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. Rubin & 1 others Charles Keller

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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
Volume3
Issue number1
DOIs
StatePublished - Nov 25 2013

Fingerprint

Alveolar Rhabdomyosarcoma
Embryonal Rhabdomyosarcoma
Neoplasms
Anaplasia
Rhabdomyosarcoma
Gene Fusion
RNA Interference
Sarcoma
Biomarkers
Genome
Gene Expression
Mutation

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Orthopedics and Sports Medicine

Cite this

Kikuchi, K., Taniguchi, E., Chen, H. I. H., Svalina, M. N., Abraham, J., Huang, E. T., ... Keller, C. (2013). Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma. Skeletal Muscle, 3(1), [27]. https://doi.org/10.1186/2044-5040-3-27

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma. / Kikuchi, Ken; Taniguchi, Eri; Chen, Hung I H; Svalina, Matthew N.; Abraham, Jinu; Huang, Elaine T.; Nishijo, Koichi; Davis, Sean; Louden, Christopher; Zarzabal, Lee A.; Recht, Olivia; Bajwa, Ayeza; Berlow, Noah; Suelves, Mònica; Perkins, Sherrie L.; Meltzer, Paul S.; Mansoor, Atiya; Michalek, Joel E.; Chen, Yidong; Rubin, Brian P.; Keller, Charles.

In: Skeletal Muscle, Vol. 3, No. 1, 27, 25.11.2013.

Research output: Contribution to journalArticle

Kikuchi, K, Taniguchi, E, Chen, HIH, Svalina, MN, Abraham, J, Huang, ET, Nishijo, K, Davis, S, Louden, C, Zarzabal, LA, Recht, O, Bajwa, A, Berlow, N, Suelves, M, Perkins, SL, Meltzer, PS, Mansoor, A, Michalek, JE, Chen, Y, Rubin, BP & Keller, C 2013, 'Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma', Skeletal Muscle, vol. 3, no. 1, 27. https://doi.org/10.1186/2044-5040-3-27
Kikuchi K, Taniguchi E, Chen HIH, Svalina MN, Abraham J, Huang ET et al. Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma. Skeletal Muscle. 2013 Nov 25;3(1). 27. https://doi.org/10.1186/2044-5040-3-27
Kikuchi, Ken ; Taniguchi, Eri ; Chen, Hung I H ; Svalina, Matthew N. ; Abraham, Jinu ; Huang, Elaine T. ; Nishijo, Koichi ; Davis, Sean ; Louden, Christopher ; Zarzabal, Lee A. ; Recht, Olivia ; Bajwa, Ayeza ; Berlow, Noah ; Suelves, Mònica ; Perkins, Sherrie L. ; Meltzer, Paul S. ; Mansoor, Atiya ; Michalek, Joel E. ; Chen, Yidong ; Rubin, Brian P. ; Keller, Charles. / Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma. In: Skeletal Muscle. 2013 ; Vol. 3, No. 1.
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abstract = "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.",
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T1 - Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

AU - Kikuchi, Ken

AU - Taniguchi, Eri

AU - Chen, Hung I H

AU - Svalina, Matthew N.

AU - Abraham, Jinu

AU - Huang, Elaine T.

AU - Nishijo, Koichi

AU - Davis, Sean

AU - Louden, Christopher

AU - Zarzabal, Lee A.

AU - Recht, Olivia

AU - Bajwa, Ayeza

AU - Berlow, Noah

AU - Suelves, Mònica

AU - Perkins, Sherrie L.

AU - Meltzer, Paul S.

AU - Mansoor, Atiya

AU - Michalek, Joel E.

AU - Chen, Yidong

AU - Rubin, Brian P.

AU - Keller, Charles

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Y1 - 2013/11/25

N2 - 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.

AB - 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.

KW - Alveolar rhabdomyosarcoma

KW - Disease modifier

KW - Rb1

KW - Retinoblastoma

KW - Sarcoma

KW - Spindle cell

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