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1 December 2021
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In addition to its tumor suppressor gene function, p53 has been shown to contribute to silencing of repetitive elements including endogenous retrovirus (ERV) long terminal repeat sequences. Zhou, Singh, and colleagues made the unexpected observation that upon p53 activation through pharmacologic inhibition of its negative regulator MDM2, ERV expression was increased due to increased p53 occupancy on ERV promoters and p53-mediated suppression of LSD1 and DNMT1, two major ERV repressors. ERV derepression following MDM2 inhibition contributed to double-stranded RNA stress leading to type I/III interferon (IFN) expression, antigen processing/presentation, and increased T-cell infiltration. Additionally, dual treatment with an anti–PD-1 antibody along with an MDM2 inhibitor markedly reduced tumor growth in a poorly immunogenic murine model of melanoma as compared with checkpoint therapy alone. An augmentation of IFN signaling and immune cell recruitment was also observed in patients who received an MDM2 inhibitor. For more information, see the article by Zhou, Singh, and colleagues on page 3090.Close Modal - PDF Icon PDF LinkTable of Contents
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ISSN 2159-8274
EISSN 2159-8290
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Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma
Antoni Ribas; Theresa Medina; John M. Kirkwood; Yousef Zakharia; Rene Gonzalez; Diwakar Davar; Bartosz Chmielowski; Katie M. Campbell; Riyue Bao; Heather Kelley; Aaron Morris; David Mauro; James E. Wooldridge; Jason J. Luke; George J. Weiner; Arthur M. Krieg; Mohammed M. Milhem
Research Articles
Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing
Scott Newman; Joy Nakitandwe; Chimene A. Kesserwan; Elizabeth M. Azzato; David A. Wheeler; Michael Rusch; Sheila Shurtleff; Dale J. Hedges; Kayla V. Hamilton; Scott G. Foy; Michael N. Edmonson; Andrew Thrasher; Armita Bahrami; Brent A. Orr; Jeffery M. Klco; Jiali Gu; Lynn W. Harrison; Lu Wang; Michael R. Clay; Annastasia Ouma; Antonina Silkov; Yanling Liu; Zhaojie Zhang; Yu Liu; Samuel W. Brady; Xin Zhou; Ti-Cheng Chang; Manjusha Pande; Eric Davis; Jared Becksfort; Aman Patel; Mark R. Wilkinson; Delaram Rahbarinia; Manish Kubal; Jamie L. Maciaszek; Victor Pastor; Jay Knight; Alexander M. Gout; Jian Wang; Zhaohui Gu; Charles G. Mullighan; Rose B. McGee; Emily A. Quinn; Regina Nuccio; Roya Mostafavi; Elsie L. Gerhardt; Leslie M. Taylor; Jessica M. Valdez; Stacy J. Hines-Dowell; Alberto S. Pappo; Giles Robinson; Liza-Marie Johnson; Ching-Hon Pui; David W. Ellison; James R. Downing; Jinghui Zhang; Kim E. Nichols
Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation
Alvaro Quintanal-Villalonga; Hirokazu Taniguchi; Yingqian A. Zhan; Maysun M. Hasan; Shweta S. Chavan; Fanli Meng; Fathema Uddin; Parvathy Manoj; Mark T.A. Donoghue; Helen H. Won; Joseph M. Chan; Metamia Ciampricotti; Andrew Chow; Michael Offin; Jason C. Chang; Jordana Ray-Kirton; Sam E. Tischfield; Jacklynn Egger; Umesh K. Bhanot; Irina Linkov; Marina Asher; Sonali Sinha; Joachim Silber; Christine A. Iacobuzio-Donahue; Michael H. Roehrl; Travis J. Hollmann; Helena A. Yu; Juan Qiu; Elisa de Stanchina; Marina K. Baine; Natasha Rekhtman; John T. Poirier; Brian Loomis; Richard P. Koche; Charles M. Rudin; Triparna Sen
Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History
Livius Penter; Satyen H. Gohil; Caleb Lareau; Leif S. Ludwig; Erin M. Parry; Teddy Huang; Shuqiang Li; Wandi Zhang; Dimitri Livitz; Ignaty Leshchiner; Laxmi Parida; Gad Getz; Laura Z. Rassenti; Thomas J. Kipps; Jennifer R. Brown; Matthew S. Davids; Donna S. Neuberg; Kenneth J. Livak; Vijay G. Sankaran; Catherine J. Wu
AKT Degradation Selectively Inhibits the Growth of PI3K/PTEN Pathway–Mutant Cancers with Wild-Type KRAS and BRAF by Destabilizing Aurora Kinase B
Jia Xu; Xufen Yu; Tiphaine C. Martin; Ankita Bansal; Kakit Cheung; Abigail Lubin; Elias Stratikopoulos; Kaitlyn M. Cahuzac; Li Wang; Ling Xie; Royce Zhou; Yudao Shen; Xuewei Wu; Shen Yao; Ruifang Qiao; Poulikos I. Poulikakos; Xian Chen; Jing Liu; Jian Jin; Ramon Parsons
AKT depletion using a degrader proved superior to kinase inhibition due to sustained repression of AKT signaling and destabilization of AURKB, leading to induction of G2/M arrest, hyperploidy, and cell death.
Pharmacologic Activation of p53 Triggers Viral Mimicry Response Thereby Abolishing Tumor Immune Evasion and Promoting Antitumor Immunity
Xiaolei Zhou; Madhurendra Singh; Gema Sanz Santos; Vincent Guerlavais; Luis A. Carvajal; Manuel Aivado; Yue Zhan; Mariana M.S. Oliveira; Lisa S. Westerberg; D. Allen Annis; John Inge Johnsen; Galina Selivanova
Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma
Romain Riscal; Caroline J. Bull; Clementina Mesaros; Jennifer M. Finan; Madeleine Carens; Elaine S. Ho; Jimmy P. Xu; Jason Godfrey; Paul Brennan; Mattias Johansson; Mark P. Purdue; Stephen J. Chanock; Daniela Mariosa; Nicholas J. Timpson; Emma E. Vincent; Brian Keith; Ian A. Blair; Nicolas Skuli; M. Celeste Simon
A Humanized Animal Model Predicts Clonal Evolution and Therapeutic Vulnerabilities in Myeloproliferative Neoplasms
Hamza Celik; Ethan Krug; Christine R. Zhang; Wentao Han; Nancy Issa; Won Kyun Koh; Hassan Bjeije; Ostap Kukhar; Maggie Allen; Tiandao Li; Daniel A.C. Fisher; Jared S. Fowles; Terrence N. Wong; Matthew C. Stubbs; Holly K. Koblish; Stephen T. Oh; Grant A. Challen
Tumor Microenvironment–Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy
Yuting Tang; Qian Xu; Liang Hu; Xiaomei Yan; Xiaomin Feng; Asumi Yokota; Weinan Wang; Di Zhan; Durga Krishnamurthy; David E. Ochayon; Lijun Wen; Li Huo; Huimin Zeng; Yingwan Luo; L. Frank Huang; Mark Wunderlich; Jiwang Zhang; Eric Vivier; Jianfeng Zhou; Stephen N. Waggoner; Gang Huang
Genetic Screens Identify a Context-Specific PI3K/p27Kip1 Node Driving Extrahepatic Biliary Cancer
Chiara Falcomatà; Stefanie Bärthel; Angelika Ulrich; Sandra Diersch; Christian Veltkamp; Lena Rad; Fabio Boniolo; Myriam Solar; Katja Steiger; Barbara Seidler; Magdalena Zukowska; Joanna Madej; Mingsong Wang; Rupert Öllinger; Roman Maresch; Maxim Barenboim; Stefan Eser; Markus Tschurtschenthaler; Arianeb Mehrabi; Stephanie Roessler; Benjamin Goeppert; Alexander Kind; Angelika Schnieke; Maria S. Robles; Allan Bradley; Roland M. Schmid; Marc Schmidt-Supprian; Maximilian Reichert; Wilko Weichert; Owen J. Sansom; Jennifer P. Morton; Roland Rad; Günter Schneider; Dieter Saur
Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy
Hsin-Chieh Wu; Domitille Rérolle; Caroline Berthier; Rita Hleihel; Takashi Sakamoto; Samuel Quentin; Shirine Benhenda; Claudia Morganti; Chengchen Wu; Lidio Conte; Sylvie Rimsky; Marie Sebert; Emmanuelle Clappier; Sylvie Souquere; Stéphanie Gachet; Jean Soulier; Sylvère Durand; Jennifer J. Trowbridge; Paule Bénit; Pierre Rustin; Hiba El Hajj; Emmanuel Raffoux; Lionel Ades; Raphael Itzykson; Hervé Dombret; Pierre Fenaux; Olivier Espeli; Guido Kroemer; Lorenzo Brunetti; Tak W. Mak; Valérie Lallemand-Breitenbach; Ali Bazarbachi; Brunangelo Falini; Keisuke Ito; Maria Paola Martelli; Hugues de Thé
Rlf–Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer
Metamia Ciampricotti; Triantafyllia Karakousi; Allison L. Richards; Àlvaro Quintanal-Villalonga; Angeliki Karatza; Rebecca Caeser; Emily A. Costa; Viola Allaj; Parvathy Manoj; Kyle B. Spainhower; Faruk E. Kombak; Francisco J. Sanchez-Rivera; Janneke E. Jaspers; Anastasia-Maria Zavitsanou; Danilo Maddalo; Andrea Ventura; William M. Rideout, III; Elliot H. Akama-Garren; Tyler Jacks; Mark T.A. Donoghue; Triparna Sen; Trudy G. Oliver; John T. Poirier; Thales Papagiannakopoulos; Charles M. Rudin
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