针对T细胞急性淋巴细胞白血病和淋巴瘤中的高活性血小板衍生的生生长因子受体-β信号
Stien De Coninck1, Renate De Smedt1, Beatrice Lintermans1
1Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent.
Haematologica
|November 9, 2023
概括
一种新的MYH9::PDGFRB融合驱动了攻击性的T细胞急性淋巴细胞白血病 (T-ALL) 和T细胞淋巴细胞淋巴瘤 (T-LBL). 用CP-673451准PDGFRB显示了这些罕见的血液癌症的治疗潜力.
科学领域:
- 血液学 血液学 血液学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- T细胞急性淋巴细胞白血病 (T-ALL) 和T细胞淋巴细胞淋巴瘤 (T-LBL) 是具有重大未满足需求的侵袭性血液瘤.
- 目前的密集化疗提供了有限的生存率和严重的毒性,需要新的向疗法.
- 复发性或耐药性疾病发生在10-20%的患者中,突出显示了对较少毒性治疗策略的需求.
研究的目的:
- 为了确定T-ALL/T-LBL中的新瘤原因驱动因素.
- 研究PDGFRB (血小板衍生生生长因子受体β) 在T-ALL/T-LBL病变发生过程中的作用.
- 在T-ALL/T-LBL模型中评估PDGFRB抑制的治疗疗效.
主要方法:
- 在T-LBL患者中识别和描述一种新的MYH9::PDGFRB融合.
- 融合蛋白的致癌潜力的体外和体外功能研究.
- 在T-ALL细胞系和患者衍生的异种移植中分析PDGFRB表达和激活.
- 在体外和体内对PDGFRB抑制剂CP-673451的评估.
主要成果:
- 发现了一种新型的,构成性活跃的MYH9::PDGFRB融合,驱动瘤转化.
- 在T-ALL细胞系和异种移植模型中观察到PDGFRB过活化,特别是在TLX3和HOXA亚型中.
- 选择性PDGFRB抑制剂CP-673451在体外和体内证明了治疗功效.
- 对CP-673451的敏感性与PDGFRB过活化相关.
结论:
- 在T-ALL/T-LBL中,PDGFRB过度活化是显著的致癌驱动因素.
- 酸化PDGFRB水平可以作为针对性治疗的预测生物标志物.
- 抑制PDGFRB代表了对T-ALL/T-LBL患者的有前途的新疗法策略.
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