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IKZF1基因缺失导致B细胞前体急性淋巴细胞白血病中对cytarabine的耐药性

Britt M T Vervoort¹, Miriam Butler¹, Kari J T Grünewald¹

¹Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.

|June 6, 2024

概括

在B细胞前体急性淋巴细胞白血病 (BCP-ALL) 中,IKZF1的丧失导致对细胞因子 (AraC) 治疗的耐药性. 向特定的激酶可能会恢复这些高风险患者的敏感性.

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:

在10-15%的B细胞前体急性淋巴细胞白血病 (BCP-ALL) 病例中存在IKZF1缺失.
这些删除与患者的不良结果有关.
在BCP-ALL中,IKZF1损失对药物敏感性的影响尚不清楚.

研究的目的:

为了研究IKZF1损失对BCP-ALL.在BCP-ALL中对细胞氨酸 (AraC) 敏感性的影响.
为了阐明在IKZF1删除的BCP-ALL中Arac耐药性背后的机制.
确定潜在的治疗策略来克服AraC耐药性.

主要方法:

利用实验模型和患者数据.
评估了与IKZF1状态相关的AraC敏感性.
溶解物载体hENT1和Evi1.1的量化表达
进行了酶导向的CRISPR/Cas9屏幕来识别药物标.

主要成果:

失去IKZF1会导致对cytarabine (AraC) 的耐药性.
耐药性部分是由于核酸载体hENT1的表达减少,影响了AraC的进口和纳入.
在IKZF1-deleted BCP-ALL.中观察到Evi1mRNA表达的升高.
在实验模型中,抑制介质激酶CDK8/19或素激酶2恢复了AraC敏感性.

结论:

IKZF1损失是BCP-ALL中细胞氨基酸耐药性的机制.
向CDK8/19或素激酶2可能会使白血病细胞对AraC重新敏感.
患有IKZF1缺失的患者可能会从替代抗代谢剂或向治疗中受益.

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