Insertion sites of replication-deficient retroviral vectors may trigger clonal dominance of hematopoietic cells in vivo. Here, we tested whether this would also be the case when using vectors that express powerful oncogenes, such as the large tumor antigen (TAg) of simian virus 40. TAg inactivates the tumor-suppressor proteins p53 and Rb by virtue of a chaperone-like activity. Primary hematopoietic stem/progenitor cells transduced with retroviral vectors encoding TAg-induced histiocytic sarcoma (HS) or myeloid leukemia (ML) in transplanted mice (average survival of 21 weeks). Retrovirally introducing TAg into pretransformed 32D cells generated a monocytic leukemia, with faster kinetics ( approximately 8 weeks). Leukemic clones showed retroviral insertions in genes contributing to all known TAg cooperation pathways, acting mitogenic and/or modulating apoptosis (such as BclX, Crk, Pim2, Csfr1/Pdgfrb, Osm/Lif, Axl, Fli, Sema4b, Sox4). 32D-derived monocytic leukemias showed hits in Pim2 and Max proto-oncogenes, or the chaperone Hspa4, plus additional signaling genes. Vector-mediated insertional mutagenesis thus revealed a broad spectrum of potential TAg complementation genes. These findings have important implications for the use of retroviral transgenesis in cancer research, and the expression of signaling genes in somatic gene therapy.

Insertional Mutagenesis by Replication-Deficient Retroviral Vectors Encoding the Large T Oncogene

Assessment of F-MuLV-induced tumorigenesis reveals new candidate tumor genes including Pecam1 , St7 , and Prim2

Assessment of F-MuLV-induced tumorigenesis reveals new candidate tumor genes including Pecam1, St7, and Prim2.

In leukemic mice, the native host's explicit and well-defined immune reactions to the leukemia virus (a strong exogenous antigen) and to leukemia cells (pretending in their native hosts to be protected "self" elements) are extinguished and replaced in GvHD (graft-versus-host disease) by those of the immunocompetent donor cells. In many cases, the GvHD-inducer donors display genetically encoded resistance to the leukemia virus. In human patients only antileukemia and anti-tumor cell immune reactions are mobilized; thus, patients are deprived of immune reactions to a strong exogenous antigen (the elusive human leukemia-sarcoma retroviruses). The innate and adaptive immune systems of mice have to sustain the immunosuppressive effects of leukemia-inducing retroviruses. Human patients due to the lack of leukemiainducing retroviral pathogens (if they exist, they have not as yet been discovered), escape such immunological downgrading. After studying leukemogenic retroviruses in murine and feline (and other mammalian) hosts, it is very difficult to dismiss retroviral etiology for human leukemias and sarcomas. Since no characterized and thus recognized leukemogenic-sarcomagenic retroviral agents are being isolated from the vast majority of human leukemias-sarcomas, the treatment for these conditions in mice and in human patients vastly differ. It is immunological and biological modalities (alpha interferons; vaccines; adoptive lymphocyte therapy) that dominate the treatment of murine leukemias, whereas combination chemotherapy remains the main remission-inducing agent in human leukemias-lymphomas and sarcomas (as humanized monoclonal antibodies and immunotoxins move in). Yet, in this apparently different backgrounds in Mus and Homo, GvHD, as a treatment modality, appears to work well in both hosts, by replacing the hosts' anti-leukemia and anti-tumor immune faculties with those of the donor. The clinical application of GvHD in the treatment of human leukemias-lymphomas and malignant solid tumors remains a force worthy of pursuit, refinement and strengthening. Graft engineering and modifications of the inner immunological environment of the recipient host by the activation or administration of tumor memory T cells, selected Treg cells and natural killer (NKT) cell classes and cytokines, and the improved pharmacotherapy of GvHD without reducing its antitumor efficacy, will raise the value of GvHD to the higher ranks of the effective antitumor immunotherapeutical measures. Clinical interventions of HCT/HSCT (hematopoietic cell/stem cell transplants) are now applicable to an extended spectrum of malignant diseases in human patients, being available to elderly patients, who receive non-myeloablative conditioning, are re-enforced by post-transplant donor lymphocyte (NK cell and immune T cell) infusions and post-transplant vaccinations, and the donor cells may derive from engineered grafts, or from cord blood with reduced GvHD, but increased GvL/GvT-inducing capabilities (graft-versus leukemia/tumor). Post-transplant T cell transfusions are possible only if selected leukemia antigen-specific T cell clones are available. In verbatim quotation: "Ultimately, advances in separation of GvT from GvHD will further enhance the potential of allogeneic HCT as a curative treatment for hematological malignancies" (Rezvani, A.R. and Storb, R.F., Journal of Autoimmunity 30:172-179, 2008 (see in the text)). It may be added: for cure, a combination of the GvL/T effects with new targeted therapeutic modalities, as elaborated on in this article, will be necessary.

Antileukemia and antitumor effects of the graft-versus-host disease: a new immunovirological approach.

Adult T-cell leukemia/lymphoma (ATL) is characterized by monoclonal proliferation of tumor cells that harbor integrated human T-cell leukemia virus type-1 (HTLV-1). These malignant cells accumulate in various organs including the liver, spleen and skin in addition to blood and lymph nodes. Although there have been several reports of animal models of HTLV-1 infection in which proviral distribution has been examined, clonal expansion of the experimentally infected host cells has not been extensively analyzed. Here we provide experimental evidence that clonal proliferation of the infected host cells occurs in the spleen for more than one year. During a 15 month period of persistent infection, two out of ten mice developed spontaneous tumors. Although the tumors were not ATL-like, cells exhibiting mono- or oligoclonal proliferation and having the same site of HTLV-1 integration were identified in tumor tissues as well as in the spleen. Quantitative analysis of the cells belonging to each cell clone suggested that these proliferating cell clones were associated with the tumors and that spontaneous tumor tissues might provide a suitable microenvironment for proliferation and accumulation of infected cell clones at the late stage of infection.

/pdf/clonal-proliferation-of-htlv-1-infected-cells-is-associated-4rxx099mv5.pdf

Clonal proliferation of HTLV-1-infected cells is associated with spontaneous malignant tumor formation in mice

Identificazione di una firma molecolare associata alla prognosi e alla platino sensibilità in pazienti affette da carcinoma ovarico avanzato

We describe here the development of a murine system for the identification of genes involved in myelomonocytic neoplasms. Transgenic C57BL/6J mice expressing SV40 early region under a myelomonocytic promoter develop histiocytic sarcomas with a latency of 167 days. We used retroviral proviral tagging to accelerate tumorigenesis and to uncover genetic changes that contribute to tumor development. Infection of transgenic mice with Friend murine leukemia virus (F-MuLV) shortened the latency of morbidity to 103 days (P< 0.001); this was associated with clonal proviral integrations in tumor DNA. As expected for F-MuLV, proviral insertions occurred at Fli1 in both transgenic and nontransgenic tumors. Four insertions were found at a novel locus, termed Fim4, on chromosome 6. This region is syntenic to human 7q32, a region that is commonly deleted in human myelodysplastic syndrome and acute myeloid leukemia. A murine BAC containing Fim4 was sequenced and analyzed, and while there was significant human-mouse homology in the area of the insertions, no candidate gene has been identified. Thus we have established a system to identify genes involved in myelomonocytic tumors, and have used it to identify Fim4, a new common site of proviral insertion. Study of this locus may provide insight into genes involved in AML-associated 7q32 deletions in humans.

F-MuLV acceleration of myelomonocytic tumorigenesis in SV40 large T antigen transgenic mice is accompanied by retroviral insertion at Fli1 and a novel locus, Fim4

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Y. Wu

Author Tools

Chat about Author

Papers

F-MuLV acceleration of myelomonocytic tumorigenesis in SV40 large T antigen transgenic mice is accompanied by retroviral insertion at Fli1 and a novel locus, Fim4