Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

Ken Kikuchi, Eri Taniguchi, Hung I.H. Chen, Matthew N. Svalina, Jinu Abraham, Elaine T. Huang, Koichi Nishijo, Sean Davis, Christopher Louden, Lee A. Zarzabal, Olivia Recht, Ayeza Bajwa, Noah Berlow, Mònica Suelves, Sherrie L. Perkins, Paul S. Meltzer, Atiya Mansoor, Joel E. Michalek, Yidong Chen, Brian P. RubinCharles Keller

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background: Alveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a.Methods: We investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models.Results: Rb1 loss was not a necessary and sufficient mutational event for rhabdomyosarcomagenesis, nor a strong cooperative initiating mutation. Instead, Rb1 loss was a modifier of progression and increased anaplasia and pleomorphism. Whereas Pax3:Foxo1a expression was unaltered, biomarkers of aRMS versus embryonal rhabdomyosarcoma were both increased, questioning whether these diagnostic markers are reliable in the context of Rb1 loss. Genome-wide gene expression in Pax3:Foxo1a,Rb1 tumors more closely approximated aRMS than embryonal rhabdomyosarcoma. Intrinsic loss of pRb function in aRMS was evidenced by insensitivity to a Cdk4/6 inhibitor regardless of whether Rb1 was intact or null. This loss of function could be attributed to low baseline Rb1, pRb and phospho-pRb expression in aRMS tumors for which the Rb1 locus was intact. Pax3:Foxo1a RNA interference did not increase pRb or improve Cdk inhibitor sensitivity. Human aRMS shared the feature of low and/or heterogeneous tumor cell pRb expression.Conclusions: Rb1 loss from an already low pRb baseline is a significant disease modifier, raising the possibility that some cases of pleomorphic rhabdomyosarcoma may in fact be Pax3:Foxo1a-expressing aRMS with Rb1 or pRb loss of function.

Original languageEnglish (US)
Article number27
JournalSkeletal Muscle
Issue number1
StatePublished - Nov 25 2013


  • Alveolar rhabdomyosarcoma
  • Disease modifier
  • Rb1
  • Retinoblastoma
  • Sarcoma
  • Spindle cell

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Molecular Biology
  • Cell Biology


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