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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.
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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
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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,
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Published April 2014 http://jci.me/70577 Times cited: 51
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Sample article: T cell repertoire following autologous stem cell transplantation
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Paolo A. Muraro, Harlan Robins, Sachin Malhotra, Michael Howell, Deborah Phippard, Cindy Desmarais,
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