Browse Articles

  • Letter |

    The N6-methyladenosine (m6A) modification in mRNAs, generated by the enzyme METTL3, controls normal human hematopoietic stem/progenitor cell differentiation and maintains the undifferentiated leukemic phenotype of human acute myeloid leukemia cells.

    • Ly P Vu
    • , Brian F Pickering
    • , Yuanming Cheng
    • , Sara Zaccara
    • , Diu Nguyen
    • , Gerard Minuesa
    • , Timothy Chou
    • , Arthur Chow
    • , Yogesh Saletore
    • , Matthew MacKay
    • , Jessica Schulman
    • , Christopher Famulare
    • , Minal Patel
    • , Virginia M Klimek
    • , Francine E Garrett-Bakelman
    • , Ari Melnick
    • , Martin Carroll
    • , Christopher E Mason
    • , Samie R Jaffrey
    •  & Michael G Kharas
  • Article |

    A silent single-nucleotide variant (SNV) affecting the transcription of a long noncoding RNA (lncRNA EGFR-AS1) within the EGFR coding region alters the EGFR isoform ratio and modulates oncogene addiction and response to EGFR tyrosine kinase inhibitors in squamous-cell cancers. Proof-of-concept validation in patients supports the notion that this SNV and levels of the lncRNA could be used to predict response to therapy in a clinical setting. These results, together with findings by Bal et al., uncover the functional role of noncoding RNAs in modulating the response to targeted therapies in cancer.

    • Daniel S W Tan
    • , Fui Teen Chong
    • , Hui Sun Leong
    • , Shen Yon Toh
    • , Dawn P Lau
    • , Xue Lin Kwang
    • , Xiaoqian Zhang
    • , Gopinath M Sundaram
    • , Gek San Tan
    • , Mei Mei Chang
    • , Boon Tin Chua
    • , Wan Teck Lim
    • , Eng Huat Tan
    • , Mei Kim Ang
    • , Tony K H Lim
    • , Prabha Sampath
    • , Balram Chowbay
    • , Anders J Skanderup
    • , Ramanuj DasGupta
    •  & N Gopalakrishna Iyer
  • Article |

    Factors secreted by metastatic a primary tumors induce an early phenotypic switch in perivascular cells at distant pre-metastatic niches. By using sophisticated lineage-tracing mouse models, the authors demonstrate that enhanced KLF4 expression in these cells increases their ability to proliferate and migrate away from the vasculature, and augments fibronectin deposition, which contributes to metastatic growth. These findings increase the mechanistic understanding of the metastatic process and uncover a role for perivascular plasticity that could be targeted to prevent metastasis.

    • Meera Murgai
    • , Wei Ju
    • , Matthew Eason
    • , Jessica Kline
    • , Daniel W Beury
    • , Sabina Kaczanowska
    • , Markku M Miettinen
    • , Michael Kruhlak
    • , Haiyan Lei
    • , Jack F Shern
    • , Olga A Cherepanova
    • , Gary K Owens
    •  & Rosandra N Kaplan
  • Letter |

    Treatment with tyrosine kinase inhibitors results in a survival benefit in patients with chronic myeloid leukemia (CML). However, relapse due to persistent leukemic stem cells (LSCs) requires additional selective targets for efficient eradication of the disease. Metabolomic analyses on patient-derived CML LSCs reveal that these have an increased dependency on oxidative metabolism that renders them sensitive to treatment with tigecycline, an FDA-approved inhibitor of mitochondrial translation. These findings uncover a new metabolic vulnerability in CML and provide a rational approach for further clinical evaluation.

    • Elodie M Kuntz
    • , Pablo Baquero
    • , Alison M Michie
    • , Karen Dunn
    • , Saverio Tardito
    • , Tessa L Holyoake
    • , G Vignir Helgason
    •  & Eyal Gottlieb
  • Letter |

    John Harty and colleagues report that, in mouse models of malaria, regulatory T cells expand, as in humans, and inhibit conventional T cells and germinal center B cells, thereby impairing protective responses against blood-stage disease. Timed blockade of the inhibitory receptor CTLA-4 cured infection in mice and promoted cross-protective blood-stage immunity against a different Plasmodium species.

    • Samarchith P Kurup
    • , Nyamekye Obeng-Adjei
    • , Scott M Anthony
    • , Boubacar Traore
    • , Ogobara K Doumbo
    • , Noah S Butler
    • , Peter D Crompton
    •  & John T Harty
  • Article |

    Simultaneous activation of Wnt and Shh pathways in murine neural precursor cells results in the formation of embryonal tumors with multilayered rosettes (ETMR) that recapitulate the histological and molecular features of human tumors. This novel mouse model represents a platform for evaluating therapeutic approaches for this rare malignant pediatric brain tumor, and provides novel insights into the cell of origin and molecular mechanisms driving the disease.

    • Julia E Neumann
    • , Annika K Wefers
    • , Sander Lambo
    • , Edoardo Bianchi
    • , Marie Bockstaller
    • , Mario M Dorostkar
    • , Valerie Meister
    • , Pia Schindler
    • , Andrey Korshunov
    • , Katja von Hoff
    • , Johannes Nowak
    • , Monika Warmuth-Metz
    • , Marlon R Schneider
    • , Ingrid Renner-Müller
    • , Daniel J Merk
    • , Mehdi Shakarami
    • , Tanvi Sharma
    • , Lukas Chavez
    • , Rainer Glass
    • , Jennifer A Chan
    • , M Mark Taketo
    • , Philipp Neumann
    • , Marcel Kool
    •  & Ulrich Schüller
  • News and Views |

    A recent study reveals sexually dimorphic disease-associated gene-expression modules and hub genes in postmortem brains from female and male individuals with depression. These modules are conserved in mouse models of depression.

    • Ronald S Duman
  • Review |

    In this Review, Salter and Stevens discuss the role of microglia in CNS disorders such as autism, neurodegenerative disorders, Alzheimer’s disease, and chronic pain.

    • Michael W Salter
    •  & Beth Stevens
  • Editorial |

    Drugs administered to children with cancer were typically developed under the assumption that childhood cancers are similar to their tissue-matched adult counterparts. Focusing on identifying and targeting alterations present specifically in childhood tumors will accelerate the development of tailored therapies and improve the prognosis of children with cancer.

  • News and Views |

    Cancer-associated mutations in speckle-type POZ (pox virus and zinc-finger) protein confer neomorphic activity, altering its substrate affinities and its response to bromodomain and extraterminal inhibitors in prostate and endometrial cancer.

    • Katie A Fennell
    •  & Mark A Dawson
  • Brief Communication |

    Thomas Geisbert and colleagues show that a cocktail of monoclonal antibodies protects cynomolgus monkeys from lethal Lassa fever virus infection, including when administration is delayed by more than a week after viral challenge.

    • Chad E Mire
    • , Robert W Cross
    • , Joan B Geisbert
    • , Viktoriya Borisevich
    • , Krystle N Agans
    • , Daniel J Deer
    • , Megan L Heinrich
    • , Megan M Rowland
    • , Augustine Goba
    • , Mambu Momoh
    • , Mathew L Boisen
    • , Donald S Grant
    • , Mohamed Fullah
    • , Sheik Humarr Khan
    • , Karla A Fenton
    • , James E Robinson
    • , Luis M Branco
    • , Robert F Garry
    •  & Thomas W Geisbert
  • Letter |

    Inactivating mutations in ACTRT1 or surrounding noncoding sequences transcribed into functional enhancer RNAs cause aberrant activation of Hedgehog signaling in both sporadic and inherited forms, such as Bazex–Dupré–Christol syndrome, of basal cell carcinoma. These findings identify a new tumor-suppressor gene and underscore the functional relevance of genomic alterations in noncoding transcribed regions in tumor development.

    • Elodie Bal
    • , Hyun-Sook Park
    • , Zakia Belaid-Choucair
    • , Hülya Kayserili
    • , Magali Naville
    • , Marine Madrange
    • , Elena Chiticariu
    • , Smail Hadj-Rabia
    • , Nicolas Cagnard
    • , Francois Kuonen
    • , Daniel Bachmann
    • , Marcel Huber
    • , Cindy Le Gall
    • , Francine Côté
    • , Sylvain Hanein
    • , Rasim Özgür Rosti
    • , Ayca Dilruba Aslanger
    • , Quinten Waisfisz
    • , Christine Bodemer
    • , Olivier Hermine
    • , Fanny Morice-Picard
    • , Bruno Labeille
    • , Frédéric Caux
    • , Juliette Mazereeuw-Hautier
    • , Nicole Philip
    • , Nicolas Levy
    • , Alain Taieb
    • , Marie-Françoise Avril
    • , Denis J Headon
    • , Gabor Gyapay
    • , Thierry Magnaldo
    • , Sylvie Fraitag
    • , Hugues Roest Crollius
    • , Pierre Vabres
    • , Daniel Hohl
    • , Arnold Munnich
    •  & Asma Smahi
  • Article |

    GDF15 has potent anti-obesity effects, but its receptor was unknown. GFRAL has now been identified as the receptor and mediates GDF15's effects through central actions in the hindbrain.

    • Shannon E Mullican
    • , Xiefan Lin-Schmidt
    • , Chen-Ni Chin
    • , Jose A Chavez
    • , Jennifer L Furman
    • , Anthony A Armstrong
    • , Stephen C Beck
    • , Victoria J South
    • , Thai Q Dinh
    • , Tanesha D Cash-Mason
    • , Cassandre R Cavanaugh
    • , Serena Nelson
    • , Chichi Huang
    • , Michael J Hunter
    •  & Shamina M Rangwala
  • Article |

    GDF15 has potent anti-obesity effects, but its receptor was unknown. GFRAL has now been identified as the receptor that mediates GDF15's effects via central actions in the hindbrain.

    • Linda Yang
    • , Chih-Chuan Chang
    • , Zhe Sun
    • , Dennis Madsen
    • , Haisun Zhu
    • , Søren B Padkjær
    • , Xiaoai Wu
    • , Tao Huang
    • , Karin Hultman
    • , Sarah J Paulsen
    • , Jishu Wang
    • , Anne Bugge
    • , Jane Boesen Frantzen
    • , Per Nørgaard
    • , Jacob Fuglsbjerg Jeppesen
    • , Zhiru Yang
    • , Anna Secher
    • , Haibin Chen
    • , Xun Li
    • , Linu Mary John
    • , Bing Shan
    • , Zhenhua He
    • , Xiang Gao
    • , Jing Su
    • , Kristian T Hansen
    • , Wei Yang
    •  & Sebastian Beck Jørgensen
  • Letter |

    GDF15 has potent anti-obesity effects, but its receptor was previously unknown. GFRAL has now been identified as the receptor for GDF15, and it mediates the effects of GDF15 via central actions in the hindbrain.

    • Paul J Emmerson
    • , Feng Wang
    • , Yong Du
    • , Qian Liu
    • , Richard T Pickard
    • , Malgorzata D Gonciarz
    • , Tamer Coskun
    • , Matthew J Hamang
    • , Dana K Sindelar
    • , Kimberly K Ballman
    • , Lisa A Foltz
    • , Avinash Muppidi
    • , Jorge Alsina-Fernandez
    • , Gavin C Barnard
    • , Jason X Tang
    • , Xilin Liu
    • , Xudong Mao
    • , Robert Siegel
    • , John H Sloan
    • , Pamela J Mitchell
    • , Bei B Zhang
    • , Ruth E Gimeno
    • , Bei Shan
    •  & Xinle Wu
  • Letter |

    Genetic or pharmacological depletion of senescent cells or inhibition of their function reduces bone loss in aged mice.

    • Joshua N Farr
    • , Ming Xu
    • , Megan M Weivoda
    • , David G Monroe
    • , Daniel G Fraser
    • , Jennifer L Onken
    • , Brittany A Negley
    • , Jad G Sfeir
    • , Mikolaj B Ogrodnik
    • , Christine M Hachfeld
    • , Nathan K LeBrasseur
    • , Matthew T Drake
    • , Robert J Pignolo
    • , Tamar Pirtskhalava
    • , Tamara Tchkonia
    • , Merry Jo Oursler
    • , James L Kirkland
    •  & Sundeep Khosla
  • Resource |

    Brain-region-specific RNA-seq from humans with major depressive disorder reveals unique transcriptomic profiles in males and females, with little overlap.

    • Benoit Labonté
    • , Olivia Engmann
    • , Immanuel Purushothaman
    • , Caroline Menard
    • , Junshi Wang
    • , Chunfeng Tan
    • , Joseph R Scarpa
    • , Gregory Moy
    • , Yong-Hwee E Loh
    • , Michael Cahill
    • , Zachary S Lorsch
    • , Peter J Hamilton
    • , Erin S Calipari
    • , Georgia E Hodes
    • , Orna Issler
    • , Hope Kronman
    • , Madeline Pfau
    • , Aleksandar L J Obradovic
    • , Yan Dong
    • , Rachael L Neve
    • , Scott Russo
    • , Andrew Kazarskis
    • , Carol Tamminga
    • , Naguib Mechawar
    • , Gustavo Turecki
    • , Bin Zhang
    • , Li Shen
    •  & Eric J Nestler
  • Letter |

    On the basis of new mechanistic studies of a mutant form of the apolipoprotein apoC-III that protects against coronary heart disease, Khetarpal et al. have developed therapeutic apoC-III-targeting monoclonal antibodies that lower circulating apoC-III protein and triglyceride levels in mice.

    • Sumeet A Khetarpal
    • , Xuemei Zeng
    • , John S Millar
    • , Cecilia Vitali
    • , Amritha Varshini Hanasoge Somasundara
    • , Paolo Zanoni
    • , James A Landro
    • , Nicole Barucci
    • , William J Zavadoski
    • , Zhiyuan Sun
    • , Hans de Haard
    • , Ildikó V Toth
    • , Gina M Peloso
    • , Pradeep Natarajan
    • , Marina Cuchel
    • , Sissel Lund-Katz
    • , Michael C Phillips
    • , Alan R Tall
    • , Sekar Kathiresan
    • , Paul DaSilva-Jardine
    • , Nathan A Yates
    •  & Daniel J Rader
  • Article |

    Different mutations found in endometrial and prostate tumors affecting the substrate-recognition domain of SPOP, a component of the E3 ubiquitin ligase complex, result in opposing degradation activity of BET proteins and response to BET inhibitors. This work, along with findings by Zhang et al. and Dai et al., highlights the divergent effects of recurrent mutations affecting different residues within the same functional domain of SPOP and provides scientific rationale to guide the administration of BET inhibitors in endometrial and prostate cancer patients harboring SPOP mutations.

    • Hana Janouskova
    • , Geniver El Tekle
    • , Elisa Bellini
    • , Namrata D Udeshi
    • , Anna Rinaldi
    • , Anna Ulbricht
    • , Tiziano Bernasocchi
    • , Gianluca Civenni
    • , Marco Losa
    • , Tanya Svinkina
    • , Craig M Bielski
    • , Gregory V Kryukov
    • , Luciano Cascione
    • , Sara Napoli
    • , Radoslav I Enchev
    • , David G Mutch
    • , Michael E Carney
    • , Andrew Berchuck
    • , Boris J N Winterhoff
    • , Russell R Broaddus
    • , Peter Schraml
    • , Holger Moch
    • , Francesco Bertoni
    • , Carlo V Catapano
    • , Matthias Peter
    • , Steven A Carr
    • , Levi A Garraway
    • , Peter J Wild
    •  & Jean-Philippe P Theurillat
  • Letter |

    Recurrent mutations in SPOP-encoding a Cullin 3-based E3 ubiquitin ligase- in prostate cancer disrupt the recognition and degradation of ubiquitination substrates, including BET proteins. Consequently, stability of BET proteins is enhanced and this increases the resistance to BET inhibitors in SPOP-mutant prostate tumors. These results, together with those in Janouskova et al. and Zhang et al., uncover a novel non genetic mechanism of resistance to BET inhibition involving cancer type-specific mutations in SPOP, and support the evaluation of SPOP mutations to inform the administration of BET inhibitors in the clinic.

    • Xiangpeng Dai
    • , Wenjian Gan
    • , Xiaoning Li
    • , Shangqian Wang
    • , Wei Zhang
    • , Ling Huang
    • , Shengwu Liu
    • , Qing Zhong
    • , Jianping Guo
    • , Jinfang Zhang
    • , Ting Chen
    • , Kouhei Shimizu
    • , Francisco Beca
    • , Mirjam Blattner
    • , Divya Vasudevan
    • , Dennis L Buckley
    • , Jun Qi
    • , Lorenz Buser
    • , Pengda Liu
    • , Hiroyuki Inuzuka
    • , Andrew H Beck
    • , Liewei Wang
    • , Peter J Wild
    • , Levi A Garraway
    • , Mark A Rubin
    • , Christopher E Barbieri
    • , Kwok-Kin Wong
    • , Senthil K Muthuswamy
    • , Jiaoti Huang
    • , Yu Chen
    • , James E Bradner
    •  & Wenyi Wei