Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in genes that encode chromatin remodelers raise the possibility that perturbation of chromatin structure and epigenetic regulation are capable of driving cancer formation. Here we sequenced the exomes of 35 rhabdoid tumors, highly aggressive cancers of early childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. We identified an extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event. Indeed, in 2 of the cancers there were no other identified mutations. Our results demonstrate that high mutation rates are dispensable for the genesis of cancers driven by mutation of a chromatin remodeling complex. Consequently, cancer can be a remarkably genetically simple disease.
Ryan S. Lee, Chip Stewart, Scott L. Carter, Lauren Ambrogio, Kristian Cibulskis, Carrie Sougnez, Michael S. Lawrence, Daniel Auclair, Jaume Mora, Todd R. Golub, Jaclyn A. Biegel, Gad Getz, Charles W.M. Roberts
Diamond-Blackfan anemia (DBA) is a hypoplastic anemia characterized by impaired production of red blood cells, with approximately half of all cases attributed to ribosomal protein gene mutations. We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1. This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full-length form of the protein. We further identified an additional patient carrying a distinct mutation at the same splice site of the GATA1 gene. These findings provide insight into the pathogenesis of DBA, showing that the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes. These results also illustrate the multifactorial role of GATA1 in human hematopoiesis.
Vijay G. Sankaran, Roxanne Ghazvinian, Ron Do, Prathapan Thiru, Jo-Anne Vergilio, Alan H. Beggs, Colin A. Sieff, Stuart H. Orkin, David G. Nathan, Eric S. Lander, Hanna T. Gazda
Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc–/–), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.
Yvonne Begus-Nahrmann, Daniel Hartmann, Johann Kraus, Parisa Eshraghi, Annika Scheffold, Melanie Grieb, Volker Rasche, Peter Schirmacher, Han-Wong Lee, Hans A. Kestler, André Lechel, K. Lenhard Rudolph
Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell–derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell–mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor–null (Daf1–/–) host BM and Daf1–/– donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell–mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.
Wing-Hong Kwan, Daigo Hashimoto, Estela Paz-Artal, Katya Ostrow, Melanie Greter, Hugo Raedler, M. Edward Medof, Miriam Merad, Peter S. Heeger
Effective control and eradication of malaria will require new tools to prevent transmission. Current antimalarial therapies targeting the asexual stage of Plasmodium do not prevent transmission of circulating gametocytes from infected humans to mosquitoes. Here, we describe a new class of transmission-blocking compounds, bumped kinase inhibitors (BKIs), which inhibit microgametocyte exflagellation. Oocyst formation and sporozoite production, necessary for transmission to mammals, were inhibited in mosquitoes fed on either BKI-1–treated human blood or mice treated with BKI-1. BKIs are hypothesized to act via inhibition of Plasmodium calcium-dependent protein kinase 4 and predicted to have little activity against mammalian kinases. Our data show that BKIs do not inhibit proliferation of mammalian cell lines and are well tolerated in mice. Used in combination with drugs active against asexual stages of Plasmodium, BKIs could prove an important tool for malaria control and eradication.
Kayode K. Ojo, Claudia Pfander, Natascha R. Mueller, Charlotte Burstroem, Eric T. Larson, Cassie M. Bryan, Anna M.W. Fox, Molly C. Reid, Steven M. Johnson, Ryan C. Murphy, Mark Kennedy, Henning Mann, David J. Leibly, Stephen N. Hewitt, Christophe L.M.J. Verlinde, Stefan Kappe, Ethan A. Merritt, Dustin J. Maly, Oliver Billker, Wesley C. Van Voorhis
Psoriasis is a common, relapsing inflammatory skin disease characterized by erythematous scaly plaques. Histological manifestations of psoriasis include keratinocyte dysregulation and hyperproliferation, elongated rete ridges, and inflammatory infiltrates consisting of T cells, macrophages, dendritic cells, and neutrophils. Despite the availability of new effective drugs to treat psoriasis, the underlying mechanisms of pathogenesis are still poorly understood. Recent studies have shown that Aldara cream, used to treat benign skin abnormalities, triggers psoriasis-like disease in humans and mice and have implicated Th17 cells in disease initiation. Using this as a model, we found a predominant role for the Th17 signature cytokines IL-17A, IL-17F, and IL-22 in psoriasiform plaque formation in mice. Using gene-targeted mice, we observed that loss of Il17a, Il17f, or Il22 strongly reduced disease the severity of psoriasis. However, we found that Th17 cells were not the primary source of these pathogenic cytokines. Rather, IL-17A, IL-17F, and IL-22 were produced by a skin-invading population of γδ T cells and RORγt+ innate lymphocytes. Furthermore, our findings establish that RORγt+ innate lymphocytes and γδ T cells are necessary and sufficient for psoriatic plaque formation in an experimental disease model that closely resembles human psoriatic plaque formation.
Stanislav Pantelyushin, Stefan Haak, Barbara Ingold, Paulina Kulig, Frank L. Heppner, Alexander A. Navarini, Burkhard Becher
Hyperimmune activation is a strong predictor of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I IFN signaling in response to adventitious microbial infection. The immune inhibitory receptor programmed death–1 (PD-1) regulates functional exhaustion of virus-specific CD8+ T cells during chronic infections, and in vivo PD-1 blockade has been shown to improve viral control of SIV. Here, we show that PD-1 blockade during chronic SIV infection markedly reduced the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RMs). The effect of PD-1 blockade on type I IFN signaling was durable and persisted even under conditions of high viremia. Reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in colorectal tissue and with a profound decrease in plasma LPS levels, suggesting a possible repair of gut-associated junctions and decreased microbial translocation into the blood. PD-1 blockade enhanced immunity to gut-resident pathogenic bacteria, control of gut-associated opportunistic infections, and survival of SIV-infected RMs. Our results suggest PD-1 blockade as a potential novel therapeutic approach to enhance combination antiretroviral therapy by suppressing hyperimmune activation in HIV-infected individuals.
Ravi Dyavar Shetty, Vijayakumar Velu, Kehmia Titanji, Steven E. Bosinger, Gordon J. Freeman, Guido Silvestri, Rama Rao Amara
Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.
Dimitra Kiritsi, Yinghong He, Anna M.G. Pasmooij, Meltem Onder, Rudolf Happle, Marcel Jonkman, Leena Bruckner-Tuderman, Cristina Has
Radiation gastrointestinal (GI) syndrome is a major lethal toxicity that may occur after a radiation/nuclear incident. Currently, there are no prophylactic countermeasures against radiation GI syndrome lethality for first responders, military personnel, or remediation workers entering a contaminated area. The pathophysiology of this syndrome requires depletion of stem cell clonogens (SCCs) within the crypts of Lieberkühn, which are a subset of cells necessary for postinjury regeneration of gut epithelium. Recent evidence indicates that SCC depletion is not exclusively a result of DNA damage but is critically coupled to ceramide-induced endothelial cell apoptosis within the mucosal microvascular network. Here we show that ceramide generated on the surface of endothelium coalesces to form ceramide-rich platforms that transmit an apoptotic signal. Moreover, we report the generation of 2A2, an anti-ceramide monoclonal antibody that binds to ceramide to prevent platform formation on the surface of irradiated endothelial cells of the murine GI tract. Consequently, we found that 2A2 protected against endothelial apoptosis in the small intestinal lamina propria and facilitated recovery of crypt SCCs, preventing the death of mice from radiation GI syndrome after high radiation doses. As such, we suggest that 2A2 represents a prototype of a new class of anti-ceramide therapeutics and an effective countermeasure against radiation GI syndrome mortality.
Jimmy Rotolo, Branka Stancevic, Jianjun Zhang, Guoqiang Hua, John Fuller, Xianglei Yin, Adriana Haimovitz-Friedman, Kisu Kim, Ming Qian, Marina Cardó-Vila, Zvi Fuks, Renata Pasqualini, Wadih Arap, Richard Kolesnick
The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.
Lee J. Quinton, Matthew T. Blahna, Matthew R. Jones, Eri Allen, Joseph D. Ferrari, Kristie L. Hilliard, Xiaoling Zhang, Vishakha Sabharwal, Hana Algül, Shizuo Akira, Roland M. Schmid, Stephen I. Pelton, Avrum Spira, Joseph P. Mizgerd
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