New perspective on MyoD function and differentiation in rhabdomyosarcoma

摘要 横纹肌肉瘤 (RMS) 是美国儿童和青少年中最常见的软组织肉瘤 国家。虽然通常可以治疗，但晚期 RMS 通常对治疗有抵抗力，并导致效果不佳 生存。 RMS 与肌肉谱系有关，并且被认为至少部分是由于肌肉功能障碍造成的。 转录因子 MyoD 具有促进终末分化的功能。我们实验室长期研究 NF-κB 作为骨骼肌分化调节剂的作用，并表明活跃的 NF-κB 可以防止 肌肉的成熟，这与许多疾病有关，包括 RMS。因为 NF-κB 已知 在许多癌症抵抗细胞死亡的能力中发挥重要作用，我们检查了 NF-κB 是否 作为化学抗性的潜在机制，在 RMS 细胞中具有相同的细胞存活活性。 有趣的是，耗尽 NF-κB 的 RMS 细胞仍然能够抵抗压力。这一发现使我们发现 RMS 细胞的存活依赖于 MyoD。此外，我们已经确定这种由 MyoD 介导的 对细胞死亡的抵抗是通过 MyoD 的新型转录抑制功能发生的。我们的目标 该项目旨在探索 MyoD 作为细胞存活因子在 RMS 进展中的潜在新功能， 揭示 MyoD 抑制基因转录的方式，可能与 RMS 相关 发病机制。因为未来 RMS 治疗的当前范式是促进细胞分化 通过刺激 MyoD，我们目前的发现与我们提出的目标相结合，有可能改变 未来的 RMS 疗法。 ！

ABSTRACT Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents in the United States. While generally very treatable, advanced RMS often proves resistant to treatment and results in poor survival. RMS is linked to a muscle lineage and is believed to result, at least in part, from a failure of the transcription factor MyoD to functionally promote terminal differentiation. Our laboratory has long studied the role of NF-κB as a regulator of skeletal muscle differentiation, and has shown that active NF-κB prevents the maturation of muscle, which is relevant in a number of diseases, including RMS. Because NF-κB is known to play an important role in the ability of a number of cancers to resist cell death, we examined whether NF-κB would have the same cell survival activity in RMS cells as a potential mechanism of chemoresistance. Interestingly, RMS cells depleted of NF-κB remained resistant to stress. This finding led us to uncover that RMS cells depend upon MyoD for cell survival. Further, we have determined that this MyoD-mediated resistance to cell death occurs through a novel transcriptional repressive function of MyoD. The goal of our project is to explore a potential new function of MyoD as a cell survival factor in the progression of RMS and unravel the manner in which MyoD is acting to repress gene transcription, potentially relevant to RMS pathogenesis. Because the current paradigm of future RMS treatments is to promote cell differentiation through stimulation of MyoD, our current findings paired with our proposed aims have the potential to alter future RMS therapies. !