PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.

PTEN启动子高甲基化几乎是普遍存在的，约 25% 的融合阴性横纹肌肉瘤 (FN-RMS) 中发生PTEN拷贝数丢失。在这里，我们展示了 FN-RMS 小鼠模型中Pten缺失导致分化程度较低的肿瘤更接近人类胚胎 RMS。 PTEN 缺失会激活 PI3K 通路，但不会增加 mTOR 活性。在野生型肿瘤中，PTEN 在细胞核中表达，表明核 PTEN 功能的丧失可以解释这些表型。 Pten缺失的肿瘤增加了对神经和骨骼肌发育重要的转录因子（包括Dbx1和Pax7 ）的表达。 Pax7缺失完全挽救了Pten缺失的影响。引人注目的是，这些Pten;Pax7缺失的肿瘤不再是 FN-RMS，而是表现出类似于平滑肌肉瘤的平滑肌分化。这些数据强调了 FN-RMS 中的Pten丢失如何与 PAX7 谱系特异性转录输出相关联，从而产生对转录因子 PAX7 的依赖性或合成必要性以维持肿瘤身份。