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最常见的软组织肉瘤。 states.虽然通常是非常可治疗的，但晚期RMS通常证明对治疗有抵抗力，并导致不良的预后。 生存RMS与肌肉谱系有关，并且被认为至少部分地是由于肌肉系统的失败。 转录因子MyoD在功能上促进终末分化。我们的实验室长期研究 NF-κ B作为骨骼肌分化的调节因子的作用，并且已经表明活性NF-κ B阻止了骨骼肌分化。 肌肉的成熟，这与许多疾病有关，包括RMS。因为已知NF-κ B NF-κ B在许多癌症抵抗细胞死亡的能力中起重要作用，我们检测了NF-κ B是否 在RMS细胞中具有相同的细胞存活活性作为化学抗性的潜在机制。 有趣的是，去除NF-κ B的RMS细胞仍然对应激具有抗性。这一发现使我们发现， RMS细胞依赖于MyoD进行细胞存活。此外，我们已经确定这种MyoD介导的 通过MyoD的新的转录抑制功能发生对细胞死亡的抗性。我们的目标 该项目旨在探索MyoD作为RMS进展中的细胞存活因子的潜在新功能， 揭示MyoD抑制基因转录的方式，可能与RMS相关 发病机制因为目前未来RMS治疗的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. !