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首页> 外文期刊>Skeletal Muscle >Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma
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Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

机译：Rb1丢失会改变但不会引发肺泡横纹肌肉瘤

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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.
机译：背景肺泡横纹肌肉瘤（aRMS）是一种成肌性的儿童肉瘤，通常与易位介导的融合基因Pax3：Foxo1a相关。方法我们使用条件小鼠模型研究了Rb1缺失在aRMS肿瘤发生和发展中的互补作用。结果Rb1丢失不是横纹肌肉瘤发生的必要和充分的突变事件，也不是强烈的协同启动突变。取而代之的是，Rb1丢失是进展的修饰因子，且发育不全和多态性增加。 Pax3：Foxo1a表达未改变，而aRMS与胚胎横纹肌肉瘤的生物标志物均增加，从而质疑这些诊断标志物在Rb1缺失的情况下是否可靠。 Pax3：Foxo1a，Rb1肿瘤中全基因组基因表达比胚胎横纹肌肉瘤更接近aRMS。通过对Cdk4 / 6抑制剂不敏感来证明aRMS中pRb功能的内在丧失，无论Rb1是完整的还是无效的。这种功能丧失可能归因于Rb1基因座完整的aRMS肿瘤中较低的基线Rb1，pRb和磷酸化pRb表达。 Pax3：Foxo1a RNA干扰不会增加pRb或提高Cdk抑制剂的敏感性。人类aRMS具有低和/或异质性肿瘤细胞pRb表达的特征。结论从已经很低的pRb基线中丢失Rb1是一种重要的疾病改良剂，增加了某些多形性横纹肌肉瘤病例实际上可能是表达Pax3：Foxo1a的aRMS伴Rb1或pRb功能丧失的可能性。

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