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在抑制干扰素反应方面,STAT3β的新功能改善了急性髓性白血病的结果

Sophie Edtmayer¹, Agnieszka Witalisz-Siepracka¹, Bernhard Zdársky¹

¹Division Pharmacology, Department of Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences, Krems, Austria.

Cell death & disease

|May 28, 2024

概括

信号传感器和转录3β (STAT3β) 的激活剂在急性髓性白血病 (AML) 中起到瘤抑制作用. 失去STAT3β会增强干扰素信号传递,使白血病细胞对向治疗更敏感.

科学领域:

血液学血液学血液学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

信号传感器和转录激活器3 (STAT3) 在急性髓性白血病 (AML) 中过度表达.
STAT3有两个异型:STAT3α (致癌) 和STAT3β (瘤抑制剂).
STAT3β在AML病变发生过程中的确切作用尚未完全阐明.

研究的目的:

研究在MLL-AF9驱动的AML中STAT3β的功能.
确定STAT3β缺乏对白血病进展和治疗反应的影响.
探索STAT3β表达,干扰素信号传递和AML患者存活率之间的关系.

主要方法:

产生一个STAT3β缺乏MLL-AF9驱动的AML的小鼠模型.
用RNA测序分析STAT3β缺陷白血病中的基因表达变化.
评估白血病细胞对干扰素信号阻断 (抗IFNAR1抗体,鲁克索利提尼布) 的敏感性.
对人类AML患者样本进行STAT3β表达和干扰素诱导基因与生存相关性的分析.

主要成果:

在白血病小鼠中,STAT3β缺乏显著降低了生存率,证实了它的瘤抑制作用.
失去STAT3β导致STAT1表达增加和干扰素信号增强.
缺乏STAT3β的白血病细胞对IFNAR1阻断和鲁克索利提尼布治疗的敏感性增加.
在人类AML患者中,干扰素诱导基因的高表达与生存率差和STAT3β表达率低相关.

结论:

通过抑制STAT1介导的干扰素信号传递,STAT3β作为AML中的瘤抑制剂起作用.
STAT3β/α mRNA比率作为AML的预后标志物.
针对STAT1/干扰素信号传递可能有利于AML患者的低STAT3β表达和不良预后.

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