Tonks I.D.,QIMR Berghofer Medical Research Institute
Oncogene | Year: 2017
Deregulation of p16INK4A is a critical event in melanoma susceptibility and progression. It is generally assumed that the major effect of loss of p16 function is mediated through the CDK−cyclin pathway via its influence on the pocket protein (PP) pRb. However, there are also two other PPs, p107 and p130, which, when phosphorylated by CDK–cyclin complexes, play a role in permitting cell progression. Cohorts of mice carrying melanocyte-specific knockouts (KOs) of various combinations of the three PPs were generated. Mice null for pRb, p107, p130 or any combination of double mutants did not develop melanoma. Surprisingly, melanocyte-specific loss of all three PPs facilitated melanoma development (median age of onset 308 days, penetrance 40% at 1 year). Tumorigenesis was exacerbated by Trp53 co-deletion (median age of onset 275 days, penetrance 82% at 1 year), with cell culture studies indicating that this difference may result from the apoptotic role of Trp53. Melanomas in PP;Trp53-deficient mice lacked either Ras or Braf mutations, and hence developed in the absence of constitutive MAPK pathway activation. The lag period between induction of total PP or PP/Trp53 KO and melanoma development indicates that additional genetic or epigenetic alterations may account for neoplastic progression. However, exome sequencing of PP;Trp53 KO melanomas failed to reveal any additional recurrent driver mutations. Analysis of the putative mutation signature of the PP;Trp53 KO melanomas suggests that melanocytes are primed for transformation via a mutagenic mechanism involving an excess of T>G substitutions, but not involving a preponderance of C>T substitutions at CpG sites, which is the case for most spontaneous cancers not driven by a specific carcinogen. In sum, deregulation of all three PPs appears central to neoplastic progression for melanoma, and the customary reference to the p16INKA/CDK4/pRB pathway may no longer be accurate; all PPs are potentially critical targets of CDK-cyclins in melanoma.Oncogene advance online publication, 13 February 2017; doi:10.1038/onc.2016.511. © 2017 Macmillan Publishers Limited, part of Springer Nature.
Al-Ejeh F.,QIMR Berghofer Medical Research Institute
Leukemia | Year: 2017
The human EphA3 gene was discovered in a pre-B acute lymphoblastic leukemia (pre-B-ALL) using the EphA3-specific monoclonal antibody (mAb), IIIA4, which binds and activates both human and mouse EphA3. We use two models of human pre-B-ALL to examine EphA3 function, demonstrating effects on pre-B-cell receptor signaling. In therapeutic targeting studies, we demonstrated antitumor effects of the IIIA4 mAb in EphA3-expressing leukemic xenografts and no antitumor effect in the xenografts with no EphA3 expression providing evidence that EphA3 is a functional therapeutic target in pre-B-ALL. Here we show that the therapeutic effect of the anti-EphA3 antibody was greatly enhanced by adding an α-particle-emitting 213Bismuth payload.Leukemia advance online publication, 31 January 2017 ; doi:10.1038/leu.2016.371. © 2017 The Author(s)
News Article | February 16, 2017
An immune system proteinase called granzyme A appears to promote arthritic inflammation in mice infected with chikungunya virus, scientists report in a new PLOS Pathogens study. The study also suggested that granzyme A could serve as a potential target for new drugs to treat chikungunya and related viral arthritides in people. Chikungunya virus is transmitted by mosquitoes, with a recent epidemic causing millions of cases globally. While it is rarely fatal, chikungunya can cause severe, chronic polyarthritis (inflammation in multiple joints) and/or polyarthralgia (pain in multiple joints). Current standard anti-inflammatory drug treatment can relieve these symptoms, but they are often not particularly effective. To aid research into potential new treatments, Jane Wilson and Natalie Prow of QIMR Berghofer Medical Research Institute, Australia, and colleagues exploited an adult wild-type mouse model of chikungunya virus infection and diseases previously developed by the group. In the new study, they use RNA-Seq technology to examine in detail the mouse inflammatory responses to infection. They found that genes activated in the mouse model closely mirrored genes known to be activated in infected humans, providing a level of validation of the model. Particularly prominent in the RNA-Seq analysis was the up-regulation of a number of granzymes, a group of proteinases secreted by immune cells that were originally thought to be involved in killing (via apoptosis) virus infected cells or other target cells. However, an emerging consensus supported by the new PLOS Pathogens study, is that some granzymes (particularly granzyme A and K) have a role in promoting inflammation. Exploring further, the scientists showed that mice missing the granzyme A gene, when infected with chikungunya virus, experienced dramatically less foot swelling and arthritis. Furthermore, treating mice with a granzyme A inhibitor also significantly reduced foot swelling and arthritis. They also found elevated granzyme A levels in blood samples taken from non-human primates infected with chikungunya, as well as from human chikungunya patients. Overall the findings suggest that granzyme A could serve as a potential drug target for anti-inflammatory treatments for chikungunya -- and perhaps also for other inflammatory diseases. Further research will be needed to explore this potential and determine how well the new findings can be extended from mice to humans. In your coverage please use this URL to provide access to the freely available article in PLOS Pathogens: http://dx. Citation: Wilson JAC, Prow NA, Schroder WA, Ellis JJ, Cumming HE, Gearing LJ, et al. (2017) RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation. PLoS Pathog 13(2): e1006155. doi:10.1371/journal.ppat.1006155 Funding: The work was primarily funded by the National Health and Medical Research Council (NHMRC), Australia (grant APP613622) . JACW was awarded an Australian Postgraduate Award scholarship by the School of Medicine, University of Queensland. NAP was in part supported by an Advance Queensland Research Fellowship from the Queensland government. AS is a principal research fellow with the NHMRC. BSL3 equipment was funded by the Queensland Tropical Health Alliance. The NHP studies were funded by (i) "Programme d'Investissements d'Avenir" (PIA) under Grant ANR-11-INBS-0008 funding the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay-aux-Roses, France) infrastructure and (ii) the Integrated Chikungunya Research (ICRES) project of the European Union FP7 project grant agreement no. 261202. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
Fornito A.,Monash University |
Zalesky A.,University of Melbourne |
Breakspear M.,QIMR Berghofer Medical Research Institute |
Breakspear M.,Royal Brisbane and Womens Hospital
Nature Reviews Neuroscience | Year: 2015
Pathological perturbations of the brain are rarely confined to a single locus; instead, they often spread via axonal pathways to influence other regions. Patterns of such disease propagation are constrained by the extraordinarily complex, yet highly organized, topology of the underlying neural architecture; the so-called connectome. Thus, network organization fundamentally influences brain disease, and a connectomic approach grounded in network science is integral to understanding neuropathology. Here, we consider how brain-network topology shapes neural responses to damage, highlighting key maladaptive processes (such as diaschisis, transneuronal degeneration and dedifferentiation), and the resources (including degeneracy and reserve) and processes (such as compensation) that enable adaptation. We then show how knowledge of network topology allows us not only to describe pathological processes but also to generate predictive models of the spread and functional consequences of brain disease. © 2015 Macmillan Publishers Limited. All rights reserved.
Rossjohn J.,Monash University |
Rossjohn J.,University of Cardiff |
Gras S.,Monash University |
Miles J.J.,University of Cardiff |
And 4 more authors.
Annual Review of Immunology | Year: 2015
The Major Histocompatibility Complex (MHC) locus encodes classical MHC class I and MHC class II molecules and nonclassical MHC-I molecules. The architecture of these molecules is ideally suited to capture and present an array of peptide antigens (Ags). In addition, the CD1 family members and MR1 are MHC class I-like molecules that bind lipid-based Ags and vitamin B precursors, respectively. These Ag-bound molecules are subsequently recognized by T cell antigen receptors (TCRs) expressed on the surface of T lymphocytes. Structural and associated functional studies have been highly informative in providing insight into these interactions, which are crucial to immunity, and how they can lead to aberrant T cell reactivity. Investigators have determined over thirty unique TCR-peptide-MHC-I complex structures and twenty unique TCR-peptide-MHC-II complex structures. These investigations have shown a broad consensus in docking geometry and provided insight into MHC restriction. Structural studies on TCR-mediated recognition of lipid and metabolite Ags have been mostly confined to TCRs from innate-like natural killer T cells and mucosal-associated invariant T cells, respectively. These studies revealed clear differences between TCR-lipid-CD1, TCR-metabolite-MR1, and TCR-peptide-MHC recognition. Accordingly, TCRs show remarkable structural and biological versatility in engaging different classes of Ag that are presented by polymorphic and monomorphic Ag-presenting molecules of the immune system. © 2015 by Annual Reviews. All rights reserved.
Martinet L.,QIMR Berghofer Medical Research Institute |
Martinet L.,Institute National Of La Sante Et Of La Recherche Medicale Unite Mixte Of Recherche 1037 |
Smyth M.J.,QIMR Berghofer Medical Research Institute |
Smyth M.J.,University of Queensland
Nature Reviews Immunology | Year: 2015
Natural killer (NK) cells are innate lymphocytes that are crucial for the control of infections and malignancies. NK cells express a variety of inhibitory and activating receptors that facilitate fine discrimination between damaged and healthy cells. Among them, a family of molecules that bind nectin and nectin-like proteins has recently emerged and has been shown to function as an important regulator of NK cell functions. These molecules include CD226, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), CD96, and cytotoxic and regulatory T cell molecule (CRTAM). In this Review, we focus on the recent advances in our understanding of how these receptors regulate NK cell biology and of their roles in pathologies such as cancer, infection and autoimmunity. © 2015 Macmillan Publishers Limited. All rights reserved.
Mittal D.,QIMR Berghofer Medical Research Institute |
Gubin M.M.,University of Washington |
Schreiber R.D.,University of Washington |
Smyth M.J.,QIMR Berghofer Medical Research Institute |
Smyth M.J.,University of Queensland
Current Opinion in Immunology | Year: 2014
The principles of cancer immunoediting have set the foundations for understanding the dual host-protective and tumor sculpting actions of immunity on cancer and establishing the basis for novel individualized cancer immunotherapies. During cancer immunoediting, the host immune system shapes tumor fate in three phases through the activation of innate and adaptive immune mechanisms. In the first phase, Elimination, transformed cells are destroyed by a competent immune system. Sporadic tumor cells that manage to survive immune destruction may then enter an Equilibrium phase where editing occurs. The Escape phase represents the third and final phase of the process, where immunologically sculpted tumors begin to grow progressively, become clinically apparent and establish an immunosuppressive tumor microenvironment. This review focuses on important recent developments that have enhanced our understanding of each phase of the cancer immunoediting process, summarizes the discovery of new predictive and prognostic biomarkers and discusses development of novel and objectively effective cancer immunotherapies. © 2014 Elsevier Ltd.
Nyholt D.R.,QIMR Berghofer Medical Research Institute
Bioinformatics | Year: 2014
The genomics era provides opportunities to assess the genetic overlap across phenotypes at the measured genotype level; however, current approaches require individual-level genome-wide association (GWA) single nucleotide polymorphism (SNP) genotype data in one or both of a pair of GWA samples. To facilitate the discovery of pleiotropic effects and examine genetic overlap across two phenotypes, I have developed a user-friendly web-based application called SECA to perform SNP effect concordance analysis using GWA summary results. The method is validated using publicly available summary data from the Psychiatric Genomics Consortium. © 2014 The Author 2014.
Cloonan N.,QIMR Berghofer Medical Research Institute
BioEssays | Year: 2015
Despite a library full of literature on miRNA biology, core issues relating to miRNA target detection, biological effect, and mode of action remain controversial. This essay proposes that the predominant mechanism of direct miRNA action is translational inhibition, whereas the bulk of miRNA effects are mRNA based. It explores several issues confounding miRNA target detection, and discusses their impact on the dominance of "miRNA seed" dogma and the exploration of non-canonical binding sites. Finally, it makes comparisons between miRNA target prediction and transcription factor binding prediction, and questions the value of characterizing miRNA binding sites based on which miRNA nucleotides are paired with an mRNA. © 2015 The Author. Bioessays published by WILEY Periodicals, Inc.
Whitfield J.B.,QIMR Berghofer Medical Research Institute
Clinical Biochemist Reviews | Year: 2014
Many biochemical traits are recognised as risk factors, which contribute to or predict the development of disease. Only a few are in widespread use, usually to assist with treatment decisions and motivate behavioural change. The greatest effort has gone into evaluation of risk factors for cardiovascular disease and/or diabetes, with substantial overlap as 'cardiometabolic' risk. Over the past few years many genome-wide association studies (GWAS) have sought to account for variation in risk factors, with the expectation that identifying relevant polymorphisms would improve our understanding or prediction of disease; others have taken the direct approach of genomic case-control studies for the corresponding diseases. Large GWAS have been published for coronary heart disease and Type 2 diabetes, and also for associated biomarkers or risk factors including body mass index, lipids, C-reactive protein, urate, liver function tests, glucose and insulin. Results are not encouraging for personal risk prediction based on genotyping, mainly because known risk loci only account for a small proportion of risk. Overlap of allelic associations between disease and marker, as found for low density lipoprotein cholesterol and heart disease, supports a causal association, but in other cases genetic studies have cast doubt on accepted risk factors. Some loci show unexpected effects on multiple markers or diseases. An intriguing feature of risk factors is the blurring of categories shown by the correlation between them and the genetic overlap between diseases previously thought of as distinct. GWAS can provide insight into relationships between risk factors, biomarkers and diseases, with potential for new approaches to disease classification.