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

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.

• Authors: Tahereh Javaheri, Zahra Kazemi, Jan Pencik, Ha Tt Pham, Maximilian Kauer, Rahil Noorizadeh, Barbara Sax, Harini Nivarthi, Michaela Schlederer, Barbara Maurer, Maximillian Hofbauer, Dave Nt Aryee, Marc Wiedner, Eleni M Tomazou, Malcolm Logan, Christine Hartmann, Jan P Tuckermann, Lukas Kenner, Mario Mikula, Helmut Dolznig, Aykut Üren, Günther H Richter, Florian Grebien, Heinrich Kovar, Richard Moriggl
• Journal: Cell death & disease (Cell Death Dis) Vol. 7 Issue 10 Pg. e2419 (10 13 2016) ISSN: 2041-4889 [Electronic] England
• PMID: 27735950 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• EWS-FLI fusion protein
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• Oncogene Proteins, Fusion
• Proto-Oncogene Protein c-fli-1
• Proto-Oncogene Proteins c-bcl-2
• RNA-Binding Protein EWS

Topics

• Animals
• Animals, Newborn
• Apoptosis
• Bone and Bones (pathology)
• Cell Cycle
• Cell Cycle Checkpoints
• Cell Differentiation
• Cell Proliferation
• Cell Survival
• Cell Transformation, Neoplastic (metabolism, pathology)
• Extremities (pathology)
• Gene Expression Profiling
• Gene Knockdown Techniques
• Human Embryonic Stem Cells (metabolism)
• Humans
• Mesenchymal Stem 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