转变生长因子-β信号在达沙替尼抗性和BCR前急性淋巴细胞白血病的功能性表征+
Gila Mostufi-Zadeh-Haghighi1, Pia Veratti1,2,3, Kyra Zodel1
1Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Cancers
|September 9, 2023
概括
急性淋巴细胞白血病 (ALL) 的达沙替尼抗性涉及高调的TGFβ通路. 这一途径,包括SMAD3,影响细胞生长和细胞亡,为药物耐药性机制提供了洞察力.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
背景情况:
- 达沙替尼对具有E2A-PBX1融合的B细胞前受体 (BCR前) 阳性急性淋巴细胞白血病 (ALL) 有效.
- TGFβ信号通路在癌症中具有复杂的作用,影响瘤抑制和进展.
研究的目的:
- 研究TGFβ信号通路在BCR+/E2A-PBX1+前ALL中达沙替尼抗性的作用.
- 为了确定与获得的对达沙替尼布耐药性相关的特定分子变化.
主要方法:
- 对抗达沙替尼布的BCR+/E2A-PBX1+前ALL细胞进行全球转录组分析.
- 在转录和翻译层面确认SMAD3的上调.
- 对达沙替尼对TGFβ诱导的SMAD3酸化的影响的评估.
主要成果:
- 在抗达沙替尼布ALL细胞中发现了TGFβ信号通路和SMAD3的升调.
- 达沙替尼在ALL细胞系中部分抑制TGFβ诱导的SMAD3酸化.
- 在BCR+/E2A-PBX1+前的ALL细胞中TGFβ1激活诱导了细胞周期停止,细胞亡和c-MYC下调.
结论:
- TGFβ信号通路在B细胞前体ALL的白血病发生中发挥着重要作用.
- 提升TGFβ通路的调节,特别是SMAD3,有助于对达沙替尼的二次耐药性.
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