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

Tahereh Javaheri1,2, Zahra Kazemi3,4, Jan Pencik1,3,5

  • 1Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

Cell Death & Disease
|October 14, 2016
PubMed

Insights

Ewing sarcoma (ES) development in mice is driven by EWS/FLI1 (EF) expression, which disrupts bone cell differentiation. Targeting survival and cell cycle pathways offers a promising strategy against this childhood cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Developmental Biology

Background:

  • Ewing sarcoma (ES) is a prevalent childhood bone cancer.
  • The EWS/FLI1 (EF) fusion protein drives ES pathogenesis.
  • Understanding EF's role in bone development and ES initiation is crucial for targeted therapies.

Purpose of the Study:

  • To establish a genetically defined mouse model for ES.
  • To investigate how EF expression impacts bone precursor cell differentiation.
  • To identify mechanisms for targeting ES.

Main Methods:

  • Mesenchymal Prx1-directed conditional EF expression in mice.
  • Analysis of signaling pathways affected by EF.
  • Transplantation of EF-expressing mesenchymal stem cells (MSCs) into immunocompromised mice.
  • Investigating the role of BCL2 family members, CDK4, P53, and INK4A.
  • Knockdown and pharmacologic inhibition of Mcl1 and Cdk4.

Main Results:

  • EF expression arrested chondrocyte and osteoblast differentiation via altered signaling pathways.
  • EF-expressing MSCs exhibited enhanced self-renewal and resistance to apoptosis.
  • Enforced BCL2 family expression in MSCs promoted rapid sarcoma formation.
  • High BCL2 family and CDK4, with low P53 and INK4A, synergized in ES development.
  • Inhibition of Mcl1 or Cdk4 induced growth arrest and apoptosis in ES cells.

Conclusions:

  • EF disrupts normal bone development and drives ES.
  • BCL2 family members and cell cycle regulators are key in ES pathogenesis.
  • Combinatorial targeting of survival and cell cycle pathways shows therapeutic potential for ES.

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