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Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation
1Molecular Biology Institute, Gwynne Hazen Cherry Memorial Labs, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Abstract:
Ewings sarcoma and primitive neuroectodermal tumors (ES/PNET) are characterized by the fusion of the N-terminus of the EWS gene to the C-terminus of a member of the ETS family of transcription factors. While such fusion proteins are thought to play dominant oncogenic roles, it is unlikely that a single genetic alteration by itself will support cellular transformation. Given that EWS/FLI1 is only able to transform immortalized 3T3 fibroblasts and that 30% of ES/PNET tumors contain a homozygous deletion of the p16 locus, it is likely that other genetic events are required for EWS/FLI1 oncogenesis. Here we describe a complementary mechanism utilized in the establishment ES/PNET tumors. EWS/FLI1 has the capacity to induce apoptosis and growth arrest in normal MEFs. Such effects prevent the establishment of stable expression of the protein in these cells. When expressed in p16, p19(ARF), or p53 deficient MEFs, the apoptotic and growth arrest effects are attenuated, creating a environment permissive for stable expression of the protein. While loss of a single tumor suppressor is sufficient to establish expression of EWS/FLI1, cellular transformation requires further genetic perturbation.
Insights
Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) require additional genetic events beyond the EWS/FLI1 fusion protein for oncogenesis. Loss of tumor suppressors like p16 or p53 facilitates EWS/FLI1 expression, but further alterations are needed for cellular transformation.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ewing sarcoma and primitive neuroectodermal tumors (ES/PNET) are driven by EWS/ETS gene fusions.
- The EWS/FLI1 fusion protein is a key oncogenic driver, but likely insufficient alone for tumor development.
Purpose of the Study:
- To investigate the role of tumor suppressor genes in the oncogenesis of ES/PNET.
- To understand the mechanisms by which EWS/FLI1 establishes a transformed cellular environment.
Main Methods:
- Utilized mouse embryonic fibroblasts (MEFs) with deficiencies in p16, p19ARF, or p53.
- Assessed the impact of these deficiencies on EWS/FLI1-induced apoptosis and growth arrest.
- Evaluated the stability of EWS/FLI1 expression in deficient MEFs.
Main Results:
- EWS/FLI1 induces apoptosis and growth arrest in normal MEFs, preventing stable expression.
- Deficiencies in p16, p19ARF, or p53 attenuate these anti-proliferative effects.
- Loss of a single tumor suppressor gene permits stable EWS/FLI1 expression in MEFs.
Conclusions:
- Tumor suppressor pathways, particularly involving p16, p19ARF, and p53, normally restrict EWS/FLI1 oncogenic activity.
- Inactivation of these pathways creates a permissive environment for ES/PNET development.
- Complete cellular transformation necessitates additional genetic alterations beyond EWS/FLI1 fusion and tumor suppressor loss.