依赖体的刺信号保持了一个不分化的,恶性骨髓瘤表型
Vijesh G Vaghjiani1, Catherine R Cochrane1,2, W Samantha N Jayasekara1
1Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia.
Oncogene
|October 16, 2023
概括
骨髓瘤中TP53和RB1的损失通过Smoothened (SMO) 激活了黑 (Hh) 信号. 用sonidegib准SMO可以阻止瘤生长,并促进小鼠模型的分化.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 发展生物学 发展生物学
背景情况:
- 在骨髓瘤中,TP53和RB1突变很常见.
- 这些突变破坏了自并促进了初级乳毛形成,增强了 (Hh) 信号传递.
- 异常的Hh通路激活与骨髓瘤的发展有关.
研究的目的:
- 研究Hh通路激活在TP53和RB1损失的骨髓瘤中所起的作用.
- 为了确定向骨髓瘤中Hh通路的治疗潜力.
主要方法:
- 使用了小鼠和人类骨髓瘤模型.
- 在骨质细胞原始体中使用了Trp53和Rb1的条件遗传失活.
- 评估了SMO删除,SHH带过度表达和SMO功能增益突变的影响.
- 用SMO对手sonidegib (LDE225) 进行治疗,以评估治疗疗效.
主要成果:
- 具有TP53/RB1突变的骨肉瘤通过SMO增加了Hh通路的激活.
- 损伤的自和增加的初级乳毛/Hh体表达伴随着这种激活.
- 删除SMO可以逆转恶性骨髓瘤表型,变成良性骨瘤.
- 在体内,sonidegib诱导了生长停止和终端分化.
结论:
- TP53和RB1的损失通过异常的Hh信号驱动骨肉瘤恶性病变.
- SMO是这种致癌途径的关键调解者.
- 对于具有特定基因变异的骨髓瘤,SMO对抗是一种有前途的治疗策略.
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