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针对细胞周期和细胞命运调节程序的连续药物治疗阻断了急性淋巴细胞白血病中非遗传癌症的演变

Alena Malyukova¹, Mari Lahnalampi², Ton Falqués-Costa³

¹Department of Cell and Molecular Biology, Karolinska Institutet, Biomedicum, Solnavägen 9, 171 77, Stockholm, Sweden. aljona.maljukova@ki.se.

|June 1, 2024

概括

在急性淋巴细胞白血病 (ALL) 中准WEE1会破坏癌细胞状态,揭示药物耐受性机制. 结合WEE1抑制剂与BCR信号或代谢抑制剂的序列疗法克服了这种耐受性,提供了新的治疗策略.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
癌细胞生物学癌细胞生物学

背景情况:

向治疗提供了更好的结果,但由于瘤异质性而面临限制.
了解跨不同癌细胞状态的药物效应是有效的组合疗法和预防复发的关键.

研究的目的:

研究WEE1抑制对急性淋巴细胞白血病 (ALL) 细胞命运调节的影响.
确定由WEE1抑制诱导的耐药性机制,并探索克服它的策略.

主要方法:

利用单细胞RNA-seq和ATAC-seq分析用WEE1抑制剂AZD1775.5治疗ALL细胞中的细胞状态多样化.
研究了KMT2A-RUNX1-MYC监管网络和p53驱动过程的作用.
评估了使用BCR信号抑制剂 (达沙替尼,易布鲁替尼) 或代谢抑制剂 (脂肪,AZD2014) 的顺序治疗策略.

主要成果:

在ALL细胞中抑制WEE1,特别是那些具有KMT2A重组的细胞中,诱导了细胞状态多样化.
一部分细胞通过激活前B细胞命运,脂质新陈代谢和BCR前信号传递而产生耐药性.
用BCR抑制剂或代谢调节剂进行连续治疗有效抵消药物耐受性,诱导细胞死亡并减少干细胞标志物.

结论:

抑制WEE1会影响控制细胞周期和ALL细胞命运的基因调节程序.
与低毒性BCR信号传递或代谢抑制剂连续使用WEE1抑制剂是一种有前途的治疗策略.

关键词:

AZD17757575 在线观看 B-ALL,所有的人.在 BCL6 中.细胞状态过渡细胞状态过渡染色素状态染色素状态在KMT2A-rr中使用.在白血病中,白血病.在BCR之前的BCR.在RUNX1中,使用RUNX1.单细胞多组的多组学在WEE1中,WEE1是WEE1的代名词.

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