Blood:TLR9,慢性淋巴细胞白血病的新治疗靶点!

2021-06-10 MedSci原创 MedSci原创

双重靶向TLR9和Bruton酪氨酸激酶(BTK)具有很强的协同作用,TLR9,可作为慢性淋巴细胞白血病的新治疗靶点

中心点:

TLR9表达及其激动剂、血浆游离DNA均与CLL加速转移和不良预后相关。

双重靶向TLR9和BTK可协同抑制CLL细胞迁移,阻断p65 NF-κB和pSTAT3激活。

尽管 B 细胞受体靶向抑制剂彻底改变了慢性淋巴细胞白血病 (CLL) 的治疗方法,但CLL仍然无法治愈,提示还有其他信号分子参与了CLL的逃逸机制和耐药性。

Toll样受体9(TLR9)可被未甲基化的胞嘧啶鸟嘌呤二核苷酸 DNA 激活,是一种很有前景的CLL治疗候选靶点。

血浆游离DNA与首次治疗前时间的相关性

Kennedy等人发现,与健康对照受试者相比,CLL患者的血浆中含有明显更多的未甲基化DNA(p<0.0001);还发现游离DNA水平与预后标志物 CD38、β2-微球蛋白和淋巴细胞倍增时间相关。此外,游离DNA升高还与首次治疗前的时间较短有关(风险比 4.0;p=0.003)。

研究人员还发现TLR9表达与CLL细胞体外迁移有关(p<0.001),细胞内体的TLR9与细胞表面的TLR9(sTLR9)的异常表达密切相关(r=0.9)。此外,淋巴结来源的CLL细胞的sTLR9表达增多(p=0.016)。对成对的高表达sTLR9(sTLRhi)和低表达sTLR9(sTLRlo)的CLL细胞进行RNA测序发现,在sTLRhi细胞中,参与TLR信号、黏连、运动和炎症的基因存在差异性转录。

在机制上,TLR9激动剂ODN2006可促进CLL细胞迁移(p<0.001),这一作用是通过p65 NF-κB和STAT3转录因子激活介导的。重要地是,自体血浆可诱导出相同的效果,这一作用可被TLR9拮抗剂逆转。

阻断TLR9可抑制CLL细胞迁移并与依鲁替尼具有协同作用

此外,在NOD/Shi-scid/IL-2Rγnull小鼠异种移植模型中,高TLR9表达可促进肿瘤移植和快速进展。最后,研究人员还证明了双重靶向TLR9和Bruton酪氨酸激酶(BTK)具有很强的协同作用,强调了TLR9信号在CLL中的不同作用,以及联合靶向TLR9和BTK的潜在治疗价值

原始出处:

Emma Kennedy, et al. TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target. Blood (2021) 137 (22): 3064–3078.

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    2022-05-18 lilianxiang
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    2021-08-18 147ec62cm09(暂无昵称)

    学习了

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1746635, encodeId=7c121e46635c0, content=<a href='/topic/show?id=989d1e525e5' target=_blank style='color:#2F92EE;'>#TLR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17525, encryptionId=989d1e525e5, topicName=TLR)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=bd2d35803070, createdName=lilianxiang, createdTime=Wed May 18 04:08:44 CST 2022, time=2022-05-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1895418, encodeId=75ec189541863, content=<a href='/topic/show?id=18ae64e21d3' target=_blank style='color:#2F92EE;'>#治疗靶点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64721, encryptionId=18ae64e21d3, topicName=治疗靶点)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55683, createdName=仁医06, createdTime=Sat Sep 25 21:08:44 CST 2021, time=2021-09-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1998013, encodeId=b91d19980130b, content=<a href='/topic/show?id=75ff66001cd' target=_blank style='color:#2F92EE;'>#淋巴细胞白血病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=66001, encryptionId=75ff66001cd, topicName=淋巴细胞白血病)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1be8234, createdName=sunyl07, createdTime=Tue Feb 15 16:08:44 CST 2022, time=2022-02-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1008869, encodeId=a22d1008869a4, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=88c25254749, createdName=147ec62cm09(暂无昵称), createdTime=Wed Aug 18 00:05:32 CST 2021, time=2021-08-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1302383, encodeId=e4a6130238379, content=<a href='/topic/show?id=82a6659902c' target=_blank style='color:#2F92EE;'>#淋巴细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65990, encryptionId=82a6659902c, topicName=淋巴细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1e34303, createdName=wetgdt, createdTime=Sat Jun 12 09:08:44 CST 2021, time=2021-06-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972837, encodeId=7fdb9e283740, content=不错,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210606/e8b96fdba070433da10cd357c0646807/28bf16f46e314caaad8396c0c7df7a04.jpg, createdBy=adb15496357, createdName=仁术2021, createdTime=Fri Jun 11 13:40:40 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972632, encodeId=06009e263220, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmhead/Q3auHgzwzM6P57Bs8gOPaY1cQP9lIia0lmZOEXraGaoicqNToIslXDKw/0, createdBy=7a041951742, createdName=衣带渐宽, createdTime=Thu Jun 10 19:47:28 CST 2021, time=2021-06-10, status=1, ipAttribution=)]
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    2021-06-11 仁术2021

    不错,学习了

    0

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    2021-06-10 衣带渐宽

    学习

    0

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