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Blood:用钙调神经磷酸酶抑制剂治疗DLBCL

2019-12-05 QQY MedSci原创

Bucher等人的研究表明,转录因子NFAT的活性在两种DLBCL亚型中都是慢性升高的。令人惊讶的是,NFAT激活并不依赖于BCR信号,而是由钙通量增加和钙调神经磷酸酶介导的NFAT去磷酸化调控的。但有趣的是,虽然NFAT在两种DLBCL亚型中都被激活,但用环孢素A或FK506(两种获批的临床药物)长期抑制钙调磷酸酶都可触发ABC DLBCL细胞的强细胞毒性。

中心点:

DLBCL细胞系表现出BCR介导信号非依赖于的慢性NFAT活化。

长期采用钙调神经磷酸酶抑制剂治疗ABC DLBCL可诱导BCL-2和MCL-1抑制剂的细胞毒性和协同作用。

摘要:

弥漫大B细胞淋巴瘤(DLBCL)是最常见的成人淋巴瘤,主要分为两种分子亚型:生发中心B细胞样淋巴瘤(GCB)和侵袭性激活B细胞样淋巴瘤(ABC)DLBCL。既往研究表明,慢性BCR信号和NF-κB活化增强可促进ABC DLBCL的发生发展。

Bucher等人的研究表明,转录因子NFAT的活性在两种DLBCL亚型中都是慢性升高的。令人惊讶的是,NFAT激活并不依赖于BCR信号,而是由钙通量增加和钙调神经磷酸酶介导的NFAT去磷酸化调控的。但有趣的是,虽然NFAT在两种DLBCL亚型中都被激活,但用环孢素A或FK506(两种获批的临床药物)长期抑制钙调磷酸酶都可触发ABC DLBCL细胞的强细胞毒性。

钙调神经磷酸酶抑制剂的抗肿瘤作用与c-Jun、IL-6和IL-10的下调有关;c-Jun、IL-6和IL-10被认为是NFAT的靶基因,对ABC DLBCL存活至关重要。此外,钙调神经磷酸酶抑制剂与BCL-2和MCL-1抑制剂可协同杀灭ABC DLBCL细胞。

综上所述,本研究发现构成型NFAT信号是ABC DLBCL的重要功能性驱动因素,同时强调了钙调神经磷酸酶抑制是治疗ABC DLBCL的新策略。

原始出处:


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    2020-09-25 jklm09
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    2019-12-07 cathymary
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