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

被引:249
作者
Keller, C
Arenkiel, BR
Coffin, CM
El-Bardeesy, N
DePinho, RA
Capecchi, MR [1 ]
机构
[1] Univ Utah, Div Pediat Hematol Oncol, Salt Lake City, UT 84112 USA
[2] Univ Utah, Dept Pediat, Salt Lake City, UT 84112 USA
[3] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA
[4] Univ Utah, Div Pediat Pathol, Salt Lake City, UT 84112 USA
[5] Univ Utah, Dept Pathol, Salt Lake City, UT 84112 USA
[6] Univ Utah, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA
[7] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA
[8] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA
[9] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[10] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA
关键词
alveolar rhabdomyosarcoma; Pax3 : Fkhr; Pax3; Fkhr; FoxO1A; chromosome translocation; satellite cell;
D O I
10.1101/gad.1244004
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:2614 / 2626
页数:13
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