Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection.
During cell-to-cell transmission of human immunodeficiency virus type 1 (HIV-1), many viral particles can be simultaneously transferred from infected to uninfected CD4 T cells through structures called virological synapses (VS). Here we directly examine how cell-free and cell-to-cell infections differ from infections initiated with cell-free virus in the number of genetic copies that are transmitted from one generation to the next, i.e., the genetic inheritance. Following exposure to HIV-1-expressing cells, we show that target cells with high viral uptake are much more likely to become infected. Using T cells that coexpress distinct fluorescent HIV-1 variants, we show that multiple copies of HIV-1 can be cotransmitted across a single VS. In contrast to cell-free HIV-1 infection, which titrates with Poisson statistics, the titration of cell-associated HIV-1 to low rates of overall infection generates a constant fraction of the newly infected cells that are cofluorescent. Triple infection was also readily detected when cells expressing three fluorescent viruses were used as donor cells. A computational model and a statistical model are presented to estimate the degree to which cofluorescence underestimates coinfection frequency. Lastly, direct detection of HIV-1 proviruses using fluorescence in situ hybridization confirmed that significantly more HIV-1 DNA copies are found in primary T cells infected with cell-associated virus than in those infected with cell-free virus. Together, the data suggest that multiploid inheritance is common during cell-to-cell HIV-1 infection. From this study, we suggest that cell-to-cell infection may explain the high copy numbers of proviruses found in infected cells in vivo and may provide a mechanism through which HIV preserves sequence heterogeneity in viral quasispecies through genetic complementation.
Key Points• A high survival rate was seen in primary or secondary MF patients transplanted from matched related donors using the FluMel regimen.• FluMel plus ATG in HSCT from unrelated donors for MF patients is associated with an increased risk of graft failure.From 2007 to 2011, 66 patients with primary myelofibrosis or myelofibrosis (MF) preceded by essential thrombocythemia or polycythemia vera were enrolled into a prospective phase 2 clinical trial of reduced-intensity allogeneic hematopoietic stem cell transplantation (AHSCT), Myeloproliferative Disorder Research Consortium 101 trial. The study included patients with sibling donors (n 5 32) receiving fludarabine/melphalan (FluMel) as a preparative regimen and patients with unrelated donors (n 5 34) receiving conditioning with FluMel plus anti-thymocyte globulin (ATG). Patient characteristics in the 2 cohorts were similar. Engraftment occurred in 97% of siblings and 76% of unrelated transplants, whereas secondary graft failure occurred in 3% and 12%, respectively. With a median follow-up of 25 months for patients alive, the overall survival (OS) was 75% in the sibling group (median not reached) and 32% in the unrelated group (median OS: 6 months, 95% confidence interval [CI]: 3, 25) (hazard ratio 3.9, 95% CI: 1.8,8.9) (P < .001). Nonrelapse mortality was 22% in sibling and 59% in unrelated AHSCT. Survival correlated with type of donor, but not with the degree of histocompatibility match, age, or JAK2 V617F status. In patients with MF with sibling donors, AHSCT is an effective therapy, whereas AHSCT from unrelated donors with FluMel/ATG conditioning led to a high rate of graft failure and limited survival. This trial was registered at www.clinicaltrials.gov as
Yacoub et al report excellent responses to pegylated interferon alfa-2a in patients with hydroxyurea-resistant/intolerant polycythemia vera or essential thrombocythemia.
In this study, we explored dermal dendritic cell (DC) homeostasis in mice and humans both in the steady state and after hematopoietic cell transplantation. We discovered that dermal DCs proliferate in situ in mice and human quiescent dermis. In parabiotic mice with separate organs but shared blood circulation, the majority of dermal DCs failed to be replaced by circulating precursors for >6 mo. In lethally irradiated mice injected with donor congenic bone marrow (BM) cells, a subset of recipient DCs remained in the dermis and proliferated locally throughout life. Consistent with these findings, a large proportion of recipient dermal DCs remained in patients' skin after allogeneic hematopoietic cell transplantation, despite complete donor BM chimerism. Collectively, our results oppose the traditional view that DCs are nondividing terminally differentiated cells maintained by circulating precursors and support the new paradigm that tissue DCs have local proliferative properties that control their homeostasis in the steady state. Given the role of residual host tissue DCs in transplant immune reactions, these results suggest that dermal DC homeostasis may contribute to the development of cutaneous graft-versus-host disease in clinical transplantation.
Emerging evidence suggests that chromatin adopts a nonrandom 3D topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further investigation. To address these questions, we performed unbiased high-resolution mapping of intra-and interchromosome interactions upon overexpression of ERG, an oncogenic transcription factor frequently overexpressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding, and gene expression, we demonstrate that oncogenic transcription factor overexpression is associated with global, reproducible, and functionally coherent changes in chromatin organization. The results presented here have broader implications, as genomic alterations in other cancer types frequently give rise to aberrant transcription factor expression, e.g., EWS-FLI1, c-Myc, n-Myc, and PML-RARα.M ounting evidence suggests that many genes dynamically colocalize to shared nuclear compartments that favor gene activation or silencing (1-3). As demonstrated by chromosome conformation capture (3C) (4), ligand-bound androgen receptors (AR) and estrogen receptors mediate looped chromatin structures resulting in coordinated transcription of target genes (5, 6). In embryonic carcinoma cells, the PolyComb complex subunit EZH2 represses some of its target genes via the formation of similar looped chromatin structures (7). Trans-interactions that regulate gene expression have also been reported (8-10). These data suggest that oncogenic transcriptional regulators are capable of inducing changes in chromatin structures. These studies have mainly focused on local chromatin structures, and it is still unclear whether more global changes occur in the process of oncogene-mediated transformation. A broader implication of these observations is that global chromatin organization changes could impact functional and phenotypic aspects of cancer.To globally investigate oncogene-mediated chromatin structure changes we focused on ERG, the ETS-family transcription factor most frequently rearranged and overexpressed in prostate cancer through the TMPRSS2-ERG and other gene fusions involving androgen-responsive promoters (11-13). ERG interacts with several cofactors (14) and other transcription factors including AR to regulate the expression of thousands of genes that favor dedifferentiation, cell invasion, and neoplastic transformation of prostate epithelium when overexpressed (15-20). We therefore hypothesized that changes in global gene expression induced by ERG overexpression could be associated with global changes in the 3D structure of chromosomes.Results ERG Overexpression Is Associated with Chromatin Topology. To test our hypothesis, we used...
To determine whether acute nonlymphocytic leukemia develops clonally, to study the pattern of differentiation of the involved stem cells, and to determine whether clinical remissions are true remissions, we studied 27 patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome-linked glucose-6-phosphate dehydrogenase. In each case, leukemic blast cells manifested only one type of glucose-6-phosphate dehydrogenase, indicating that the malignant process had developed from a single cell. In six elderly patients, circulating erythrocytes, platelets, or both expressed only the glucose-6-phosphate dehydrogenase found in blast cells, indicating that these leukemias had arisen from stem cells with multipotent differentiative expression. In 16 younger adults and children, erythroid cells and platelets were predominantly derived from normal stem cells. In three other cases, the stem cell that gave rise to leukemic blasts apparently also gave rise to erythroid progenitors but not to mature erythrocytes. Heterogeneity was also found during remissions. In 8 of 13 patients, restoration of nonclonal hemopoiesis and repopulation of the marrow by normal stem cells was observed during remission. In the other five patients, marrow stem cells remained partially or completely clonal, even during remission. These data indicate that acute nonlymphocytic leukemia is a heterogeneous disease with respect to differentiation of the stem cells involved by leukemia and the nature of remissions.
High levels of circular viral extrachromosomal DNA (E-DNA) are normally produced after infection with integration-competent and -incompetent lentiviruses. Although E-DNA has been shown to be transcriptionally active, it lasts for only a short time in replicating cells. Here, we report an integrase (IN)-defective lentiviral episomal vector in which insertion of the simian virus 40 (SV40) promoter, containing the origin of replication (ori), is associated with long-term expression and persistence of E-DNA in the presence of SV40 large T antigen (TAg) from 293T cells. 293 and 293T cell lines transduced with IN-competent lentiviral vectors expressing green fluorescent protein (GFP) or luciferase from the cytomegalovirus (CMV) or SV40 promoter gave similar levels of transduction and expression. In contrast, only transient reporter expression occurred when using the CMV IN-defective control vector in both 293 and 293T cells. However, reporter gene expression was maintained for more than 8 weeks in 293T, but not 293, cells transduced with the IN-defective lentiviral vector containing the SV40-ori promoter. Polymerase chain reaction for two-long terminal repeat (2LTR) extrachromosomal circular forms, a marker of lentiviral E-DNA, and fluorescence in situ hybridization analysis confirmed the persistence and episomal nature of circular E-DNA up to 60 days after transduction. Taken together, these results indicate that insertion of the SV40-ori promoter in a lentiviral vector contributes to long-term expression by promoting episomal replication when TAg is provided in trans. Lentiviral episomal vectors may serve as specific tools for therapeutic approaches to diseases, particularly those associated with episomal replication of DNA viruses including papillomaviruses, polyomaviruses, and herpesviruses.
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