Volume 24 Issue 7, July 2018

Volume 24 Issue 7

The premalignant mutational landscape of AML

Studying a cohort of women who were healthy at study baseline but eventually developed acute myeloid leukemia (AML) during follow-up, Pinkal Desai and colleagues(p1015) find that specific somatic mutations impacting the risk of developing disease can be detected years before the clinical diagnosis. Benjamin Ebert discusses the implications of this study and a related manuscript in Nature by Liran Shlush and colleagues in a News & Views(p904). The cover depicts a conceptual representation of the passage of time and transformation of normal cells into leukemia.

See Desai et al. and News & Views by Ebert

Image: cybrain / iStock / Getty Images Plus. Cover Design: Erin Dewalt.

Editorial

News Feature

  • News Feature |

    Nationwide trials pair children with targeted cancer therapies.

    • Shraddha Chakradhar
  • News Feature |

    First-of-its-kind US trial hopes to bring hospital treatment to the home.

    • Shraddha Chakradhar

Correspondence

Q&A

  • Q&A |

    The pathological hallmarks of Alzheimer’s disease (AD) include extracellular beta-amyloid plaques, neurofibrillary tangles, neuronal loss and tau deposits in brain. Therapies targeting these known hallmarks are yet to yield any meaningful benefit in clinical trials. We spoke to four researchers in the fields of AD research and therapy development to find out where they think the fields should head next.

    • Hannah Stower

Research Highlights

News & Views

  • News & Views |

    Signaling by the tumor-suppressor protein p53 antagonizes CRISPR–Cas9 gene editing of human pluripotent stem cells and immortalized human retinal pigment epithelial cells.

    • Fyodor D. Urnov

    Collection:

  • News & Views |

    A glucagon-like peptide receptor 1 (GLP-1R) agonist inhibits the conversion of astrocytes into a neurotoxic phenotype and protects against neurodegeneration, shedding light on the pathogenesis of Parkinson’s disease.

    • Lena Brundin
    • , Liza Bergkvist
    •  & Patrik Brundin
  • News & Views |

    Studies in KRAS-mutant lung and pancreatic adenocarcinoma and in KRAS-amplified gastric carcinoma reveal that SHP2 inhibition augments the antitumor effect of MEK inhibitor treatment.

    • Trang T. Mai
    •  & Piro Lito
  • News & Views |

    The number, identity, and burden of mutations in clonal hematopoiesis are associated with the risk and timing of progression to acute myeloid leukemia.

    • Rob S. Sellar
    • , Siddhartha Jaiswal
    •  & Benjamin L. Ebert
  • News & Views |

    An integrative multiomics approach in nondiabetic obese women identifies phenylacetate as a microbial metabolite contributing to the accumulation of lipids in the liver and hence to nonalcoholic steatohepatitis.

    • Nathalie M. Delzenne
    •  & Laure B. Bindels

Review Articles

  • Review Article |

    Understanding of pathogenic mechanisms and clinical features of NAFLD is driving progress in therapeutic strategies now in clinical trials.

    • Scott L. Friedman
    • , Brent A. Neuschwander-Tetri
    • , Mary Rinella
    •  & Arun J. Sanyal

Brief Communications

  • Brief Communication |

    Initiation of antiretroviral therapy in the first 2 weeks of HIV infection fails to prevent resurgence of virus after stopping treatment, indicating early establishment of a resilient viral reservoir.

    • Donn J. Colby
    • , Lydie Trautmann
    • , Suteeraporn Pinyakorn
    • , Louise Leyre
    • , Amélie Pagliuzza
    • , Eugène Kroon
    • , Morgane Rolland
    • , Hiroshi Takata
    • , Supranee Buranapraditkun
    • , Jintana Intasan
    • , Nitiya Chomchey
    • , Roshell Muir
    • , Elias K. Haddad
    • , Sodsai Tovanabutra
    • , Sasiwimol Ubolyam
    • , Diane L. Bolton
    • , Brandie A. Fullmer
    • , Robert J. Gorelick
    • , Lawrence Fox
    • , Trevor A. Crowell
    • , Rapee Trichavaroj
    • , Robert O’Connell
    • , Nicolas Chomont
    • , Jerome H. Kim
    • , Nelson L. Michael
    • , Merlin L. Robb
    • , Nittaya Phanuphak
    • , Jintanat Ananworanich
    • , P. Phanuphak
    • , N. Teeratakulpisarn
    • , S. Chottanapund
    • , M. de Souza
    • , J. Fletcher
    • , P. Tantivitayakul
    • , P. Eamyoung
    • , D. Sutthichom
    • , P. Prueksakaew
    • , S. Puttamaswin
    • , S. Tipsuk
    • , K. Benjapornpong
    • , N. Ratnaratorn
    • , C. Munkong
    • , K. Tanjnareel
    • , R. Kanaprach
    • , R. Rerknimitr
    • , P. Wattanaboonyongcharoen
    • , P. Rojnuckarin
    • , S. Manasnayakorn
    • , A. Schuetz
    • , S. Akapirat
    • , B. Nuntapinit
    • , N. Tantibul
    • , H. Savadsuk
    • , Y. Phuang-Ngern
    • , S. Jongrakthaitae
    • , W. Chuenaron
    • , N. Churikanont
    • , S. Getchalarat
    • , S. Krebs
    • , B. Slike
    • , A. Tokarev
    • , E. Sanders-Buell
    • , M. Bose
    • , C. Ogega
    • , J. Buahen
    • , M. Ouellette
    • , C. McCullough
    • , O. Butterworth
    • , E. Turk
    • , L. A. Eller
    • , M. Milazzo
    • , J. Mitchell
    • , C. Subra
    • , N. Lima
    • , J. Garnett
    • , F. Fatmi
    • , A. Sy
    • , N. Dawson
    • , S. Spudich
    • , V. Valcour
    • , F. Maldarelli
    • , I. Sereti
    • , J. Lifson
    • , R. Paul
    • , R. Fromentin
    •  & P. Dawson

Letters

  • Letter |

    Agonism of microglial glucagon-like peptide-1 receptor (GLP1R) using a brain-penetrant peptide prevents the generation of neurotoxic astrocytes and ameliorates disease progression in two rodent models of Parkinson’s disease.

    • Seung Pil Yun
    • , Tae-In Kam
    • , Nikhil Panicker
    • , SangMin Kim
    • , Yumin Oh
    • , Jong-Sung Park
    • , Seung-Hwan Kwon
    • , Yong Joo Park
    • , Senthilkumar S. Karuppagounder
    • , Hyejin Park
    • , Sangjune Kim
    • , Nayeon Oh
    • , Nayoung Alice Kim
    • , Saebom Lee
    • , Saurav Brahmachari
    • , Xiaobo Mao
    • , Jun Hee Lee
    • , Manoj Kumar
    • , Daniel An
    • , Sung-Ung Kang
    • , Yunjong Lee
    • , Kang Choon Lee
    • , Dong Hee Na
    • , Donghoon Kim
    • , Sang Hun Lee
    • , Viktor V. Roschke
    • , Shane A. Liddelow
    • , Zoltan Mari
    • , Ben A. Barres
    • , Valina L. Dawson
    • , Seulki Lee
    • , Ted M. Dawson
    •  & Han Seok Ko
  • Letter |

    CRISPR–Cas9-induced DNA damage triggers p53 to limit the efficiency of gene editing in human pluripotent cells.

    • Robert J. Ihry
    • , Kathleen A. Worringer
    • , Max R. Salick
    • , Elizabeth Frias
    • , Daniel Ho
    • , Kraig Theriault
    • , Sravya Kommineni
    • , Julie Chen
    • , Marie Sondey
    • , Chaoyang Ye
    • , Ranjit Randhawa
    • , Tripti Kulkarni
    • , Zinger Yang
    • , Gregory McAllister
    • , Carsten Russ
    • , John Reece-Hoyes
    • , William Forrester
    • , Gregory R. Hoffman
    • , Ricardo Dolmetsch
    •  & Ajamete Kaykas

    Collection:

  • Letter |

    In vivo shRNA screens in sensitized genetic backgrounds identify p53-activated target genes involved in DNA repair that enable its tumor suppressor function.

    • Ana Janic
    • , Liz J. Valente
    • , Matthew J. Wakefield
    • , Leon Di Stefano
    • , Liz Milla
    • , Stephen Wilcox
    • , Haoyu Yang
    • , Lin Tai
    • , Cassandra J. Vandenberg
    • , Andrew J. Kueh
    • , Shinsuke Mizutani
    • , Margs S. Brennan
    • , Robyn L. Schenk
    • , Lisa M. Lindqvist
    • , Anthony T. Papenfuss
    • , Liam O’Connor
    • , Andreas Strasser
    •  & Marco J. Herold
  • Letter |

    The phosphatase SHP2 is required for mutant KRAS signaling in pancreatic and non-small-cell lung cancers and drives resistance to MEK inhibition.

    • Dietrich A. Ruess
    • , Guus J. Heynen
    • , Katrin J. Ciecielski
    • , Jiaoyu Ai
    • , Alexandra Berninger
    • , Derya Kabacaoglu
    • , Kivanc Görgülü
    • , Zahra Dantes
    • , Sonja M. Wörmann
    • , Kalliope N. Diakopoulos
    • , Angeliki F. Karpathaki
    • , Marlena Kowalska
    • , Ezgi Kaya-Aksoy
    • , Liang Song
    • , Eveline A. Zeeuw van der Laan
    • , María P. López-Alberca
    • , Marc Nazaré
    • , Maximilian Reichert
    • , Dieter Saur
    • , Mert M. Erkan
    • , Ulrich T. Hopt
    • , Bruno Sainz Jr
    • , Walter Birchmeier
    • , Roland M. Schmid
    • , Marina Lesina
    •  & Hana Algül
  • Letter |

    Combined inhibition of SHP2 and MEK is an effective therapeutic approach in non-small-cell lung cancer.

    • Sara Mainardi
    • , Antonio Mulero-Sánchez
    • , Anirudh Prahallad
    • , Giovanni Germano
    • , Astrid Bosma
    • , Paul Krimpenfort
    • , Cor Lieftink
    • , Jeffrey D. Steinberg
    • , Niels de Wit
    • , Samuel Gonçalves-Ribeiro
    • , Ernest Nadal
    • , Alberto Bardelli
    • , Alberto Villanueva
    •  & Rene Bernards
  • Letter |

    Amplification of wild-type KRAS in a subset of gastroesophageal tumors drives intrinsic resistance to MAPK inhibition that can be overcome by combined targeting of MEK and SHP2.

    • Gabrielle S. Wong
    • , Jin Zhou
    • , Jie Bin Liu
    • , Zhong Wu
    • , Xinsen Xu
    • , Tianxia Li
    • , David Xu
    • , Steven E. Schumacher
    • , Jens Puschhof
    • , James McFarland
    • , Charles Zou
    • , Austin Dulak
    • , Les Henderson
    • , Peng Xu
    • , Emily O’Day
    • , Rachel Rendak
    • , Wei-li Liao
    • , Fabiola Cecchi
    • , Todd Hembrough
    • , Sarit Schwartz
    • , Christopher Szeto
    • , Anil K. Rustgi
    • , Kwok-Kin Wong
    • , J. Alan Diehl
    • , Karin Jensen
    • , Francesco Graziano
    • , Annamaria Ruzzo
    • , Shaunt Fereshetian
    • , Philipp Mertins
    • , Steven A. Carr
    • , Rameen Beroukhim
    • , Kenichi Nakamura
    • , Eiji Oki
    • , Masayuki Watanabe
    • , Hideo Baba
    • , Yu Imamura
    • , Daniel Catenacci
    •  & Adam J. Bass
  • Letter |

    Deep single-cell RNA sequencing of tumor-infiltrating T cells in non-small-cell lung cancer identifies features associated with functional states and clinical outcome

    • Xinyi Guo
    • , Yuanyuan Zhang
    • , Liangtao Zheng
    • , Chunhong Zheng
    • , Jintao Song
    • , Qiming Zhang
    • , Boxi Kang
    • , Zhouzerui Liu
    • , Liang Jin
    • , Rui Xing
    • , Ranran Gao
    • , Lei Zhang
    • , Minghui Dong
    • , Xueda Hu
    • , Xianwen Ren
    • , Dennis Kirchhoff
    • , Helge Gottfried Roider
    • , Tiansheng Yan
    •  & Zemin Zhang
  • Letter |

    Extensive, high-dimensional characterization of T cells in breast cancer reveals activated TRM population and a gene signature associated with improved prognosis.

    • Peter Savas
    • , Balaji Virassamy
    • , Chengzhong Ye
    • , Agus Salim
    • , Christopher P. Mintoff
    • , Franco Caramia
    • , Roberto Salgado
    • , David J. Byrne
    • , Zhi L. Teo
    • , Sathana Dushyanthen
    • , Ann Byrne
    • , Lironne Wein
    • , Stephen J. Luen
    • , Catherine Poliness
    • , Sophie S. Nightingale
    • , Anita S. Skandarajah
    • , David E. Gyorki
    • , Chantel M. Thornton
    • , Paul A. Beavis
    • , Stephen B. Fox
    • , Phillip K. Darcy
    • , Terence P. Speed
    • , Laura K. Mackay
    • , Paul J. Neeson
    •  & Sherene Loi

Articles

  • Article |

    Tumor-infiltrating CD8+ T cells with high expression of PD-1 in non-small-cell lung cancer are distinct from exhausted T cells in chronic virus infection, have high tumor reactivity and associate with response to PD-1-targeted immunotherapy.

    • Daniela S. Thommen
    • , Viktor H. Koelzer
    • , Petra Herzig
    • , Andreas Roller
    • , Marcel Trefny
    • , Sarah Dimeloe
    • , Anna Kiialainen
    • , Jonathan Hanhart
    • , Catherine Schill
    • , Christoph Hess
    • , Spasenija Savic Prince
    • , Mark Wiese
    • , Didier Lardinois
    • , Ping-Chih Ho
    • , Christian Klein
    • , Vaios Karanikas
    • , Kirsten D. Mertz
    • , Ton N. Schumacher
    •  & Alfred Zippelius
  • Article |

    A human anti-IL-2 antibody that selectively expands regulatory T cells is developed in this study for clinical applications aiming to mitigate autoimmune and inflammatory disorders and to promote transplant tolerance.

    • Eleonora Trotta
    • , Paul H. Bessette
    • , Stephanie L. Silveria
    • , Lauren K. Ely
    • , Kevin M. Jude
    • , Duy T. Le
    • , Charles R. Holst
    • , Anthony Coyle
    • , Marc Potempa
    • , Lewis L. Lanier
    • , K. Christopher Garcia
    • , Natasha K. Crellin
    • , Isaac J. Rondon
    •  & Jeffrey A. Bluestone
  • Article |

    Reactive astrocytes expressing STAT3 support the metastatic growth of tumor cells colonizing the brain and can be pharmacologically targeted to improve the clinical management of patients with secondary brain tumors.

    • Neibla Priego
    • , Lucía Zhu
    • , Cátia Monteiro
    • , Manon Mulders
    • , David Wasilewski
    • , Wendy Bindeman
    • , Laura Doglio
    • , Liliana Martínez
    • , Elena Martínez-Saez
    • , Santiago Ramón y Cajal
    • , Diego Megías
    • , Elena Hernández-Encinas
    • , Carmen Blanco-Aparicio
    • , Lola Martínez
    • , Eduardo Zarzuela
    • , Javier Muñoz
    • , Coral Fustero-Torre
    • , Elena Piñeiro-Yáñez
    • , Aurelio Hernández-Laín
    • , Luca Bertero
    • , Valeria Poli
    • , Melchor Sanchez-Martinez
    • , Javier A. Menendez
    • , Riccardo Soffietti
    • , Joaquim Bosch-Barrera
    •  & Manuel Valiente
  • Article |

    A new inhibitor targeting the mitochondrial complex I shows antitumor activity in preclinical models of acute myeloid leukemia and glioblastoma relying on oxidative phosphorylation.

    • Jennifer R. Molina
    • , Yuting Sun
    • , Marina Protopopova
    • , Sonal Gera
    • , Madhavi Bandi
    • , Christopher Bristow
    • , Timothy McAfoos
    • , Pietro Morlacchi
    • , Jeffrey Ackroyd
    • , Ahmed-Noor A. Agip
    • , Gheath Al-Atrash
    • , John Asara
    • , Jennifer Bardenhagen
    • , Caroline C. Carrillo
    • , Christopher Carroll
    • , Edward Chang
    • , Stefan Ciurea
    • , Jason B. Cross
    • , Barbara Czako
    • , Angela Deem
    • , Naval Daver
    • , John Frederick de Groot
    • , Jian-Wen Dong
    • , Ningping Feng
    • , Guang Gao
    • , Jason Gay
    • , Mary Geck Do
    • , Jennifer Greer
    • , Virginia Giuliani
    • , Jing Han
    • , Lina Han
    • , Verlene K. Henry
    • , Judy Hirst
    • , Sha Huang
    • , Yongying Jiang
    • , Zhijun Kang
    • , Tin Khor
    • , Sergej Konoplev
    • , Yu-Hsi Lin
    • , Gang Liu
    • , Alessia Lodi
    • , Timothy Lofton
    • , Helen Ma
    • , Mikhila Mahendra
    • , Polina Matre
    • , Robert Mullinax
    • , Michael Peoples
    • , Alessia Petrocchi
    • , Jaime Rodriguez-Canale
    • , Riccardo Serreli
    • , Thomas Shi
    • , Melinda Smith
    • , Yoko Tabe
    • , Jay Theroff
    • , Stefano Tiziani
    • , Quanyun Xu
    • , Qi Zhang
    • , Florian Muller
    • , Ronald A. DePinho
    • , Carlo Toniatti
    • , Giulio F. Draetta
    • , Timothy P. Heffernan
    • , Marina Konopleva
    • , Philip Jones
    • , M. Emilia Di Francesco
    •  & Joseph R. Marszalek
  • Article |

    SMARCA4 loss in non-small-cell lung cancer creates a metabolic dependency on oxidative phosphorylation that can be targeted using a new small-molecule inhibitor.

    • Yonathan Lissanu Deribe
    • , Yuting Sun
    • , Christopher Terranova
    • , Fatima Khan
    • , Juan Martinez-Ledesma
    • , Jason Gay
    • , Guang Gao
    • , Robert A. Mullinax
    • , Tin Khor
    • , Ningping Feng
    • , Yu-Hsi Lin
    • , Chia-Chin Wu
    • , Claudia Reyes
    • , Qian Peng
    • , Frederick Robinson
    • , Akira Inoue
    • , Veena Kochat
    • , Chang-Gong Liu
    • , John M. Asara
    • , Cesar Moran
    • , Florian Muller
    • , Jing Wang
    • , Bingliang Fang
    • , Vali Papadimitrakopoulou
    • , Ignacio I. Wistuba
    • , Kunal Rai
    • , Joseph Marszalek
    •  & P. Andrew Futreal
  • Article |

    Follistatin acts as a hepatokine to induce insulin resistance and can be targeted to improve diabetes in mice.

    • Rongya Tao
    • , Caixia Wang
    • , Oliver Stöhr
    • , Wei Qiu
    • , Yue Hu
    • , Ji Miao
    • , X. Charlie Dong
    • , Sining Leng
    • , Margaret Stefater
    • , Nicholas Stylopoulos
    • , Lin Lin
    • , Kyle D. Copps
    •  & Morris F. White
  • Article |

    Metabolic activity of specific human gut microorganisms contributes to liver steatosis in obese women.

    • Lesley Hoyles
    • , José-Manuel Fernández-Real
    • , Massimo Federici
    • , Matteo Serino
    • , James Abbott
    • , Julie Charpentier
    • , Christophe Heymes
    • , Jèssica Latorre Luque
    • , Elodie Anthony
    • , Richard H. Barton
    • , Julien Chilloux
    • , Antonis Myridakis
    • , Laura Martinez-Gili
    • , José Maria Moreno-Navarrete
    • , Fadila Benhamed
    • , Vincent Azalbert
    • , Vincent Blasco-Baque
    • , Josep Puig
    • , Gemma Xifra
    • , Wifredo Ricart
    • , Christopher Tomlinson
    • , Mark Woodbridge
    • , Marina Cardellini
    • , Francesca Davato
    • , Iris Cardolini
    • , Ottavia Porzio
    • , Paolo Gentileschi
    • , Frédéric Lopez
    • , Fabienne Foufelle
    • , Sarah A. Butcher
    • , Elaine Holmes
    • , Jeremy K. Nicholson
    • , Catherine Postic
    • , Rémy Burcelin
    •  & Marc-Emmanuel Dumas