, Erica B. Friedman, and Farbod Darvishian

Subjects
Cancer Research, medicine.anatomical_structure, Oncology, T cell, Melanoma, Immunology, medicine, Cancer research, Biology, Matrix metalloproteinase, medicine.disease, Potassium channel
Abstract

3030 Background: Matrix metalloproteinase-23 (MMP-23) can inhibit T cell activation by selectively blocking the voltage-gated potassium channel Kv1.3, and may also alter T cell activity and phenoty...

Published
2014
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22. Abstract 4595: Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Author

Renate Kirschner-Schwabe, Martin S. Tallman, Jana Hoff, Elisabeth Paietta, Jakob M. Rowe, Maddalena Paganin, Janis Racevkis, Gannie Tzoneva, Adolfo A. Ferrando, Valeria Tosello, Maddalena Allegretta, Hossein Khiabanian, Arianne Perez-Garcia, Zachary Carpenter, Teresa Palomero, and Raul Rabadan

Subjects
Cancer Research, Chemotherapy, Nucleotidase activity, business.industry, medicine.medical_treatment, Lymphoblast, Cancer, Disease, medicine.disease, Malignant transformation, Oncology, Nucleotidase, Immunology, Cancer research, Medicine, business, Exome sequencing
Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease. Using whole exome sequencing, here we identify mutations in NT5C2, a 5’-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs, in 20/103 (19%) relapse T-ALLs and in 1/35 (3%) relapse B-precursor ALLs analyzed. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside analog metabolism in disease progression and chemotherapy resistance in ALL. Citation Format: Gannie Tzoneva, Arianne Perez-Garcia, Zachary Carpenter, Hossein Khiabanian, Valeria Tosello, Maddalena Allegretta, Elisabeth Paietta, Janis Racevkis, Jakob M. Rowe, Martin S. Tallman, Maddalena Paganin, Jana Hoff, Renate Kirschner-Schwabe, Teresa Palomero, Raul Rabadan, Adolfo Ferrando. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4595. doi:10.1158/1538-7445.AM2013-4595

Published
2013
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23. Familial and Acquired SH2B3 mutations in ALL

Author

Adolfo A. Ferrando, Charles A. LeDuc, Wendy K. Chung, Arianne Perez-Garcia, Kara A. Kelly, and Chaim Jalas

Subjects
Genetics, Mutation, Immunology, Genome-wide association study, Cell Biology, Hematology, Biology, medicine.disease, medicine.disease_cause, Disease gene identification, Biochemistry, Frameshift mutation, Leukemia, Acute lymphocytic leukemia, medicine, Allele, Exome sequencing
Abstract

Abstract 1326 Acute lymphoblastic leukemia (ALL) is a heterogeneous disease in which multiple genetic alterations contribute to the malignant transformation of lymphoid progenitor cells. Although the pathogenesis of ALL is considered to be multifactorial, few environmental factors have been conclusively associated with increased risk. In addition, although recent genome-wide association studies of childhood ALL have suggested that common variation at some genetic loci may predispose to ALL, the risk associated with these variants seems to be modest. Here we hypothesized that leukemia development in the context of rare familial inherited disorders may indicate a tumor suppressor activity for the underlying genetic defect present in these kindreds. In this context, we studied a pediatric B precursor ALL female patient of Eastern European Ashkenazi Jewish background with a history of remote consanguinity, short stature and mild developmental delay. Her family history is significant for a brother with similar growth retardation and mild developmental defects, neonatal anemia, thrombocytopenia and elevated white cell count, who was diagnosed with chronic hepatitis of probable autoimmune origin and Hashimoto's autoimmune thyroiditis. A second male sibling was healthy. We proposed that an underlying autosomal recessive genetic defect resulting in dysregulation of the development and function of the immune system could contribute to the concurrence of a lymphoid neoplasia and an autoimmune disorder in two siblings in this family. We performed homozygosity mapping and linkage analysis in the family. Whole exome sequencing of each of the two affected siblings identified a homozygous frameshift c.671insGGCCCCG p.Asp231fs mutation in the SH2B3 gene. Dideoxynucleotide sequencing of SH2B3 confirmed that both affected siblings were homozygous for this mutation, while the unaffected brother and both parents were carriers. Analysis of 2,000 normal Ashkenazi Jewish adults identified 1 SH2B3 c.671insGGCCCCG p.Asp231fs carrier and no homozygous individuals. The SH2B adaptor protein gene 3 (SH2B3) encodes an adaptor protein involved in the negative regulation of the JAK STAT signaling pathway. Western Blot analysis of immortalized lymphoblastoid cell lines from the two affected siblings and an unrelated normal control showed complete loss of SH2B3 protein expression in SH2B3 mutant cells. Consistently, analysis of JAK STAT signaling in these cells showed increased JAK2 and STAT3 phosphorylation compared with controls. Moreover, SH2B3 mutant lymphoblastoid cells showed increased proliferation and accelerated cell cycle kinetics, which was particularly pronounced in low serum conditions. Consistently, expression of wild type SH2B3 in these cells impaired cell growth and decreased JAK-STAT signaling. Analysis of a cohort of 167 additional ALLs including 119 B-precursor ALLs and 48 T-ALLs identified a homozygous c.1279insCTGTTGCCGTGTGC p.Val426fs SH2B3 mutation in a B-precursor ALL sample and a homozygous nonsense c.908C>A p.Ser303* SH2B3 mutation in a pediatric T-cell ALL. Notably, analysis of normal (remission) DNA demonstrated the somatic origin of the c.908C>A p.Ser303* SH2B3 mutation. In addition, our sequence analysis of SH2B3 in ALL identified two additional heterozygous germline single nucleotide variants resulting in amino acid substitutions (c.557G>T p.Ser186Ile and c.232G>A p.Glu78Lys). Expression of each of these variants in SH2B3 null cells resulted in partial correction of the increased cell growth phenotype and JAK-STAT signaling associated with SH2B3 loss compared with wild type controls. Notably, heterozygous somatic mutations in SH2B3 have been observed in patients with myeloproliferative neoplasms and heterozygous germline SH2B3 alleles have been linked to essential erythrocytosis, suggesting that the hypomorphic SH2B3 p.Ser186Ile and p.Glu78Lys variants found in our analysis may represent rare leukemia predisposing SH2B3 alleles. Overall these results link the loss of SH2B3 with the pathogenesis of a familial developmental delay, autoimmunity and leukemia predisposition syndrome and demonstrate a tumor suppressor role for SH2B3 in the pathogenesis of B-precursor and T-cell ALL. Disclosures: No relevant conflicts of interest to declare.

Published
2012
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24. An analysis of altered melanoma matrix metalloproteinase-23 (MMP-23) expression and response to immune biologic therapy

Author

Michelle W. Ma, Russell S. Berman, Erica B. Friedman, Michelle Krogsgaard, Paul J. Christos, Iman Osman, Anna C. Pavlick, E. Vega-Saenz de Miera, Arianne Perez-Garcia, Richard L. Shapiro, and F. Darvishian

Subjects
Cancer Research, Immune system, Oncology, Downregulation and upregulation, business.industry, Melanoma, Immunology, Cancer research, Medicine, Matrix metalloproteinase, business, medicine.disease
Abstract

8541 Background: MMP-23, characterized by its unique ShK and immunoglobulin-like domains, has been shown to downregulate the immune response. The ShK domain selectively blocks the voltage-gated pot...

Published
2011
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25. Donor CTLA-4 Genotype Influences Clinical Outcome after T Cell-Depleted Allogeneic Hematopoietic Stem Cell Transplantation from HLA-Identical Sibling Donors

Author

Ismael Buño, Guillermo Sanz, Salut Brunet, Cristina Barrenetxea, Rosa Coll, Anna Bosch-Vizcaya, Ramon Guardia, Yolanda González, E Tuset, Carmen Martínez, Carlos Solano, Josep Maria Roncero, Carolina Martínez-Laperche, Vicent Guillem, Joan Buch, Santiago Gardella, Arianne Perez-Garcia, Natàlia Lloveras, David Gallardo, C. Fernández, and Anna Bustins

Subjects
Adult, Male, Adolescent, Genotype, T-Lymphocytes, T cell, medicine.medical_treatment, Human leukocyte antigen, Hematopoietic stem cell transplantation, Disease-Free Survival, Young Adult, CD34-positive selection, Humans, Transplantation, Homologous, Cytotoxic T cell, Medicine, CTLA-4 Antigen, Relapse, Transplantation, business.industry, Siblings, Hazard ratio, Hematopoietic Stem Cell Transplantation, CD28, Hematology, Middle Aged, Tissue Donors, Survival Rate, Treatment Outcome, medicine.anatomical_structure, CTLA-4, Histocompatibility, Immunology, Female, business
Abstract

CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection. We studied 136 patient-donor pairs. Overall survival (OS) was worse for those patients who received grafts from a donor with the CT60 AA genotype rather than from a donor with the AG or GG genotype (35.6% vs 49.4%; P = .043). This association was confirmed through multivariate analysis, which identified the donor CT60 genotype as an independent risk factor for OS (P = .008; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.23-4.08). The donor CT60 AA genotype was also associated with lower disease-free survival, this being related to an increased risk of relapse (P = .001; HR: 3.41, 95% CI: 1.67-6.96) and a trend toward higher transplant-related mortality. These associations were stronger when considering only patients in the early stage of disease. Our results suggest that graft-versus-leukemia (GVL) activity after T cell depletion is conditioned by the donor CTLA-4 genotype. Biol Blood Marrow Transplant 18: 100-105 (2012) (C) 2012 American Society for Blood and Marrow Transplantation

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26. Melanoma expression of matrix metalloproteinase-23 is associated with blunted tumor immunity and poor responses to immunotherapy

Author

Arianne Perez-Garcia, Duane Moogk, Farbod Darvishian, Michelle Krogsgaard, Eleazar Vega-Saenz de Miera, Paul J. Christos, Michelle W. Ma, Erica B. Friedman, Ines Pires da Silva, Iman Osman, Nina Bhardwaj, Patrick Scanlon, and Anna C. Pavlick

Subjects
Adult, Male, Chemokine, medicine.medical_treatment, T cell, T-Lymphocytes, Regulatory, Tumor-infiltrating lymphocytes, General Biochemistry, Genetics and Molecular Biology, Young Adult, Immune system, Humans, Medicine, Melanoma, Aged, Aged, 80 and over, Medicine(all), biology, business.industry, Biochemistry, Genetics and Molecular Biology(all), Research, Kv1.3, FOXP3, Matrix metalloproteinase-23, General Medicine, Immunotherapy, Middle Aged, medicine.disease, Matrix Metalloproteinases, 3. Good health, Cytokine, medicine.anatomical_structure, Immunology, biology.protein, Female, business
Abstract

Background Matrix metalloproteinase-23 (MMP-23) can block the voltage-gated potassium channel Kv1.3, whose function is important for sustained Ca2+ signaling during T cell activation. MMP-23 may also alter T cell activity and phenotype through cleavage of proteins affecting cytokine and chemokine signaling. We therefore tested the hypothesis that MMP-23 can negatively regulate the anti-tumor T cell response in human melanoma. Methods We characterized MMP-23 expression in primary melanoma patients who received adjuvant immunotherapy. We examined the association of MMP-23 with the anti-tumor immune response - as assessed by the prevalence of tumor-infiltrating lymphocytes and Foxp3+ regulatory T cells. Further, we examined the association between MMP-23 expression and response to immunotherapy. Considering also an in trans mechanism, we examined the association of melanoma MMP-23 and melanoma Kv1.3 expression. Results Our data revealed an inverse association between primary melanoma MMP-23 expression and the anti-tumor T cell response, as demonstrated by decreased tumor-infiltrating lymphocytes (TIL) (P = 0.05), in particular brisk TILs (P = 0.04), and a trend towards an increased proportion of immunosuppressive Foxp3+ regulatory T cells (P = 0.07). High melanoma MMP-23 expression is also associated with recurrence in patients treated with immune biologics (P = 0.037) but not in those treated with vaccines (P = 0.64). Further, high melanoma MMP-23 expression is associated with shorter periods of progression-free survival for patients receiving immune biologics (P = 0.025). On the other hand, there is no relationship between melanoma MMP-23 and melanoma Kv1.3 expression (P = 0.27). Conclusions Our data support a role for MMP-23 as a potential immunosuppressive target in melanoma, as well as a possible biomarker for informing melanoma immunotherapies. Electronic supplementary material The online version of this article (doi:10.1186/s12967-014-0342-7) contains supplementary material, which is available to authorized users.

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