Transgenic model of cardiac rhabdomyosarcoma formation

Köbbert, Christiane; Möllmann, Christa; Schäfers, Michael; Hermann, Sven; Baba, Hideo; Hoffmeier, A.; Breithardt, Günter; Scheld, Hans H.; Weißen-Plenz, Gabriele; Sindermann, Jürgen R.

doi:10.1016/j.jtcvs.2008.04.022

Cited by 6 publications

(6 citation statements)

References 32 publications

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“…However, these cases are generally RMS not otherwise specified rather than aRMS [31]. In mice, the T antigen (which inactivates all three Rb-family members pRb, p107 and p130) expressed as a transgene leads to the development of cardiac RMS [32]. However, in our recent study of strict conditional Rb1 loss in the Myf6 -expressing fetal/postnatal maturing myoblast or Pax7-expressing postnatal muscle stem cell (satellite cell) lineages, no tumors developed [33]; instead, satellite cell and myoblast pools expanded but were largely incapable of fusing to form mature myofibers.…”

Section: Discussionmentioning

confidence: 99%

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

Kikuchi

Taniguchi²,

Chen³

et al. 2013

Skeletal Muscle

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BackgroundAlveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a.MethodsWe investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models.ResultsRb1 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.ConclusionsRb1 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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Section: Discussionmentioning

confidence: 99%

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

Kikuchi

Taniguchi²,

Chen³

et al. 2013

Skeletal Muscle

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“…In another model, transgenic mice expressing the 2.7‐kb SV40 TAg early region under the control of the 5′ region of the SM22alpha gene (expressed in embryonic cardiac muscle) developed a rare form of cardiac RMS at the age of approximately 8–12 weeks . Authors reasoned that the SV40 TAg protein and/or its upstream regulatory region may be implicated in the binding and sequestration of specific protein partners whose identity was yet unknown and whose loss of function may be involved in RMS formation.…”

Section: Experimental Animal Models Of Rmsmentioning

confidence: 99%

Rhabdomyosarcomas: an overview on the experimental animal models

Zanola

Rossi

Faggi

et al. 2012

J Cellular Molecular Medi

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Rhabdomyosarcomas (RMS) are aggressive childhood soft-tissue malignancies deriving from mesenchymal progenitors that are committed to muscle-specific lineages. Despite the histopathological signatures associated with three main histological variants, termed embryonal, alveolar and pleomorphic, a plethora of genetic and molecular changes are recognized in RMS. Over the years, exposure to carcinogens or ionizing radiations and gene-targeting approaches in vivo have greatly contributed to disclose some of the mechanisms underlying RMS onset. In this review, we describe the principal distinct features associated with RMS variants and focus on the current available experimental animal models to point out the molecular determinants cooperating with RMS development and progression.

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“…The genetic event mostly required for RMS induction, common to all histotypes, is the knockdown of the p53 pathway, obtained through the knockout of p53 itself [120,[172][173][174][175] or of its upstream Ink4a/Arf mediator [134,174], or through functional inactivation by SV40 T [176]. Biallelic knockdown of p53 is often required to attain a 100% incidence of RMS [120,134,[173][174][175], or is observed in the tumor [134,172,175], thus showing a gene dosage effect.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Biallelic knockdown of p53 is often required to attain a 100% incidence of RMS [120,134,[173][174][175], or is observed in the tumor [134,172,175], thus showing a gene dosage effect. Some of the rel evant genetic events (SV40 T and Ink4a/Arf) are also known to affect the RB pathway [134,174,176].…”

Section: Animal Modelsmentioning

confidence: 99%

“…Concerning the site of tumor onset, a wide heterogeneity among different models could be observed, ranging from multiple sites [134,178], to a prevalence in extremities [174], to peculiar sites (such as pelvic [172], facial/orbital [173] or heart [176]). In a few models RMS also arose from ectopic nonskeletal muscle sites (a feature also observed in humans) [134].…”

Section: Animal Modelsmentioning

confidence: 99%

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