在慢性髓性白血病中克服BCR::ABL1依赖和独立的生存机制,使用多酶向方法
Caroline Busch1, Theresa Mulholland2, Michele Zagnoni2
1Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK.
Cell communication and signaling : CCS
|November 30, 2023
概括
针对多个途径,包括SRC,ABL和ALK激酶,对于消除持久性慢性髓性白血病 (CML) 干细胞至关重要. 结合疗法有效地打击CML,通过解决药物依赖和利基介导的生存信号.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 血液学 血液学 血液学
背景情况:
- 慢性髓性白血病 (CML) 需要终身治疗,原因是骨髓中持续存在的白血病干细胞 (LSCs).
- 骨形态遗传途径 (BMP) 在CML中失调,在CML干细胞上增加了BMP连接体和过度表达的BMP受体 (ALK),特别是在对伊马替尼布耐药的情况下.
- 萨拉卡丁尼布 (SC) 是一种双重SRC/ABL1抑制剂,也起到ALK抑制剂和BMP抗剂的作用,具有针对TCI耐药性CML的潜力.
研究的目的:
- 调查萨拉卡丁尼布 (SC) 在克服CML干细胞生存信号方面的疗效.
- 为了评估SC在2D和3D培养模型中的有效性,模仿骨髓.
- 评估向BMP途径与TCI结合对CML细胞的影响.
主要方法:
- 治疗CML细胞 (K562和CD34+原发性细胞) 使用伊马蒂尼布 (IM),萨拉卡蒂尼布 (SC) 和多尔索摩芬 (DOR),单独或组合,使用或不使用BMP4刺激.
- 在2D悬浮培养和3D共同培养中进行了实验,使用AggreWell和微流体装置与HS5树皮细胞和介质干细胞进行了实验.
- 细胞亡,细胞循环,增殖和蛋白质/转录的变化通过流动细胞计,殖民地试验,免疫阻塞和qPCR进行了分析.
主要成果:
- 针对BMP,SRC,ABL和ALK激酶的组合治疗显著增加了CML细胞的细胞亡和改变了细胞周期调节.
- 结合治疗后观察到CD34+细胞数量减少,长期增殖受损和分化潜力受损.
- 联合抑制的有效性在2D和3D培养系统中得到证明.
结论:
- BMP信号通路在CML细胞存活中发挥着关键作用.
- 同时向SRC,ABL和ALK激酶在CML治疗中比单独抑制ABL更有效.
- 针对多个激酶的联合疗法对于对抗CML中LSC持久性至关重要,解决目前单剂治疗的局限性.
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