Featured
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News & Views |
When catastrophe strikes a cell
In 2–3% of cancers, a single genetic event may have led to hundreds of genomic rearrangements confined to just one or a few chromosomes. This finding challenges the conventional view of how mutations accumulate in oncogenesis.
- Jose M. C. Tubio
- & Xavier Estivill
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Letter |
Prion propagation and toxicity in vivo occur in two distinct mechanistic phases
Here it is shown that during the silent phase of prion infection, prions first exponentially propagate until a defined limit is reached. Then a plateau phase follows. Prion propagation is independent of prion concentration, whereas in the plateau phase the time to clinical onset is inversely correlated to prion concentration. The similar levels of infectivity at the end of the first and second phase suggests that there is a separation between prion infectivity and toxicity. Moreover, something seems to limit prion production. It is suggested that the prions are not neurotoxic themselves but catalyse the formation of such species from PrPC. Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity to a toxic pathway.
- Malin K. Sandberg
- , Huda Al-Doujaily
- & John Collinge
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Article |
Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor
- Kerry J. Ressler
- , Kristina B. Mercer
- & Victor May
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Letter |
Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome
- Guang-Hui Liu
- , Basam Z. Barkho
- & Juan Carlos Izpisua Belmonte
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Letter |
CKIα ablation highlights a critical role for p53 in invasiveness control
This study shows, via a mouse model of intestinal cancer, that in the absence of CKIα, the loss of p53 dramatically enhances tumour progression and metastasis. p53 is shown to normally limit cancer cell invasion via the regulation of p21 and a set of invasion genes that include Prox1. This study adds important insights to the emerging picture that during tumour development the p53 tumour suppressor gene not only controls cell death and proliferation but also metastasis.
- Ela Elyada
- , Ariel Pribluda
- & Yinon Ben-Neriah
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Article
| Open AccessThe genomic complexity of primary human prostate cancer
Prostate cancer is a common cause of male cancer-related deaths. Complete sequencing of prostate cancer genomes now reveals previously unknown balanced rearrangements. Single-nucleotide resolution afforded by sequencing indicates that complex rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.
- Michael F. Berger
- , Michael S. Lawrence
- & Levi A. Garraway
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Article |
Mapping copy number variation by population-scale genome sequencing
Harnessing information from whole genome sequencing in 185 individuals, this study generates a high-resolution map of copy number variants. Nucleotide resolution of the map facilitates analysis of structural variant distribution and identification of the mechanisms of their origin. The study provides a resource for sequence-based association studies.
- Ryan E. Mills
- , Klaudia Walter
- & Jan O. Korbel
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Article |
Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells
Analysing human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample and the evolutionary path by which different subclones have emerged. Leukaemia-initiating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-initiating cells.
- Faiyaz Notta
- , Charles G. Mullighan
- & John E. Dick
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Letter |
Oncogenically active MYD88 mutations in human lymphoma
This study finds frequent mutations in MYD88 in the activated B-cell-like subtype of diffuse large B-cell lymphoma and, with lower frequency, in mucosa-associated lymphoid tissue lymphomas. MYD88 mediates signalling by Toll-like receptors, and the mutations, most of which affect the same amino acid, are shown to activate the pathway and promote cancer cell survival.
- Vu N. Ngo
- , Ryan M. Young
- & Louis M. Staudt
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Article |
Genetic variegation of clonal architecture and propagating cells in leukaemia
Analysing single cells from human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample, the evolutionary path by which different subclones have emerged, and ongoing dynamic changes associated with relapse. Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells.
- Kristina Anderson
- , Christoph Lutz
- & Mel Greaves
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Letter |
L1 retrotransposition in neurons is modulated by MeCP2
Long interspersed nuclear elements-1 (L1) retrotransposons affect gene expression and neuronal function throughout brain development. These authors show that the absence of methyl-CpG-binding protein 2, a modulator of DNA methylation implicated in several neurodevelopmental disorders, increases L1 retrotransposon activity in rodent models, with this increase in susceptibility duplicated in patients with Rett syndrome. These correlations suggest that disease-related genetic mutations may influence L1 retrotransposon activity.
- Alysson R. Muotri
- , Maria C. N. Marchetto
- & Fred H. Gage
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Research Highlights |
Cell biology: Thriving with genomic errors
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Letter |
RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis
Progestins, used in hormone replacement therapy and contraceptives, have been suggested to promote the development of breast cancer. These authors show that the ability of progestins to induce mammary tumours in mouse models is mediated by RANKL (receptor activator of NF-KB ligand). Inhibition of RANKL could reduce tumorigenesis in hormone-induced and other mouse mammary gland tumour models, suggesting a new therapeutic approach.
- Eva Gonzalez-Suarez
- , Allison P. Jacob
- & William C. Dougall
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Letter |
A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
Here, a combination of genetic studies of gene expression, cross-species network analysis and genome-wide association studies has been used to identify gene networks and the loci underlying their regulation in rats. The results show that an inflammatory network driven by interferon regulatory factor 7 contributes to susceptibility to type 1 diabetes, and implicate the innate viral-response pathway and macrophages in the aetiology of this disease.
- Matthias Heinig
- , Enrico Petretto
- & Stuart A. Cook
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Outlook |
On high alert
HIV keeps the immune system in a hyperactive state, gradually leading to its ruin, reports Emma Marris.
- Emma Marris
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Letter |
Genome-wide association study in alopecia areata implicates both innate and adaptive immunity
The genetic basis of alopecia areata, one of the most common human autoimmune diseases, is largely unknown. This study reports a genome-wide association for this trait that implies the involvement of acquired and innate immunity. Among significant associations are the cytomegalovirus UL16-binding protein genes, which encode activating ligands for the natural killer cell receptor, NKG2D, here implicated for the first time in any autoimmune disease.
- Lynn Petukhova
- , Madeleine Duvic
- & Angela M. Christiano
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Research Highlights |
Immunology: Gene plus virus
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Perspective |
Epigenetics as a unifying principle in the aetiology of complex traits and diseases
- Arturas Petronis
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Letter |
Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology
The cytokine interleukin (IL)-23 has inflammatory effects on innate immune cells and can drive colitis, but the cellular and molecular pathways involved are poorly characterized. Here it is shown that bacterial-driven innate colitis involves a previously unknown population of IL-23-responsive innate leukocytes that produce IL-17 and interferon-γ. These cells may represent a target in inflammatory bowel disease.
- Sofia Buonocore
- , Philip P. Ahern
- & Fiona Powrie
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News & Views |
Host and microbes in a pickle
Metabolic disorders such as obesity are characterized by long-term, low-grade inflammation. Under certain conditions, the resident microorganisms of the gut might contribute to this inflammation, resulting in disease.
- Ping Li
- & Gökhan S. Hotamisligil
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Review Article |
Genetics, pathogenesis and clinical interventions in type 1 diabetes
- Jeffrey A. Bluestone
- , Kevan Herold
- & George Eisenbarth
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Article |
Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Cellular senescence — an irreversible cell-cycle arrest — has been implicated in suppressing tumour formation or growth. A new cellular signalling pathway that drives senescence has now been identified. This pathway does not involve most known mediators of senescence, and instead signals via the proteins Atf4, p27 and p21. Inactivating the proto-oncogene Skp2 in the context of oncogenic signalling can induce senescence through this new pathway, indicating that drugs that target Skp2 might be useful in cancer treatment.
- Hui-Kuan Lin
- , Zhenbang Chen
- & Pier Paolo Pandolfi
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Research Highlights |
Cancer biology: Arsenic activation
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Letter |
Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses
In response to oncogenic stress, the tumour suppressor ARF activates the p53 protein. ARF protein is highly stable in most human cell lines, so it has been thought that ARF activation occurs mainly at the level of transcription. Here, however, ARF is shown to be unstable in normal human cells but stable in cancer cells, through a transcription-independent mechanism. A ubiquitin ligase for ARF is identified and shown to promote ARF degradation in normal cells. This activity is prevented in cancer cells, stabilizing ARF.
- Delin Chen
- , Jing Shan
- & Wei Gu
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Letter |
Circulating mitochondrial DAMPs cause inflammatory responses to injury
Severe trauma can lead to death and sepsis in the absence of apparent infection. Here evidence shows that mitochondrial debris, released from damaged cells, is present in the circulation of seriously injured trauma patients. Such debris is shown to activate neutrophils via specific formyl peptide receptors, triggering systemic inflammation and end organ injury.
- Qin Zhang
- , Mustafa Raoof
- & Carl J. Hauser
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News |
Soil bacteria could yield drug to treat roundworm
The natural insecticide Bt treats infections in mice.
- Janet Fang
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Research Highlights |
Cancer biology: Weighted cancer risk
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Letter |
Interaction between RasV12 and scribbled clones induces tumour growth and invasion
In human tumours, complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression. In a genetically well-defined model system in Drosophila, clones of cells bearing different mutations are now shown to cooperate to promote tumour growth and invasion. This interaction involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines.
- Ming Wu
- , José Carlos Pastor-Pareja
- & Tian Xu
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Letter |
Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma
The role of B-cell-receptor (BCR) signalling in human B cell lymphomas has been a long-standing question, with genetic and functional evidence for its oncogenic role in human lymphomas lacking. Here, a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like subtype of diffuse large B-cell lymphoma is described and analysed, with potential implications for future therapeutic strategies.
- R. Eric Davis
- , Vu N. Ngo
- & Louis M. Staudt