Molecular Mechanisms of Malignant Transformation by Oncornaviruses

1984 ◽  
pp. 35-43 ◽  
Author(s):  
K. Mölling ◽  
P. Donner ◽  
T. Bunte ◽  
I. Greiser-Wilke
Keyword(s):  
Malignant Transformation ◽  
Molecular Mechanisms

Essential Role of Jun Family Transcription Factors in PU.1-Induced Leukemic Stem Cell Transformation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 463-463 ◽  
Author(s):  
Ulrich Steidl ◽  
Frank Rosenbauer ◽  
Roel G.W Verhaak ◽  
Xuesong Gu ◽  
Hasan H. Otu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Malignant Transformation ◽  
Molecular Mechanisms ◽  
Target Cells ◽  
Leukemic Stem Cell ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Transcriptional Pattern

Abstract Knockdown of the expression of the myeloid master regulator PU.1 leads to the development of an immature acute myeloid leukemia (AML) in mice. Recent reports suggest that functional inactivation of PU.1 might also play a role in human AML. However, the molecular mechanisms underlying PU.1-mediated malignant transformation are unknown. We examined leukemic PU.1 knockdown mice and found a 3-fold expansion of lin-, c-kit+, Sca1+ (KLS) hematopoietic stem cells (HSC) as compared to wildtype controls, which was not observed during the preleukemic phase. When we transplanted double-sorted leukemic KLS-HSC into NOD-SCID mice the recipients developed AML after 9–12 weeks indicating that the leukemic stem cells derive from the HSC compartment. This finding prompted us to examine the transcriptome of PU.1 knockdown preleukemic HSC to identify early transcriptional changes underlying their malignant transformation. After lineage-depletion and FACS sorting of preleukemic KLS-HSC we performed linear amplification of RNA by 2 cycles of RT-IVT and hybridized the cRNA with Affymetrix Mouse Genome 430 2.0 arrays. Principal component analysis as well as hierarchical cluster analysis clearly distinguished PU.1 knockdown and wildtype HSC. Several in-vitro targets of PU.1 such as c-Fes, BTK, TFEC, CSF2R, and Ebi3 were downregulated demonstrating that those are also affected in HSC in vivo. Differential expression of 16 genes was corroborated by qRT-PCR. Strikingly, several Jun family transcription factors including c-Jun and JunB were downregulated. Retroviral restoration of c-Jun expression in bone marrow cells of preleukemic mice rescued the PU.1-initiated myelomonocytic differentiation block in this early phase. To target cells in the leukemic stage we applied lentiviral vectors expressing c-Jun or JunB. While c-Jun did not affect leukemic proliferation, lentiviral restoration of JunB led to an 80% reduction of clonogenic growth and a loss of leukemic self-renewal capacity in serial replating assays. Expression analysis of 285 patients with AML confirmed the correlation between PU.1 and JunB downregulation and suggests its relevance in human disease. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1 knockdown HSC and demonstrate that downregulation of c-Jun and JunB contribute to the development of PU.1-induced AML by blocking differentiation (c-Jun) and increasing self-renewal (JunB). Therefore, examination of disturbed gene expression in preleukemic HSC can identify genes whose dysregulation is essential for leukemic stem cell function and are potential targets for therapeutic interventions.

scholarly journals Screening and functional analysis of differentially expressed genes in an animal model ofEBV-associated lymphomas

2019 ◽  
Author(s):  
Yang Zhang ◽  
Chengkun Wang ◽  
Liangzhuan Liu ◽  
Qiu Peng ◽  
Xiaoning Gan ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Human Lymphocytes ◽  
Ring Finger ◽  
Tumor Formation ◽  
Scid Mice ◽  
Differentially Expressed ◽  
Normal Human

AbstractEpstein-Barr virus(EBV) is an important human oncogenic virus. This paper is to explore how EBV induce malignant transformation of human lymphocytes and the related mechanism of lymphomagenesis. We have constructedhu-PBL/SCID chimeric miceand established a model of EBV-associated human-derived lymphomas. By using Agilent human whole genome microarray and a series of bioinformatic analyses, a total of 202 differentially expressed genes were screened from the EBV-induced lymphomas inhu-PBL/SCID mice, including 44 up-regulated and 158 down-regulated genes. Calculation of the rank score (RS) values of these genes in the HIPPIE protein interaction networks showed that topoisomerase II alpha (TOP2A), ubiquitin like with PHD and ring finger domains 1 (UHRF1), histone cluster 2 H2B family member E (HIST2H2BE), phosphoglycerate dehydrogenase (PHGDH), vinculin (VCL), insulin-like growth factor 1 receptor (IGF1R), Fos proto-oncogene (FOS), snail family transcriptional repressor 1 (SNAI1), PDZ binding kinase (PBK), and ring finger protein 144B (RNF144B) were the top 10 key node genes of EBV-induced lymphoma. In which, PBK, an up-regulated genes with the highest number of GO annotations, was verified by cellular function experiments and clinical lymphoma samples.Author summaryEB virus is closely associated with human lymphoma and nasopharyngeal carcinoma. Since the susceptible hosts of EBV limit to human and cottontop tammarins, there are no appropriate animal models so far to study the EBV-associated oncogenesis. In our previous experiments, the EBV-associated lymphomas were induced inhu-PBL/SCID chimera(a new humanized mouse model). However, the cellular and molecular mechanisms of malignant transformation of normal human cells and tumor formation induced by EBV remain unclear. In this study, we examined and compared the gene expression profiles of EBV-induced lymphomas and normal human lymphocytes of the same origin in SCID mice. By constructing the gene-function relationship network, we preliminarily found that TOP2A, UHRF1, HIST2H2BE, PHGDH, VCL, IGF1R, FOS, SNAI1, PBK, and RNF144B may be the key genes in EBV-induced lymphomas. These findings suggest that the induction of lymphoma by EBV is a complex process that involves multiple genes and pathways.

scholarly journals Mechanism of Mutant p53 Using Three-Dimensional Culture on Breast Cancer Malignant Phenotype via SREBP-Dependent Cholesterol Synthesis Pathway

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1026-A1026
Author(s):  
Akitoshi Nakayama ◽  
Masataka Yokoyama ◽  
Hidekazu Nagano ◽  
Naoko Hashimoto ◽  
Kazuyuki Yamagata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Malignant Transformation ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
3D Culture ◽  
Breast Cancer Cell Lines ◽  
Mutant P53 ◽  
Gain Of Function ◽  
Mva Pathway ◽  
The Relationship

Abstract In many cancers, including hormone sensitive tumors such as breast cancer, the “gain of function” caused by mutations in the tumor suppressor gene p53 plays an important role in the acquisition of malignant phenotypes and the regulation of cancer stem cell characteristics. However, its action of molecular mechanisms, particularly in vivo conditions, has not been fully clarified. Therefore, we focused on the “gain of function” of mutant p53 and the cholesterol biosynthesis pathway, especially the mevalonate(MVA) pathway, using breast cancer cells, and clarified the interaction between them and the relationship with cancer malignancy using 3D-culture. Here, we generated knock out and knock in breast cancer cell lines for p53 using CRISPR-Cas9 system, and then confirmed malignant morphological changes by 3D-culture model. We found that the introduction of mutant p53 was solely able to mediate the malignant transformation of cancer. Next, focusing on the relationship between cancer malignant transformation and lipid metabolism pathway, we investigated the role of the MVA pathway in malignant transformation by mutation p53. When investigating the effects of the addition of HMG-CoA inhibitors and isoprenoids, intermediate metabolites were important for malignant transformation during 3D culture. Furthermore, knockdown of SREBP2, which controls the MVA pathway, suppressed malignant phenotypes, so we proceeded with analysis of the interaction between mutant p53 and SREBP2. As the result, we found that mutant p53 and SREBP2 co-localize in the nucleus and consistently mutant p53 was associated with mevalonate pathway genes in parallel with binding pattern of SREBP2. Thus, our results provide the novel insight into the potential therapeutic targets for breast cancer with poor prognosis.

scholarly journals Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis

2005 ◽  
Vol 12 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Paola Viganó ◽  
Edgardo Somigliana ◽  
Ilda Chiodo ◽  
Annalisa Abbiati ◽  
Paolo Vercellini
Keyword(s):  
Malignant Transformation ◽  
Critical Analysis ◽  
Molecular Mechanisms ◽  
Biological Plausibility

Key molecular mechanisms associated with cell malignant transformation in acute myeloid leukemia

2016 ◽  
Vol 50 (3) ◽  
pp. 344-352 ◽  
Author(s):  
N. N. Orlova ◽  
T. D. Lebedev ◽  
P. V. Spirin ◽  
V. S. Prassolov
Keyword(s):  
Acute Myeloid Leukemia ◽  
Malignant Transformation ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Acute Myeloid

scholarly journals Advances in molecular mechanisms of heavy metal induced cell malignant transformation

2018 ◽  
Vol 2 (2) ◽  
Author(s):  
Yi Liu ◽  
Miaomiao Tang ◽  
Zhongping Zhou ◽  
Haifeng Shi ◽  
Jian Lu
Keyword(s):  
Heavy Metal ◽  
Malignant Transformation ◽  
Molecular Mechanisms

scholarly journals CBFA2T3-GLIS2 oncogenic fusion is sufficient for leukemic transformation

2021 ◽  
Author(s):  
Quy Le ◽  
Brandon Hadland ◽  
Jenny Smith ◽  
Amanda Leonti ◽  
Benjamin Huang ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Molecular Mechanisms ◽  
Disease Diagnosis ◽  
Leukemic Transformation ◽  
Human Cord Blood ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cell Therapy ◽  
Car T ◽  
Stem And Progenitor Cells

Abstract Fusion oncoproteins are the initiating event in AML pathogenesis, although they are thought to require additional cooperating mutations for leukemic transformation. CBFA2T3-GLIS2 (C/G) fusion occurs exclusively in infants and is associated with highly aggressive disease1-4. Here we report that lentiviral transduction of C/G fusion is sufficient to induce malignant transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) that fully recapitulates C/G AML. Engineered CB HSPCs co-cultured with endothelial cells undergo complete malignant transformation with identical molecular, morphologic, phenotypic and disease characteristics observed in primary C/G AML. Interrogating the transcriptome of engineered cells identified a library of C/G fusion-specific targets that are candidates for chimeric antigen receptor (CAR) T cell therapy. We developed CAR-T cells directed against one of the targets, FOLR1, and demonstrated the pre-clinical efficacy against C/G AML while sparing normal hematopoiesis. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Moreover, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.

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