Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001003627 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.
| S-EPMC6606637 | biostudies-literature
Project description:We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.
2019-05-07 | GSE130743 | GEO
Project description:Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia
| PRJNA541266 | ENA
Project description:Global hypermethylations of histone H3 lysine 9 (H3K9) tri- and di-methylation (H3K9me3/2) have been identified in bovine cloned embryos at the embryonic genome activation (EGA) stage (eight-cell stage), but the intrinsic reason for these anomalies remains elusive. To ascertain key factors responsible for aberrant H3K9 methylation, we performed RNA sequencing of transcripts in eight-cell bovine in vitro fertilized (IVF) and SCNT embryo. From the differentially expressed genes (DEGs) between IVF and SCNT embryos, we identified that the unsuccessful reactivation of two histone demethylases, KDM4D and KDM4E, is responsible for the incomplete H3K9me3/2 demethylation in SCNT embryos at the EGA stage. By mRNA injection, ectopic expression of either KDM4D or KDM4E could erase H3K9me3/2 barriers, improve blastocyst formation, and elevate cloning efficiency of bovine SCNT. To examine the detailed genes responsive to KDM4E overexpression, we also performed RNA sequencing of bovine eight-cell SCNT embryos with KDM4E compensation and found an obvious restoration of global transcriptional patterns in SCNT embryos. Our study first provides the transcriptome data set of bovine IVF and SCNT embryos during EGA with or without KDM4E overexpression, which advance the understanding of incomplete nuclear reprogramming, and contribute to the practical implications for genetically modified livestock breeding using SCNT.
2018-01-16 | GSE99294 | GEO
Project description:Malignant cell transformation and the underlying reprogramming of gene expression require the cooperation of multiple oncogenic mutations. This cooperation is reflected in the synergistic regulation of non-mutant downstream genes, so-called cooperation response genes (CRGs). CRGs affect diverse hallmark features of cancer cells and are not known to be functionally connected. However, they act as critical mediators of the cancer phenotype at an unexpectedly high frequency >50%, as indicated by genetic perturbations. Here, we demonstrate that CRGs function within a network of strong genetic interdependencies that are critical to the malignant state. Our network modeling methodology, TopNet, takes the approach of incorporating uncertainty in the underlying gene perturbation data and can identify non-linear gene interactions. In the dense space of gene connectivity, TopNet reveals a sparse topological gene network architecture, effectively pinpointing functionally relevant gene interactions. Thus, among diverse potential applications, TopNet has utility for identification of non-mutant targets for cancer intervention.
| S-EPMC8803128 | biostudies-literature
Project description:Young children have higher rates of leukemia than young adults. This fact represents a fundamental conundrum, because hematopoietic cells in young children should have fewer mutations (including oncogenic ones) than such cells in adults. Here, we present the results of stochastic modeling of hematopoietic stem cell (HSC) clonal dynamics, which demonstrated that early HSC pools were permissive to clonal evolution driven by drift. We show that drift-driven clonal expansions cooperate with faster HSC cycling in young children to produce conditions that are permissive for accumulation of multiple driver mutations in a single cell. Later in life, clonal evolution was suppressed by stabilizing selection in the larger young adult pools, and it was driven by positive selection at advanced ages in the presence of microenvironmental decline. Overall, our results indicate that leukemogenesis is driven by distinct evolutionary forces in children and adults.
| S-EPMC4743806 | biostudies-other
Project description:The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse) model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL), which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI), a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.
| S-EPMC5006579 | biostudies-literature
Project description:CTCF ChIP-seq of 39 primary samples derived from human acute leukemias, namely AML, T-ALL and mixed myeloid/lymphoid leukemias with CpG Island Methylator Phenotype (CIMP). Due to patient confidentiality considerations, the raw data files for this dataset have been deposited to the EGA controlled-access archive under the accession numbers EGAS00001007094 (study); EGAD00001011059 (dataset).
2023-08-31 | E-MTAB-13117 | biostudies-arrayexpress
Project description:Pluripotent stem cells (PSCs) could provide a powerful system to model development of the human esophagus, whose distinct tissue organization compared to rodent esophagus suggests that developmental mechanisms may not be conserved between species. We therefore established an efficient protocol for generating esophageal progenitor cells (EPCs) from human PSCs. We found that inhibition of TGF-ß and BMP signaling is required for sequential specification of EPCs, which can be further purified using cell-surface markers. These EPCs resemble their human fetal counterparts and can recapitulate normal development of esophageal stratified squamous epithelium during in vitro 3D cultures and in vivo. Importantly, combining hPSC differentiation strategies with mouse genetics elucidated a critical role for Notch signaling in the formation of this epithelium. These studies therefore not only provide an efficient approach to generate EPCs, but also offer a model system to study the regulatory mechanisms underlying development of the human esophagus.
| S-EPMC6282026 | biostudies-literature
Project description:BackgroundSynthetic lethality defines a genetic interaction where the combination of mutations in two or more genes leads to cell death. The implications of synthetic lethal screens have been discussed in the context of drug development as synthetic lethal pairs could be used to selectively kill cancer cells, but leave normal cells relatively unharmed. A challenge is to assess genome-wide experimental data and integrate the results to better understand the underlying biological processes. We propose statistical and computational tools that can be used to find relationships between synthetic lethality and cellular organizational units.ResultsIn Saccharomyces cerevisiae, we identified multi-protein complexes and pairs of multi-protein complexes that share an unusually high number of synthetic genetic interactions. As previously predicted, we found that synthetic lethality can arise from subunits of an essential multi-protein complex or between pairs of multi-protein complexes. Finally, using multi-protein complexes allowed us to take into account the pleiotropic nature of the gene products.ConclusionsModeling synthetic lethality using current estimates of the yeast interactome is an efficient approach to disentangle some of the complex molecular interactions that drive a cell. Our model in conjunction with applied statistical methods and computational methods provides new tools to better characterize synthetic genetic interactions.
| S-EPMC2592713 | biostudies-literature