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The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence.

Publication ,  Journal Article
Linardic, CM; Naini, S; Herndon, JE; Kesserwan, C; Qualman, SJ; Counter, CM
Published in: Cancer Res
July 15, 2007

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of <30%. ARMS is characterized by a chromosomal translocation generating the PAX3-FKHR fusion gene. However, ectopic expression of PAX3-FKHR often induces inhibition of cell proliferation, or cell death, when expressed in nonmuscle cells. This prompted us to explore the effect of expressing PAX3-FKHR in more relevant cells, specifically primary human skeletal muscle cells because these cells can be converted to a tumorigenic state that mimics rhabdomyosarcoma. PAX3-FKHR expression promoted both fetal and postnatal primary human skeletal muscle cell precursors to bypass the senescence growth arrest checkpoint. This bypass was accompanied by epigenetic DNA methylation of the p16(INK4A) promoter and correspondingly a loss of expression of this tumor suppressor. Knockdown of p16(INK4A) cooperated with PAX3-FKHR to drive proliferation past senescence, whereas reintroduction of wild-type p16(INK4A) in post-senescent cells caused growth arrest. Thus, PAX3-FKHR acts in concert with loss of p16(INK4A) to promote inappropriate proliferation of skeletal muscle cells. This association between PAX3-FKHR expression and p16(INK4A) loss was seen in human ARMS tumor tissue, as both human rhabdomyosarcoma cell lines and tissue microarrays showed a trend toward down-regulation of p16(INK4A) protein in alveolar subsets. We surmise that the generation of the PAX3-FKHR fusion protein may require loss of p16(INK4A) to promote malignant proliferation of skeletal muscle cells as an early step in ARMS tumorigenesis.

Duke Scholars

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

July 15, 2007

Volume

67

Issue

14

Start / End Page

6691 / 6699

Location

United States

Related Subject Headings

  • Rhabdomyosarcoma
  • Recombinant Fusion Proteins
  • Promoter Regions, Genetic
  • Paired Box Transcription Factors
  • PAX3 Transcription Factor
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis
  • Muscle, Skeletal
  • Lung Neoplasms
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Linardic, C. M., Naini, S., Herndon, J. E., Kesserwan, C., Qualman, S. J., & Counter, C. M. (2007). The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence. Cancer Res, 67(14), 6691–6699. https://doi.org/10.1158/0008-5472.CAN-06-3210
Linardic, Corinne M., Sarasija Naini, James E. Herndon, Chimen Kesserwan, Stephen J. Qualman, and Christopher M. Counter. “The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence.Cancer Res 67, no. 14 (July 15, 2007): 6691–99. https://doi.org/10.1158/0008-5472.CAN-06-3210.
Linardic CM, Naini S, Herndon JE, Kesserwan C, Qualman SJ, Counter CM. The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence. Cancer Res. 2007 Jul 15;67(14):6691–9.
Linardic, Corinne M., et al. “The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence.Cancer Res, vol. 67, no. 14, July 2007, pp. 6691–99. Pubmed, doi:10.1158/0008-5472.CAN-06-3210.
Linardic CM, Naini S, Herndon JE, Kesserwan C, Qualman SJ, Counter CM. The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence. Cancer Res. 2007 Jul 15;67(14):6691–6699.

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

July 15, 2007

Volume

67

Issue

14

Start / End Page

6691 / 6699

Location

United States

Related Subject Headings

  • Rhabdomyosarcoma
  • Recombinant Fusion Proteins
  • Promoter Regions, Genetic
  • Paired Box Transcription Factors
  • PAX3 Transcription Factor
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis
  • Muscle, Skeletal
  • Lung Neoplasms
  • Humans