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Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation

B Deneen1, C T Denny

  • 1Molecular Biology Institute, Gwynne Hazen Cherry Memorial Labs, University of California at Los Angeles, Los Angeles, CA 90095, USA.

Oncogene
|December 26, 2001
PubMed

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.

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