Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.

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Publication Type Journal Article
School or College College of Science; School of Medicine
Department Oncological Sciences; Human Genetics; Pathology; Pediatrics; Biology
Program Institute of Human Genetics; Howard Hughes Medical Institute (HHMI)
Creator Coffin, Cheryl M.; Capecchi, Mario R.
Other Author Keller, Charles; Arenkiel, Benjamin R; El-Bardeesy, Nabeel; DePinho, Ronald A
Title Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.
Date 2004-11-01
Description Alveolar rhabdomyosarcoma is an aggressive childhood muscle cancer for which outcomes are poor when the disease is advanced. Although well-developed mouse models exist for embryonal and pleomorphic rhabdomyosarcomas, neither a spontaneous nor a transgenic mouse model of alveolar rhabdomyosarcoma has yet been reported. We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle. In these mice, alveolar rhabdomyosarcomas occur but at low frequency, and Fkhr haploinsufficiency does not appear to accelerate tumorigenesis. However, Pax3:Fkhr homozygosity with accompanying Ink4a/ARF or Trp53 pathway disruption, by means of conditional Trp53 or Ink4a/ARF loss of function, substantially increases the frequencies of tumor formation. These results of successful tumor generation postnatally from a target pool of differentiating myofibers are in sharp contrast to the birth defects and lack of tumors for mice with prenatal and postnatal satellite cell triggering of Pax3:Fkhr. Furthermore, these murine alveolar rhabdomyosarcomas have an immunohistochemical profile similar to human alveolar rhabdomyosarcoma, suggesting that this conditional mouse model will be relevant to study of the disease and will be useful for preclinical therapeutic testing.
Type Text
Publisher Cold Spring Harbor Lab Press
Volume 18
Issue 21
First Page 2614
Last Page 2626
Subject Cell Differentiation; Forkhead Transcription Factors; Myogenic Regulatory Factors
Subject MESH ADP-Ribosylation Factors; DNA-Binding Proteins; Cyclin-Dependent Kinases
Language eng
Bibliographic Citation Keller C, Arenkiel BR, Coffin CM, El-Bardeesy N, DePinho RA, Capecchi MR. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev. 2004 Nov 1;18(21):2614-26. Retrieved September 7, 2006 from http://www.genesdev.org/cgi/content/full/18/21/2614.
Rights Management Copyright 2004 Cold Spring Harbor Laboratory Press. All Rights Reserved.
Format Medium application/pdf
ARK ark:/87278/s654361h
Setname ir_uspace
Date Created 2012-06-13
Date Modified 2012-06-13
ID 705622
Reference URL https://collections.lib.utah.edu/ark:/87278/s654361h
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