Blood:Bcl-2成员表达变化揭示了CLL维奈托克耐药机制

2020-07-04 QQY MedSci原创

依鲁替尼和维奈托克治疗时,Bcl-2家族成员的表达会发生变化;依鲁替尼治疗后复发时,Bcl-2家族成员的表达又会恢复。在CLL维奈托克耐药发生过程中,相比Mcl-1,Bcl-XL发挥更重要的作用。

慢性淋巴细胞白血病(CLL)细胞在淋巴结(LN)和外周血(PB)之间循环,Bcl-2家族成员在这些间室之间表现出明显的摇摆。具体而言,Bcl-XL和Mcl-1,不是Bcl-2抑制剂维奈托克的靶点,在LN中表达增加。鉴于依鲁替尼会促进CLL细胞脱离LN,研究人员推测依鲁替尼可能在使CLL细胞脱离LN后,又影响其Bcl-XL和Mcl-1的表达,进而使CLL细胞对维奈托克敏感。因此,研究人员研究了Bcl-2家族成员在接受依鲁替尼或维奈托克治疗的患者中的表达,并在维奈托克耐药的体外模型中解析Bcl-2家族成员的功能相互作用。

在PB中,刚从LN迁移出来的细胞的Bcl-XL和Mcl-1的表达水平高于迁移会LN的细胞。依鲁替尼治疗时,这种区别消失,而且特别的是,在依鲁替尼治疗后复发的患者中,这种区别再次出现。

但维奈托克治疗时,Bcl-2家族成员较早就出现增高,说明这两种药物的作用机制不同。在对维奈托克完全耐药(由CD40介导的Bcl-XL、Mcl-1和Bfl-1诱导导致的)的CLL细胞中,使用BH3模拟物进行了谱分析。几种BH3模拟物的双重或三重组合在恢复对CLL细胞的杀伤作用上具有高度协同作用。

最后,研究人员证实促凋亡蛋白Bim与抗凋亡Bcl-2成员以一定顺序的方式相互作用:Bcl-2>Bcl-XL>Mcl-1>Bfl-1。

综上,本研究表明Bcl-XL在维奈托克耐药中的作用比Mcl-1更重要,为依鲁替尼和维奈托克之间潜在的协同作用提供了生物学依据。

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    2020-07-06 1209e435m98(暂无昵称)

    学习了,谢谢分享

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1971361, encodeId=5aa219e13619e, content=<a href='/topic/show?id=ee288039ece' target=_blank style='color:#2F92EE;'>#耐药机制#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=80397, encryptionId=ee288039ece, topicName=耐药机制)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=263b421, createdName=zhaozuguo, createdTime=Wed Dec 09 02:59:24 CST 2020, time=2020-12-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1707329, encodeId=49aa1e07329e9, content=<a href='/topic/show?id=9948325e6d' target=_blank style='color:#2F92EE;'>#BCL-2#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3257, encryptionId=9948325e6d, topicName=BCL-2)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e84031401266, createdName=ms3323097325231039, createdTime=Mon Jul 20 03:59:24 CST 2020, time=2020-07-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=801537, encodeId=ddd680153e17, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=85, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Mon Jul 06 23:17:17 CST 2020, time=2020-07-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1039267, encodeId=a792103926eb9, content=机制研究离临床仍然有距离,不过与临床结合思考,仍然有帮助的,不能仅仅是纯临床思维,转化思维同样重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=肿肿, createdTime=Sat Jul 04 23:59:24 CST 2020, time=2020-07-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=801253, encodeId=e5fa80125304, content=有点意思, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=2, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210706/5924e86cc73c43efb5bad9dd92ac0d7b/63609a5527c447f48b59b39dd248a66f.jpg, createdBy=cf0a5102349, createdName=站在塔尖, createdTime=Sat Jul 04 22:41:56 CST 2020, time=2020-07-04, status=1, ipAttribution=)]
    2020-07-04 肿肿

    机制研究离临床仍然有距离,不过与临床结合思考,仍然有帮助的,不能仅仅是纯临床思维,转化思维同样重要

    0

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    2020-07-04 站在塔尖

    有点意思

    2

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