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Type of publication: Journal Article
Type of document: Full Paper

Year: 2016

Authors: Javaheri, T; Kazemi, Z; Pencik, J; Pham, HT; Kauer, M; Noorizadeh, R; Sax, B; Nivarthi, H; Schlederer, M; Maurer, B; Hofbauer, M; Aryee, DN; Wiedner, M; Tomazou, EM; Logan, M; Hartmann, C; Tuckermann, JP; Kenner, L; Mikula, M; Dolznig, H; √úren, A; Richter, GH; Grebien, F; Kovar, H; Moriggl, R

Title: Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.

Source: Cell Death Dis. 2016; 7(10):e2419



Authors Vetmeduni Vienna:

Grebien Florian
Javaheri Tahereh
Kenner Lukas
Moriggl Richard
Pham Ha

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


Abstract:
Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.

Keywords Pubmed: Animals
Animals, Newborn
Apoptosis
Bone and Bones/pathology
Cell Cycle*
Cell Cycle Checkpoints
Cell Differentiation
Cell Proliferation
Cell Survival
Cell Transformation, Neoplastic/metabolism
Cell Transformation, Neoplastic/pathology*
Extremities/pathology
Gene Expression Profiling
Gene Knockdown Techniques
Human Embryonic Stem Cells/metabolism
Humans
Mesenchymal Stromal Cells/metabolism
Mice
Myeloid Cell Leukemia Sequence 1 Protein/metabolism
Oncogene Proteins, Fusion/metabolism*
Osteogenesis
Proto-Oncogene Protein c-fli-1/metabolism*
Proto-Oncogene Proteins c-bcl-2/metabolism
RNA-Binding Protein EWS/metabolism*
Signal Transduction
Transduction, Genetic


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