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Volume 23 Issue 10, October 2017

Understanding immunity to malaria is crucial to the development of effective vaccines and immune-modulating therapies. In this issue (p 1220), John Harty and colleagues report that regulatory T cells inhibit conventional T cell and germinal center B cell responses through the inhibitory receptor CTLA-4, affecting antimalarial immunity. The cover image depicts a germinal-center reaction in the spleen of a mouse infected with Plasmodium yoelii, after treatment with anti-CTLA-4. CD4+ T helper cells (green), B cells (blue), germinal-center B cells (white) and plasmablasts (red) are shown. Image credit: Samarchith P. Kurup and the University of Iowa Central Microscopy Research Facility. Artwork by Erin Dewalt.

Editorial

  • A growing number of clinical trials on combination therapies raises the question of to what degree they may be redundant. Systems biology and hypothesis-driven preclinical studies could help to identify the most promising candidates for clinical trials, and also offer new insights into the biological mechanisms that underlie drug synergies.

    Editorial

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News

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News & Views

  • Three recent studies in mice have identified a specific receptor, GFRAL, for the known anorectic peptide GDF15. The finding increases mechanistic understanding of its effect and paves the way for the development of novel anti-obesity therapeutics.

    • Irene Cimino
    • Anthony P Coll
    • Giles S H Yeo
    News & Views
  • A new mouse model of Rett syndrome, in which MECP2 can be selectively biotinylated, allows for the investigation of cell-specific effects of Rett-causing mutations on gene expression, particularly in female mice.

    • Patricia M Horvath
    • Lisa M Monteggia
    News & Views
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Review Article

  • In this Review, Ferrando and López-Otín discuss the role of clonal evolution in leukemia and propose that better understanding of the evolutionary biography of human leukemias and related blood cell malignancies may contribute to improve their clinical management.

    • Adolfo A Ferrando
    • Carlos López-Otín
    Review Article
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Brief Communication

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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
    • 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
    • Rosandra N Kaplan
    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
    • Ulrich Schüller
    Article
  • Transcriptomic profiling using a newly-developed cre-inducible method to biotinylate wild-type and mutant MeCP2 protein highlights the cellular heterogeneity of transcriptional changes in rodent models of Rett Syndrome, including cell-type- and subcellular compartment-specific differences in male brains and X-linked mosaicism in female brains.

    • Brian S Johnson
    • Ying-Tao Zhao
    • Zhaolan Zhou
    Article
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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
    • John T Harty
    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
    • Asma Smahi
    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
    • Eyal Gottlieb
    Letter
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Corrigendum

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Erratum

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