拼接因子YBX1调节了JAK2突变瘤的持续性
Ashok Kumar Jayavelu1, Tina M Schnöder2,3, Florian Perner2
1Max Planck Institute of Biochemistry, Munich, Germany.
Nature
|November 26, 2020
概括
突变的JAK2导致骨髓增殖性瘤. 除了JAK抑制剂,还可以使YBX1,一个JAK2标,失活,从而诱导JAK2突变细胞的亡和缓解.
科学领域:
- 血液学
- 分子生物学
- 癌症生物学
背景情况:
- 简氏激酶 (JAKs) 对于细胞信号传递至关重要,而JAK2突变驱动骨髓增殖性瘤 (MPNs).
- 目前的JAK抑制剂在根除JAK2突变克隆方面有效性有限,因此需要对疾病持续机制进行研究.
研究的目的:
- 尽管接受了JAK抑制剂治疗,但仍存在JAK2突变克隆的分子机制.
- 确定可增强JAK抑制剂在MPN中的疗效的新疗法标.
主要方法:
- 进行深入的蛋白形,以确定突变JAK2的标.
- 在JAK2突变细胞和动物模型中涉及YBX1无活化和JAK抑制的功能研究.
- 对RNA拼接,转录控制和细胞外信号调节激酶 (ERK) 信号的分析.
主要成果:
- 包括YBX1在内的参与mRNA处理的蛋白质被确定为突变JAK2的标.
- 禁用YBX1使得持久细胞对细胞灭绝敏感,并导致RNA错误拼接和破坏ERK信号.
- 结合JAK抑制和YBX1无活化导致细胞亡,恶性克隆回归和分子缓解.
结论:
- 突变的JAK2对YBX1的差异蛋白酸化有助于对JAK2-ERK信号的剪接依赖性改变,维持恶性克隆.
- 针对依赖于YBX1的ERK信号与JAK2抑制相结合,为消除JAK2突变细胞提供了潜在的策略.
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