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A genetic basis for epidemic streptococcal strains
This Month September 2015 A summary of the current issue of The Journal of Clinical Investigation Also in this issue: Plasmacytoid dendritic cells in HIV-1 7 Cell therapy for remyelination 8 Adipocyte iron regulates appetite 9 Review Series: Cancer immunotherapy edited by Yiping Yang 10 jci.org/this-month Scan with your mobile device for the digital version of JCI This Month. A genetic basis for epidemic streptococcal strains p. 6 Journal of Clinical Investigation Consulting Editors Alejandro Aballay Abul K. Abbas Domenico Accili Rexford S. Ahima Qais Al-Awqati Kari Alitalo James Allison Dario C. Altieri Masayuki Amagai Mark E. Anderson Brian H. Annex Alan Attie Jane E. Aubin Steven P. Balk Michael F. Beers John A. Belperio Nina Bhardwaj Morris J. Birnbaum Joyce Bischoff Mina J. Bissell Craig Blackstone Bruce R. Blazar Nancy Bonini Brendan Boyce Jonathan Bromberg Frank C. Brosius Hal E. Broxmeyer Andrew Butler Michael J. Caplan Ruben D. Carrasco Diego H. Castrillon Harold Chapman Ajay Chawla Benjamin K. Chen Benny J. Chen Ju Chen Marie-Françoise Chesselet Vivian G. Cheung Yongwon Choi Thomas Clemens Ronald G. Collman Marco Colonna George Cotsarelis Shaun R. Coughlin Christopher M. Counter Peter D. Crompton Tyler J. Curiel David D’Alessio Richard T. D’Aquila Riccardo Dalla-Favera J. Timothy Greenamyre Theresa A. Guise David Hafler Jonathan J. Hansen Raymond C. Harris Stanley L. Hazen Peter Heeringa Brian A. Hemmings Gary Koretzky Calvin Kuo Antonio La Cava Fadi G. Lakkis Terri Laufer Mitchell A. Lazar Brendan Lee William M.F. Lee Edward Plow Jeffrey Pollard Kornelia Polyak Catherine Postic Josef Prchal Alice S. Prince Louis J. Ptáček Luigi Puglielli Alan Daugherty Ted Dawson Sudhansu Dey Harry C. Dietz III Gianpietro Dotti Michael Dustin Connie J. Eaves Dominique Eladari Jack A. Elias Joel K. Elmquist Stephen G. Emerson Jeffrey A. Engelman Jonathan A. Epstein Adrian Erlebacher Joel D. Ernst James M. Ervasti Robert V. Farese Jr. Eric R. Fearon Edward A. Fisher Susan Fisher Richard A. Flavell Tatiana Foroud Velia M. Fowler Martin Friedlander Stephen J. Galli J. Victor Garcia-Martinez Alfred L. George Jr. Stanton L. Gerson Robert E. Gerszten Todd Golde Stanley Goldfarb Larry B. Goldstein Fred Sanford Gorelick Kathleen J. Green Meenhard Herlyn Joachim Herz Katherine A. High Helen H. Hobbs Ronald Hoffman V. Michael Holers Steven M. Holland Michael J. Holtzman Lawrence B. Holzman Tamas L. Horvath Gokhan S. Hotamisligil Steven R. Houser Scott J. Hultgren Christopher A. Hunter Ciro Indolfi David E. James William G. Kaelin Jr. Klaus Kaestner Mark L. Kahn Raghu Kalluri S. Ananth Karumanchi Robert S. Kass Masato Kasuga Dontscho Kerjaschki Sundeep Khosla Richard N. Kitsis Peter S. Klein Steven Kliewer Björn C. Knollmann Walter J. Koch Jay K. Kolls Issei Komuro Christopher D. Kontos Murray Korc Rudolph L. Leibel Stanley M. Lemon Jon D. Levine Ross L. Levine Klaus Ley Richard M. Locksley Gary Lopaschuk Richard B. Mailman Andrew R. Marks Jack Martin Steven O. Marx Rodger P. McEver Elizabeth McNally Cornelius J. Melief Shlomo Melmed George Michalopoulos Jeffrey H. Miner Beverly Mitchell Peter J. Mohler Kelle Harbert Moley Jeffery Molkentin David D. Moore Edward E. Morrisey James H. Morrissey Anthony J. Muslin Martin G. Myers Jr. Benjamin G. Neel Eric N. Olson Harry T. Orr William C. Parks Warren S. Pear Richard M. Peek Jr. Sallie R. Permar David J. Pinsky Pere Puigserver Bali Pulendran Ellen Puré Susan E. Quaggin Marlene Rabinovitch Daniel J. Rader Shahin Rafii Gwendalyn J. Randolph Barbara Rehermann Steven L. Reiner Sarah A. Robertson Paul B. Rosenberg Theodora S. Ross Marc E. Rothenberg Anil Rustgi J. Evan Sadler Junichi Sadoshima Jose-Alain Sahel Jean E. Schaffer Philipp E. Scherer Michael D. Schneider Detlef Schuppan Michael W. Schwartz William K. Scott Randy Seeley Amita Sehgal Clay Semenkovich Gregg L. Semenza John Seykora Steven D. Shapiro Mari Shinohara Steven E. Shoelson Gerald I. Shulman Roy L. Silverstein M. Celeste Simon Mihaela Skobe Lois Smith Steven R. Smith Susan S. Smyth Weihong Song Ashley L. St. John Herman F. Staats Jonathan S. Stamler John R. Stanley Colin L. Stewart Doris Stoffers Warren Strober Maureen A. Su Katalin Susztak Catharina Svanborg Ira Tabas Alan R. Tall Sakae Tanaka Victor J. Thannickal Andrei Thomas-Tikhonenko Georgia D. Tomaras Peter Tontonoz Laurence A. Turka Raphael H. Valdivia Marcel R.M. van den Brink Luc Van Kaer Matthias von Herrath Yisong Y. Wan Hong Wang David Weinstock Jeffrey Weiser Stephen J. Weiss Bart O. Williams Joseph C. Wu Thomas A. Wynn Rudolf Zechner Kang Zhang Len Zon Ming-Hui Zou Weiping Zou This Month September 2015 Editor Howard A. Rockman Deputy Editors Garnett Kelsoe, Bryan L. Roth Associate Editors Soman N. Abraham, Vann Bennett, Gerard C. Blobe, Kathleen M. Caron, Marc G. Caron, John P. Chute, Thomas M. Coffman, Anna Mae Diehl, Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Yiping Yang Clinical Medicine Associate Editors Michael A. Morse, Andrew J. Muir, Scott M. Palmer, Mark A. Stacy Asia Editor David M. Virshup Chair, Executive Council Robert J. Lefkowitz Biostatisticians Cynthia Coffman, Barry Moser, Maren Olsen Bioethicist Arthur L. Caplan Senior Science Editor Sarah C. Jackson Science Editors Jillian Hurst, Corinne Williams Editor at Large Ushma S. Neill ISSN 2380-3029 (print) ISSN 2380-3037 (online) Featured Editor The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly to discuss the manuscripts undergoing review. Dr. Jonathan S. Serody, M.D., Associate Editor, is the Elizabeth Thomas Professor of Medicine at the University of North Carolina at Chapel Hill and the Associate Director for Translational Sciences of the Lineberger Comprehensive Cancer Center. His research focuses on how cellular migration and different T cell subsets affect transplantation and tumor biology. Dr. Serody’s laboratory was the first to describe a role for chemokines in the biology of acute and chronic graft-versus-host disease (GVHD), and this work has led to the development of CCR5 inhibitors to prevent acute GVHD clinically. Currently his laboratory focuses on epigenetic modulation and its role in the adaptive immune response after stem cell transplantation; the role of innate lymphoid cells in the initiation of GVHD; the use of multiphoton laser scanning microscopy in investigating the interaction between donor and host cells in GVHD; the biology of immuno suppressive populations of T cells and myeloid cells and their role in tumor growth and dissemination; and the function of B lymphocytes in the antitumor response. Publication highlights Coghill JM, Fowler KA, West ML, Fulton LM, van Deventer HW, McKinnon KP, Vincent BG, Lin K, Panoskaltsis-Mortari A, Cook DN, Blazar BR, Serody JS. CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease. Blood. 2013;122(5):825–836. Van Deventer HW, Palmieri DA, Wu QP, McCook EP, Serody JS. Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6C + monocytes via CCL2. J Immunol. 2013;190(9):4861–4867. Lin KL, Fulton LM, Berginski M, West ML, Taylor NA, Moran TP, Coghill JM, Blazar BR, Bear JE, Serody JS. Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD. Blood. 2014;123(10):1604–1610. Beginning with this issue, we have changed the title of JCI Impact to JCI This Month, which will continue to provide summaries of the most recent JCI publications and features. It is also available online at jci.org/this-month. The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI. the journal of clinical investigation For the full JCI online, go to jci.me/125/9 or scan the code at left with your mobile device. Contact the JCI The Journal of Clinical Investigation 2015 Manchester Road Ann Arbor, Michigan 48104, USA Phone: 734.222.6050 E-mail: staff@the-jci.org jci.org/this-month september 2015 1 Research articles in the current issue of the JCI AIDS/HIV Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion Zheng Zhang, Liang Cheng, Juanjuan Zhao, Guangming Li, Liguo Zhang, Weiwei Chen, Weiming Nie, Natalia J. Reszka-Blanco, Fu-Sheng Wang, and Lishan Su http://jci.me/82124 HIV-infected colonic mucosa With related Commentary by Xiaohuan Guo and Yang-Xin Fu More, p. 7 Cardiology Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis Xudong Liao, Rongli Zhang, Yuan Lu, Domenick A. Prosdocimo, Panjamaporn Sangwung, Lilei Zhang, Guangjin Zhou, Puneet Anand, Ling Lai, Teresa C. Leone, Hisashi Fujioka, Fang Ye, Mariana G. Rosca, Charles L. Hoppel, P. Christian Schulze, E. Dale Abel, Jonathan S. Stamler, Daniel P. Kelly, and Mukesh K. Jain http://jci.me/79964 Endocrinology Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss Peijian He, Luqing Zhao, Lixin Zhu, Edward J. Weinman, Roberto De Giorgio, Michael Koval, Shanthi Srinivasan, and C. Chris Yun http://jci.me/79552 More, p. 9 NHE3/IRBIT interactions Adipocyte iron regulates leptin and food intake Yan Gao, Zhonggang Li, J. Scott Gabrielsen, Judith A. Simcox, Soh-hyun Lee, Deborah Jones, Bob Cooksey, Gregory Stoddard, William T. Cefalu, and Donald A. McClain http://jci.me/81860 With related Commentary by Nancy C. Andrews More, p. 9 Gastroenterology Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis Colonic mucosa ulcer 2 Nicholas A. Manieri, Madison R. Mack, Molly D. Himmelrich, Daniel L. Worthley, Elaine M. Hanson, Lars Eckmann, Timothy C. Wang, and Thaddeus S. Stappenbeck http://jci.me/81423 the journal of clinical investigation jci.org/this-month september 2015 Research articles in the current issue of the JCI Genetics Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects Venous malformation Elisa Boscolo, Nisha Limaye, Lan Huang, Kyu-Tae Kang, Julie Soblet, Melanie Uebelhoer, Antonella Mendola, Marjut Natynki, Emmanuel Seront, Sophie Dupont, Jennifer Hammer, Catherine Legrand, Carlo Brugnara, Lauri Eklund, Miikka Vikkula, Joyce Bischoff, and Laurence M. Boon http://jci.me/76004 RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome Nina Bögershausen, I-Chun Tsai, Esther Pohl, Pelin Özlem Simsek Kiper, Filippo Beleggia, E. Ferda Percin, Katharina Keupp, Angela Matchan, Esther Milz, Yasemin Alanay, Hülya Kayserili, Yicheng Liu, Siddharth Banka, Andrea Kranz, Martin Zenker, Dagmar Wieczorek, Nursel Elcioglu, Paolo Prontera, Stanislas Lyonnet, Thomas Meitinger, A. Francis Stewart, Dian Donnai, Tim M. Strom, Koray Boduroglu, Gökhan Yigit, Yun Li, Nicholas Katsanis, and Bernd Wollnik http://jci.me/80102 Hematology Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis Femoral bone marrow Fan Liu, Guoyan Cheng, Pierre-Jacques Hamard, Sarah Greenblatt, Lan Wang, Na Man, Fabiana Perna, Haiming Xu, Madhavi Tadi, Luisa Luciani, and Stephen D. Nimer http://jci.me/81749 SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects Sarah J. Fletcher, Ben Johnson, Gillian C. Lowe, Danai Bem, Sian Drake, Marie Lordkipanidzé, Isabel Sánchez Guiú, Ban Dawood, José Rivera, Michael A. Simpson, Martina E. Daly, Jayashree Motwani, Peter W. Collins, Steve P. Watson, and Neil V. Morgan on behalf of the UK Genotyping and Phenotyping of Platelets study group http://jci.me/80347 Hepatology Elevated copper impairs hepatic nuclear receptor function in Wilson’s disease Clavia Ruth Wooton-Kee, Ajay K. Jain, Martin Wagner, Michael A. Grusak, Milton J. Finegold, Svetlana Lutsenko, and David D. Moore http://jci.me/78991 Immunology Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease Holly A. Bolton, Erhua Zhu, Alexandra M. Terry, Thomas V. Guy, Woon-Puay Koh, Sioh-Yang Tan, Carl A. Power, Patrick Bertolino, Katharina Lahl, Tim Sparwasser, Elena Shklovskaya, and Barbara Fazekas de St. Groth http://jci.me/76031 Inflammatory IL-15 is required for optimal memory T cell responses Martin J. Richer, Lecia L. Pewe, Lisa S. Hancox, Stacey M. Hartwig, Steven M. Varga, and John T. Harty http://jci.me/81261 the journal of clinical investigation jci.org/this-month september 2015 3 Research articles in the current issue of the JCI Infectious disease A molecular trigger for intercontinental epidemics of group A Streptococcus Luchang Zhu, Randall J. Olsen, Waleed Nasser, Stephen B. Beres, Jaana Vuopio, Karl G. Kristinsson, Magnus Gottfredsson, Adeline R. Porter, Frank R. DeLeo, and James M. Musser http://jci.me/82478 Group A Streptococcus More, p. 6 Nephrology Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action Ankita Roy, Lama Al-Qusairi, Bridget F. Donnelly, Caroline Ronzaud, Allison L. Marciszyn, Fan Gong, Y.P. Christy Chang, Michael B. Butterworth, Núria M. Pastor-Soler, Kenneth R. Hallows, Olivier Staub, and Arohan R. Subramanya http://jci.me/75245 DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome Gisela G. Slaats, Joshua C. Saldivar, Julien Bacal, Michelle K. Zeman, Andrew C. Kile, Ann Marie Hynes, Shalabh Srivastava, Jekaterina Nazmutdinova, Krista den Ouden, Miriam S. Zagers, Veronica Foletto, Marianne C. Verhaar, Colin Miles, John A. Sayer, Karlene A. Cimprich, and Rachel H. Giles http://jci.me/80657 Neuroscience HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models Amyloid plaque deposition Eva Benito, Hendrik Urbanke, Binu Ramachandran, Jonas Barth, Rashi Halder, Ankit Awasthi, Gaurav Jain, Vincenzo Capece, Susanne Burkhardt, Magdalena Navarro-Sala, Sankari Nagarajan, Anna-Lena Schütz, Steven A. Johnsen, Stefan Bonn, Reinhardt Lührmann, Camin Dean, and André Fischer http://jci.me/79942 Analysis of conditional heterozygous STXBP1 mutations in human neurons Christopher Patzke, Yan Han, Jason Covy, Fei Yi, Stephan Maxeiner, Marius Wernig, and Thomas C. Südhof http://jci.me/78612 Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice Sabah Mozafari, Cecilia Laterza, Delphine Roussel, Corinne Bachelin, Antoine Marteyn, Cyrille Deboux, Gianvito Martino, and Anne Baron-Van Evercooren http://jci.me/80437 More, p. 8 Halting progressive neurodegeneration in advanced retinitis pigmentosa Susanne F. Koch, Yi-Ting Tsai, Jimmy K. Duong, Wen-Hsuan Wu, Chun-Wei Hsu, Wei-Pu Wu, Luis Bonet-Ponce, Chyuan-Sheng Lin, and Stephen H. Tsang http://jci.me/82462 Retinal cones With related Commentary by James B. Hurley and Jennifer R. Chao More, p. 8 The cortical thickness phenotype of individuals with DISC1 translocation resembles schizophrenia Orla M. Doyle, Catherine Bois, Pippa Thomson, Liana Romaniuk, Brandon Whitcher, Steven C.R. Williams, Federico E. Turkheimer, Hreinn Stefansson, Andrew M. McIntosh, Mitul A. Mehta, and Stephen M. Lawrie http://jci.me/82636 4 the journal of clinical investigation jci.org/this-month september 2015 Research articles in the current issue of the JCI Oncology Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth Lymphoma proliferation Coralie Hoareau-Aveilla, Thibaud Valentin, Camille Daugrois, Cathy Quelen, Géraldine Mitou, Samuel Quentin, Jinsong Jia, Salvatore Spicuglia, Pierre Ferrier, Monica Ceccon, Sylvie Giuriato, Carlo Gambacorti-Passerini, Pierre Brousset, Laurence Lamant, and Fabienne Meggetto http://jci.me/78488 Comparative genomics reveals multistep pathogenesis of E2A-PBX1 acute lymphoblastic leukemia Jesús Duque-Afonso, Jue Feng, Florian Scherer, Chiou-Hong Lin, Stephen H.K. Wong, Zhong Wang, Masayuki Iwasaki, and Michael L. Cleary http://jci.me/81158 With related Commentary by Terry J. Fry and Peter D. Aplan More, p. 7 Reproductive biology Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss Rose G. Radin, Sunni L. Mumford, Robert M. Silver, Laurie L. Lesher, Noya Galai, David Faraggi, Jean Wactawski-Wende, Janet M. Townsend, Anne M. Lynch, Hyagriv N. Simhan, Lindsey A. Sjaarda, Neil J. Perkins, Shvetha M. Zarek, Karen C. Schliep, and Enrique F. Schisterman http://jci.me/82357 ADVERTISEMENTS the journal of clinical investigation jci.org/this-month september 2015 5 Research Editor’s picks The emergence of more virulent epidemic strains of group A Streptococcus Group A Streptococcus (GAS) causes a wide array of infections, ranging from mild to serious and even life threatening. GAS infection of the superficial fascia layer beneath the skin results in necrotizing fasciitis, which quickly destroys surrounding muscle, skin, and fat tissue. In this issue of the JCI, James Musser and colleagues sought to understand the precise molecular changes that cause increased virulence in epidemic strains of GAS. Using extensive genome sequence data and RNA sequencing transcriptome analysis, the research team examined allelic variation in epidemic GAS strains compared with pre-epidemic strains. This unbiased approach identified 3 SNPs located within a single tran scriptional unit that encodes 2 secreted toxin virulence factors, NAD+-glycohydrolase and streptolysin O. This variant exhibited marked upregulation of the transcript and functionally was associated with increased resistance to polymorphonuclear leukocyte–mediated killing. The research team also showed that elevated expression of NAD+-glycohydrolase and streptolysin O resulted in greater virulence in a mouse model of necrotizing fasciitis and in a nonhuman primate model of upper respiratory tract infection. Further, they documented similar mutations in an independent serotype of GAS that has caused recent epidemic infections in the United States, Finland, and Iceland. Cumulatively, these studies provide an elegant genetic explanation for the increased bacterial fitness and transmission in epidemic GAS strains. The accompanying image is a false-colored scanning electron micrograph of Streptococcus (orange) interacting with a neutrophil (green). Image credit: Frank DeLeo. A molecular trigger for intercontinental epidemics of group A Streptococcus Luchang Zhu, Randall J. Olsen, Waleed Nasser, Stephen B. Beres, Jaana Vuopio, Karl G. Kristinsson, Magnus Gottfredsson, Adeline R. Porter, Frank R. DeLeo, and James M. Musser http://jci.me/82478 6 the journal of clinical investigation jci.org/this-month september 2015 Research | Editor’s picks aids/hiv HIV-1 infection sensitizes innate lymphoid cells to Fas-mediated apoptosis Group 3 innate lymphoid cells (ILC3s) support survival and expansion of mature B cells and direct immune cell migration into the gut. Because ILC3s are depleted in HIV-1 patients, Zheng Zhang, Liang Cheng, and colleagues used a humanized mouse model to study ILC3s in the setting of persistent HIV-1 infection. They found that, as in humans, ILC3s were depleted in this model and that ILC3 loss was reversed by antiretroviral therapy, depletion of plasmacytoid dendritic cells (pDCs), or blockade of IFN-I or the Fas/FasL pathway. Notably, HIV-1 infection upregulated the expression of Fas on ILC3s in a pDC- and IFN-I–dependent manner. Based on these findings, Zhang, Cheng, and colleagues propose a model in which HIV-1 infection activates pDCs, thereby inducing IFN-I production, which upregulates Fas expression on ILC3s, sensitizing them to FasL-mediated apoptosis (see the accompanying image). In the accompanying Commentary, Xiaohuan Guo and Yang-Xin Fu discuss the role of chronic inflammation in HIV-1 pathogenesis. Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion Zheng Zhang, Liang Cheng, Juanjuan Zhao, Guangming Li, Liguo Zhang, Weiwei Chen, Weiming Nie, Natalia J. Reszka-Blanco, Fu-Sheng Wang, and Lishan Su http://jci.me/82124 Related Commentary The tragic fate of group 3 innate lymphoid cells during HIV-1 infection Xiaohuan Guo and Yang-Xin Fu http://jci.me/83823 oncology Acute lymphoblastic leukemia model elucidates stepwise pathogenesis Acute lymphoblastic leukemia (ALL) primarily results from acquired genomic aberrations. Recent genomic studies have revealed that leukemias are genetically complex, and a three-step model of leukemogenesis has been proposed to account for pathogenesis. To test this model, Jesús Duque-Afonso and colleagues engineered mice that conditionally express E2A-PBX1, a fusion oncogene that is present in 5% to 7% of pediatric ALL cases. Leukemia incidence was dependent on the Cre driver promoter and ranged from 5% to 50%. Activation of E2A-PBX1 in B cell precursors resulted in enhanced self-renewal, impaired differentiation of B cell progenitors, and the acquisition of secondary genomic aberrations, including mutations in JAK/STAT signaling pathway components and spontaneous loss of the transcription factor PAX5. Pax5 haploinsufficiency in E2A-PBX1–expressing mice blocked B cell progenitor differentiation, shortened latency, and increased penetrance of leukemias. In the accompanying Commentary, Terry Fry and Peter Aplan discuss how these studies establish a murine model of B cell precursor ALL. the journal of clinical investigation Comparative genomics reveals multistep pathogenesis of E2A-PBX1 acute lymphoblastic leukemia Jesús Duque-Afonso, Jue Feng, Florian Scherer, Chiou-Hong Lin, Stephen H.K. Wong, Zhong Wang, Masayuki Iwasaki, and Michael L. Cleary http://jci.me/81158 Related Commentary A robust in vivo model for B cell precursor acute lymphoblastic leukemia Terry J. Fry and Peter D. Aplan http://jci.me/83799 jci.org/this-month september 2015 7 Research | Editor’s picks neuroscience Murine induced pluripotent stem cell–derived neural precursors generate functional myelin Neural precursors derived from induced pluripotent stem cells (iPSCs) could potentially serve as an autologous source for cell-based therapeutics. Sabah Mozafari and colleagues compared the behavior of iPSC-derived neural precursors to neural precursors isolated from the CNS both in vitro and in a murine model of adult spinal cord demyelination. They found that iPSC-derived neural precursors differentiated into mature oligodendrocytes and migrated into the demyelinated regions of the adult spinal cord. Importantly, iPSC-derived cells remyelinated host axons (see the accompanying image), restored nodes of Ranvier, and improved conduction velocity as efficiently as CNS-derived neural precursors. These results indicate that patient-specific iPSCs could be used as a personalized source of neural precursor cells for myelin replacement therapy. Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice Sabah Mozafari, Cecilia Laterza, Delphine Roussel, Corinne Bachelin, Antoine Marteyn, Cyrille Deboux, Gianvito Martino, and Anne Baron-Van Evercooren http://jci.me/80437 Too little vs. too late in retinal gene therapy Gene therapy is a promising approach for treating retinal degeneration. However, this strategy is likely to be hampered by insufficient gene transduction efficiency and/or the disease being too advanced at diagnosis (the so-called “point of no return”). Susanne Koch and colleagues developed a mouse model of retinitis pigmentosa (RP) in which the mutant gene, cGMP phosphodiesterase 6b (Pde6b), can be inducibly repaired in all diseased photoreceptor cells. With gene transduction optimized, they were able to determine the therapeutic window for rescue. Gene restoration in these mice halted photoreceptor degeneration at early-, mid-, or late-stage disease (see the accompanying image). These findings indicate that RP is treatable using gene therapy even at advanced disease stages and suggest that efforts in this area should focus on improved gene delivery. 8 In the accompanying Commentary, James Hurley and Jennifer Chao discuss how this study establishes a predictive model for gene therapy response in neurodegenerative diseases. Halting progressive neurodegeneration in advanced retinitis pigmentosa Susanne F. Koch, Yi-Ting Tsai, Jimmy K. Duong, Wen-Hsuan Wu, Chun-Wei Hsu, Wei-Pu Wu, Luis Bonet-Ponce, Chyuan-Sheng Lin, and Stephen H. Tsang http://jci.me/82462 the journal of clinical investigation Related Commentary It’s never too late to save a photoreceptor James B. Hurley and Jennifer R. Chao http://jci.me/83194 jci.org/this-month september 2015 Research | Editor’s picks endocrinology Altered electrolyte transport contributes to diabetes-associated fluid loss Patients with diabetes commonly suffer from gastrointestinal complications, including diarrhea. In this issue, Peijian He and colleagues found that intestinal fluid absorption is decreased in a murine model of streptozotocin-induced diabetes compared with that in WT mice. Proteomic analysis of brush border membrane vesicles from the ilea revealed that the expression of the Na+/H+ exchanger NHE3 and several NHE3 regulators (NHERF1– NHERF3, inositol triphosphate [IP3] receptor-binding protein released with IP3 [IRBIT], and ezrin) was decreased in diabetic mice, and NHE3 expression in the microvilli was decreased in ileal biopsies from patients with type 1 diabetes compared with healthy controls (see the accompanying image). In diabetic mice, NHE3-containing macrocomplexes were disrupted, resulting in decreased NHE3 activity. Insulin treatment restored macrocomplex formation, NHE3 activity, and fluid absorption through a PI3K-mediated pathway. Additionally, oral administration of lysophosphatidic acid increased NHE3 activity and fluid absorption in diabetic mice via an insulin-independent pathway. These studies identify altered electrolyte transport as an underlying cause of diabetes-associated fluid loss. Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss Peijian He, Luqing Zhao, Lixin Zhu, Edward J. Weinman, Roberto De Giorgio, Michael Koval, Shanthi Srinivasan, and C. Chris Yun http://jci.me/79552 Examining the iron/appetite relationship Iron deficiency is associated with appetite loss and can be reversed with iron supplementation; however, the underlying mechanisms are poorly understood. Yan Gao and colleagues examined the effect of iron on leptin, which regulates food intake and energy homeostasis. In both mice and a cohort of humans with metabolic syndrome, serum ferritin levels were inversely correlated with serum leptin, independent of inflammation and BMI. Mice fed a high-iron diet exhibited increased food intake and decreased serum leptin. The effects on leptin were recapitulated in mice with adipocyte-specific deletion of the iron exporter ferroportin. Mechanistically, elevated adipocyte iron levels decrease leptin promoter activity by increasing cAMP response element–binding protein (CREB) occupancy of the leptin promoter. In the accompanying Commentary, Nancy Andrews discusses how these findings raise additional questions about the relationship between iron, leptin, and food intake. Adipocyte iron regulates leptin and food intake Yan Gao, Zhonggang Li, J. Scott Gabrielsen, Judith A. Simcox, Soh-hyun Lee, Deborah Jones, Bob Cooksey, Gregory Stoddard, William T. Cefalu, and Donald A. McClain http://jci.me/81860 Related Commentary Hungry irony Nancy C. Andrews http://jci.me/83193 the journal of clinical investigation jci.org/this-month september 2015 9 Review Series Cancer immunotherapy Series Editor: Yiping Yang Exploring the cancer/immune system relationship From mice to humans: developments in cancer immunoediting Michele W.L. Teng, Jerome Galon, Wolf-Herman Fridman, and Mark J. Smyth Immunity, inflammation, and cancer: an eternal fight between good and evil Shabnam Shalapour and Michael Karin Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected Douglas Marvel and Dmitry I. Gabrilovich Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages Stefano Ugel, Francesco De Sanctis, Susanna Mandruzzato, and Vincenzo Bronte Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade Elizabeth Buchbinder and F. Stephen Hodi Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future Lieping Chen and Xue Han CAR therapy: the CD19 paradigm Michel Sadelain Therapeutic cancer vaccines Cornelis J.M. Melief, Thorbald van Hall, Ramon Arens, Ferry Ossendorp, and Sjoerd H. van der Burg Tumor neoantigens: building a framework for personalized cancer immunotherapy Matthew M. Gubin, Maxim N. Artyomov, Elaine R. Mardis, and Robert D. Schreiber 10 the journal of clinical investigation In the early 1900s, Paul Ehrlich postulated that the immune system both recognizes and protects against cancer. Since then, researchers have been trying to elucidate the relationship between cancer, inflammation, and the innate and adaptive immune systems, starting with the theory of immunosurveillance introduced by Lewis Thomas and Sir MacFarlane Burnet. We now know that tumor cells display antigens that are recognized by immune cells but that tumor cells can circumvent antitumor immunity through a variety of escape mechanisms, including alterations in antigen presentation, recruitment of immunosuppressive immune cells, and expression of negative regulatory signals. The goal of cancer immunotherapy is to mount an effective antitumor immune response by repairing, stimulating, or enhancing the immune system’s response to cancer cells. Reviews in this series detail progress in cancer immunoediting, immunosuppressive cells in the tumor microenvironment, cancer-associated inflammation, therapeutic cancer vaccines, genomic approaches in immunotherapy, adoptive transfer of genetically engineered T cells, and checkpoint blockade therapy. Cancer immunotherapy: harnessing the immune system to battle cancer Yiping Yang http://jci.me/83871 Dr. Yiping Yang is Professor of Medicine and Immunology in the Division of Hematologic Malignancies and Cellular Therapy at Duke University. His research focuses on tumor immunology and viral immunity. He is particularly interested in innate immunity to viruses, T cell memory, and mechanisms for cancer immune evasion. His long-term goal is to understand the molecular and cellular mechanisms leading to the generation of potent and long-lasting antitumor immunity and to develop effective gene immunotherapeutic strategies for treating cancer. jci.org/this-month september 2015 Review Series | Cancer immunotherapy Cancer immunoediting: escaping immune surveillance The immune system recognizes and can eliminate transformed cells; however, cancer cells can alter their immunogenicity in order to evade detection and elimination by the immune system, a process known as immunoediting. Mark Smyth and colleagues review the three phases of cancer immunoediting: elimination, in which cancer cells are destroyed by the immune system; equilibrium, in which the growth of tumor cells that survived the elimination phase is impaired by the immune system; and escape, in which tumor cells circumvent the immune system and become clinically apparent. Additionally, Smyth and colleagues describe the characteristics of adaptive immune resistance in the tumor microenvironment (see the accompanying image) as well as the potential differences in immunoediting between metastases and the tumor of origin. From mice to humans: developments in cancer immunoediting Michele W.L. Teng, Jerome Galon, Wolf-Herman Fridman, and Mark J. Smyth http://jci.me/80004 New developments in therapeutic cancer vaccines The benefits of therapeutic cancer vaccines have been shown in both patients with viral-induced cancers (HPV-associated cervical cancer) and those with nonviral cancers (prostate cancer); however, vaccine-induced gains in survival and the proportion of patients who benefit are small. Cornelius Melief and colleagues review the modes of action of current therapeutic cancer vaccines (see the accompanying image) as well as how these vaccines can be improved. Potential improvements include a better choice of antigens, routes of administration that enhance DC antigen uptake and presentation, and appropriate adjuvants and cotreatments that could help overcome an immunosuppressive tumor microenvironment. The immune system recognizes cancer cells by the expression of mutated or aberrantly expressed antigens. There are three broad classes of tumor antigens: tumor-specific antigens (TSAs), which are not encoded in the normal host genome and arise from either oncogenic virus–associated proteins or somatic mutations (neoantigens); tumor-associated antigens (TAAs), which are overexpressed normal proteins; and cancergermline/cancer testis antigens (CTAs), which are proteins that are normally expressed in testis, fetal ovaries, and trophoblasts, but can also be expressed in cancer cells. While TSAs are typically specific to cancer cells from an individual, TAAs and CTAs are frequently shared between cancers and have previously been the focus of therapeutic cancer vaccines. Robert Schreiber and colleagues discuss how advances in next-generation sequencing and epitope prediction now permit the identification of mutant tumor neoantigens and will allow for the development of personalized cancer immunotherapies. Therapeutic cancer vaccines Cornelius J.M. Melief, Thorbald van Hall, Ramon Arens, Ferry Ossendorp, and Sjoerd H. van der Burg http://jci.me/80009 the journal of clinical investigation Identification of therapeutic tumor neoantigens Tumor neoantigens: building a framework for personalized cancer immunotherapy Matthew M. Gubin, Maxim N. Artyomov, Elaine R. Mardis, and Robert D. Schreiber http://jci.me/80008 jci.org/this-month september 2015 11 Review Series | Cancer immunotherapy An update on cytotoxic T lymphocyte antigen-4–targeted therapies Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade Elizabeth Buchbinder and F. Stephen Hodi http://jci.me/80012 Tumor-induced alterations in myelopoiesis Tumor cells express factors that help to create a tolerogenic microenvironment, partially by altering myelopoiesis. Tumorreprogrammed myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) enhance tumor growth by blocking T cell function and proliferation and also promote cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis. Vincenzo Bronte and colleagues review the common and distinctive characteristics of MDSCs and TAMs and the mechanisms by which these cells are recruited to and influenced by the tumor microenvironment. Additionally, they discuss the role of these cells in maintaining cancer growth and current efforts to develop therapeutics that disrupt the protumor functions of these cells. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages Stefano Ugel, Francesco De Sanctis, Susanna Mandruzzato, and Vincenzo Bronte http://jci.me/80006 12 Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule that suppresses T cell effector function. CTLA-4–targeted monoclonal antibodies have been shown to increase T cell function and antitumor immune responses in patients with advanced melanoma and are now being explored in the treatment of other solid tumors. In this issue, Elizabeth Buchbinder and Stephen Hodi detail the molecular mechanisms underlying anti–CTLA-4 therapy (see the accompanying image). They also review pivotal clinical trials of anti–CTLA-4 therapy and discuss therapeutic response patterns, patient selection guidelines, and common toxicities. Last, they discuss recent clinical trials of combination therapies, including anti–CTLA-4 therapy with kinase inhibitors, immune modulators, and radiation therapy. Factoring in cancer-associated inflammation Chronic inflammation is a critical driver of tumor development, progression, and metastasis. While acute inflammation frequently stimulates dendritic cell maturation and antigen presentation, driving the immune response, chronic inflammation is often immunosuppressive. Shabnam Shalapour and Michael Karin discuss how innate and adaptive immune cells control tumor progression and therapeutic responses. Tumorassociated inflammation triggers immunosuppressive mechanisms mediated by both innate immune cells (tumor-associated macrophages and neutrophils, and myeloid-derived suppressor cells) and adaptive immune cells (NK, NKT, γδ T, CD4+ T, and CD8+ T cells). Factors and cells within the tumor microenvironment, including cancer-associated fibroblasts, can tune the functions of these immune cells. These interactions must be taken into account in the design of immune-targeted cancer therapeutics. Immunity, inflammation, and cancer: an eternal fight between good and evil Shabnam Shalapour and Michael Karin http://jci.me/80007 The role of myeloid-derived suppressor cells in cancer Myeloid-derived suppressor cells (MDSCs) are a group of pathologically activated, immature immune cells with potent immunosuppressive activity. Douglas Marvel and Dmitry Gabrilovich review recent progress in defining these cells and their role in the regulation of tumor development and progression. MDSCs support tumor growth and promote metastasis by protecting tumor cells from immune-mediated killing, remodel the tumor microenvironment, establish the premetastatic niche, and interact with tumor cells to promote stemness and facilitate the epithelial-to-mesenchymal transition. Additionally, Marvel and Gabrilovich detail studies of MDSCs as biomarkers of tumor progression and response to therapy and discuss potential strategies to therapeutically target MDSCs in the tumor microenvironment (see the accompanying image). Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected Douglas Marvel and Dmitry I. Gabrilovich http://jci.me/80005 the journal of clinical investigation jci.org/this-month september 2015 Review Series | Cancer immunotherapy Targeting the programmed death-1 pathway to combat cancer Programmed cell death-1 (PD-1) is a cell surface receptor that prevents T cell activation. PD-1 is abundantly expressed in a variety of human cancers, helping tumor cells to avoid T cell–mediated destruction. Monoclonal antibodies targeting PD-1 are currently used to treat human cancer, and other therapeutic modalities that target this pathway are in development. In this issue, Lieping Chen and Xue Han review the history and development of anti-PD pathway therapy, including the initial preclinical work and recent clinical trials. They identify three basic principles that define anti-PD pathway therapy: (a) tumor site immune modulation, (b) targeting of tumor-induced immune defects, and (c) repair of ongoing antitumor immunity. These principles will help guide the development of new cancer immunotherapy approaches and help identify the patients who are most likely to benefit from anti-PD pathway therapy. Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future Lieping Chen and Xue Han http://jci.me/80011 The evolution of genetically engineered T cells T cell recognition of and response to diseased cells is mediated by the T cell receptor (TCR). Tumor antigen–specific T cells must be activated and expanded, and must also be able to localize to disease sites, overcome immunosuppressive mechanisms, and deliver their payload of cytokines and lytic compounds. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T cell activation, and costimulation to augment T cell functionality and persistence. Michel Sadelain details the evolution of genetically engineered T cells and discusses how adoptive cell transfer of CAR T cells is currently being used in the clinic (see the accompanying image). CAR therapy: the CD19 paradigm Michel Sadelain http://jci.me/80010 conversations with giants in medicine Rudolf Jaenisch In this month’s issue, Editor-at-Large Ushma Neill interviews Rudolf Jaenisch of MIT’s Whitehead Institute. Dr. Jaenisch created the first transgenic mice and conducted the first experiment demonstrating that therapeutic cloning could correct a genetic defect. Additionally, Jaenisch has been at the forefront of research on induced pluripotent stem cells and has shown that these cells can correct sickle cell anemia and Parkinson disease in rodents. In this interview, Jaenisch discusses his work as a postdoctoral fellow in Arnold Levine’s lab studying DNA replication with the tumor virus SV40, which led to his collaboration with developmental geneticist Beatrice Mintz. Additionally, Jaenisch discusses adoption of new methods and technologies to address interesting questions in genetics as well as the application of these technologies to humans. http://jci.me/82629 the journal of clinical investigation jci.org/this-month september 2015 13 The Journal of Clinical Investigation jci.org Submit your work to the JCI The JCI welcomes submissions in the following categories: Research: Substantial new mechanistic insights into biology and disease. Sample article: Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy Claudia Bang, Sandor Batkai, Seema Dangwal, Shashi Kumar Gupta, Ariana Foinquinos, Angelika Holzmann, Annette Just, Janet Remke, Karina Zimmer, Andre Zeug, Evgeni Ponimaskin, Andreas Schmiedl, Xiaoke Yin, Manuel Mayr, Rashi Halder, Andre Fischer, Stefan Engelhardt, Yuanyuan Wei, Andreas Schober, Jan Fiedler, and Thomas Thum Published April 2014 http://jci.me/70577 Times cited: 51 Clinical medicine: Research that reports early-stage, effective new therapies that impact disease outcomes in patients. Technical advance: New and important research tools and techniques with the potential for broad impact. Sample article: Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients Ele Ferrannini, Elza Muscelli, Silvia Frascerra, Simona Baldi, Andrea Mari, Tim Heise, Uli C. Broedl, and Hans-Juergen Woerle Published January 2014 http://jci.me/72227 Times cited: 46 Sample article: Optogenetic stimulation of the auditory pathway Victor H. Hernandez, Anna Gehrt, Kirsten Reuter, Zhizi Jing, Marcus Jeschke, Alejandro Mendoza Schulz, Gerhard Hoch, Matthias Bartels, Gerhard Vogt, Carolyn W. Garnham, Hiromu Yawo, Yugo Fukazawa, George J. Augustine, Ernst Bamberg, Sebastian Kügler, Tim Salditt, Livia de Hoz, Nicola Strenzke, and Tobias Moser Published February 2014 http://jci.me/69050 Times cited: 11 Brief report: Discrete, highly significant findings in a short format. Sample article: T cell repertoire following autologous stem cell transplantation for multiple sclerosis Paolo A. Muraro, Harlan Robins, Sachin Malhotra, Michael Howell, Deborah Phippard, Cindy Desmarais, Alessandra de Paula Alves Sousa, Linda M. Griffith, Noha Lim, Richard A. Nash, and Laurence A. Turka Published February 2014 http://jci.me/71691 Times cited: 19 More information: http://jci.me/aqcqs or editors@the-jci.org Citation information is from Web of Science and Scopus as of July 2015.
