Lineage of origin in rhabdomyosarcoma informs pharmacological response

Jinu Abraham, Yaiza Nuñez-Álvarez, Simone Hettmer, Elvira Carrió, Hung I Harry Chen, Koichi Nishijo, Elaine T. Huang, Suresh I. Prajapati, Robert L. Walker, Sean Davis, Jennifer Rebeles, Hunter Wiebush, Amanda T. McCleish, Sheila T. Hampton, Christopher R R Bjornson, Andrew S. Brack, Amy J. Wagers, Thomas A. Rando, Mario R. Capecchi, Frank C. MariniBenjamin R. Ehler, Lee Ann Zarzabal, Martin W. Goros, Joel E Michalek, Paul S. Meltzer, David M. Langenau, Robin D. LeGallo, Atiya Mansoor, Yidong Chen, Mònica Suelves, Brian P. Rubin, Charles Keller

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

Original languageEnglish (US)
Pages (from-to)1578-1591
Number of pages14
JournalGenes and Development
Volume28
Issue number14
DOIs
StatePublished - Jul 15 2014

Fingerprint

Rhabdomyosarcoma
Alveolar Rhabdomyosarcoma
Pharmacology
Neoplasms
Oncogene Fusion
Histone Deacetylase Inhibitors
Muscle Development
Genetic Models
Therapeutics

Keywords

  • Alveolar rhabdomyosarcoma
  • Histone
  • Myoblast
  • Pax3:Foxo1
  • Sarcoma
  • Satellite cell

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Abraham, J., Nuñez-Álvarez, Y., Hettmer, S., Carrió, E., Chen, H. I. H., Nishijo, K., ... Keller, C. (2014). Lineage of origin in rhabdomyosarcoma informs pharmacological response. Genes and Development, 28(14), 1578-1591. https://doi.org/10.1101/gad.238733.114

Lineage of origin in rhabdomyosarcoma informs pharmacological response. / Abraham, Jinu; Nuñez-Álvarez, Yaiza; Hettmer, Simone; Carrió, Elvira; Chen, Hung I Harry; Nishijo, Koichi; Huang, Elaine T.; Prajapati, Suresh I.; Walker, Robert L.; Davis, Sean; Rebeles, Jennifer; Wiebush, Hunter; McCleish, Amanda T.; Hampton, Sheila T.; Bjornson, Christopher R R; Brack, Andrew S.; Wagers, Amy J.; Rando, Thomas A.; Capecchi, Mario R.; Marini, Frank C.; Ehler, Benjamin R.; Zarzabal, Lee Ann; Goros, Martin W.; Michalek, Joel E; Meltzer, Paul S.; Langenau, David M.; LeGallo, Robin D.; Mansoor, Atiya; Chen, Yidong; Suelves, Mònica; Rubin, Brian P.; Keller, Charles.

In: Genes and Development, Vol. 28, No. 14, 15.07.2014, p. 1578-1591.

Research output: Contribution to journalArticle

Abraham, J, Nuñez-Álvarez, Y, Hettmer, S, Carrió, E, Chen, HIH, Nishijo, K, Huang, ET, Prajapati, SI, Walker, RL, Davis, S, Rebeles, J, Wiebush, H, McCleish, AT, Hampton, ST, Bjornson, CRR, Brack, AS, Wagers, AJ, Rando, TA, Capecchi, MR, Marini, FC, Ehler, BR, Zarzabal, LA, Goros, MW, Michalek, JE, Meltzer, PS, Langenau, DM, LeGallo, RD, Mansoor, A, Chen, Y, Suelves, M, Rubin, BP & Keller, C 2014, 'Lineage of origin in rhabdomyosarcoma informs pharmacological response', Genes and Development, vol. 28, no. 14, pp. 1578-1591. https://doi.org/10.1101/gad.238733.114
Abraham J, Nuñez-Álvarez Y, Hettmer S, Carrió E, Chen HIH, Nishijo K et al. Lineage of origin in rhabdomyosarcoma informs pharmacological response. Genes and Development. 2014 Jul 15;28(14):1578-1591. https://doi.org/10.1101/gad.238733.114
Abraham, Jinu ; Nuñez-Álvarez, Yaiza ; Hettmer, Simone ; Carrió, Elvira ; Chen, Hung I Harry ; Nishijo, Koichi ; Huang, Elaine T. ; Prajapati, Suresh I. ; Walker, Robert L. ; Davis, Sean ; Rebeles, Jennifer ; Wiebush, Hunter ; McCleish, Amanda T. ; Hampton, Sheila T. ; Bjornson, Christopher R R ; Brack, Andrew S. ; Wagers, Amy J. ; Rando, Thomas A. ; Capecchi, Mario R. ; Marini, Frank C. ; Ehler, Benjamin R. ; Zarzabal, Lee Ann ; Goros, Martin W. ; Michalek, Joel E ; Meltzer, Paul S. ; Langenau, David M. ; LeGallo, Robin D. ; Mansoor, Atiya ; Chen, Yidong ; Suelves, Mònica ; Rubin, Brian P. ; Keller, Charles. / Lineage of origin in rhabdomyosarcoma informs pharmacological response. In: Genes and Development. 2014 ; Vol. 28, No. 14. pp. 1578-1591.
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