Blood:Crbn I391V突变使小鼠对沙利度胺及其衍生物治疗敏感

2018-08-02 MedSci MedSci原创

中心点:Crbn[I391V]小鼠可降解已知的沙利度胺衍生物靶点,再现沙利度胺诱导的血细胞减少和致畸性。Ck1α降解可充分解释携带del(5q)的骨髓增生异常综合征的沙利度胺体内治疗的窗口期。摘要:沙利度胺及其衍生物来那度胺和泊马度胺,均可有效治疗多发性骨髓瘤和携带del(5q)的骨髓增生异常综合征。但这些分子在小鼠模型中缺乏活性,限制了对其治疗活性或体内毒性的研究。Emma C. Fink等人通

中心点:

Crbn[I391V]小鼠可降解已知的沙利度胺衍生物靶点,再现沙利度胺诱导的血细胞减少和致畸性。

Ck1α降解可充分解释携带del(5q)的骨髓增生异常综合征的沙利度胺体内治疗的窗口期。

摘要:

沙利度胺及其衍生物来那度胺和泊马度胺,均可有效治疗多发性骨髓瘤和携带del(5q)的骨髓增生异常综合征。但这些分子在小鼠模型中缺乏活性,限制了对其治疗活性或体内毒性的研究。

Emma C. Fink等人通过改变沙利度胺衍生物的直接靶点(Crbn)的一个氨基酸建立了一种对沙利度胺衍生物敏感的小鼠模型。在人类细胞中,沙利度胺及其衍生物与CRBN结合、招募蛋白靶向CRL4[CRBN]E3泛素连接酶,促进其泛素化,进而被蛋白酶体降解。研究人员发现携带Crbn单氨基酸I391V改变的小鼠表现出沙利度胺诱导的药物靶点降解,包括Ikaros(Ikzf1)、Aiolos(Ikzf3)、Zfp91和酪蛋白激酶1a1(CK1α),与既往在人类体内外细胞中所观察到的一致。

研究人员利用Crbn[I391V]小鼠模型来证明来那度胺用于del(5q)骨髓增生异常综合征的体内治疗活性可用Ck1α在del(5q)细胞中杂合表达来解释。研究人员发现来那度胺作用于杂合表达Ck1α的造血干细胞,并且失活Trp53可导致来那度胺耐药。此外,研究人员进一步证明了Crbn[I391V]小鼠模型可有效阐明沙利度胺诱导的小鼠胚胎致死,揭示了这类药物的主要毒副作用。

总而言之,Crbn[I391V]小鼠模型为研究沙利度胺及其衍生物的体内疗效和毒性作用提供一个可靠的平台。

原始出处:

Emma C. Fink,et al. CrbnI391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice. Blood  2018  :blood-2018-05-852798;  doi: https://doi.org/10.1182/blood-2018-05-852798

本文系梅斯医学(MedSci)原创编译,转载需授权!

版权声明:
本网站所有内容来源注明为“梅斯医学”或“MedSci原创”的文字、图片和音视频资料,版权均属于梅斯医学所有。非经授权,任何媒体、网站或个人不得转载,授权转载时须注明来源为“梅斯医学”。其它来源的文章系转载文章,或“梅斯号”自媒体发布的文章,仅系出于传递更多信息之目的,本站仅负责审核内容合规,其内容不代表本站立场,本站不负责内容的准确性和版权。如果存在侵权、或不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。
在此留言
评论区 (4)
#插入话题
  1. [GetPortalCommentsPageByObjectIdResponse(id=1812672, encodeId=e27e18126e2c1, content=<a href='/topic/show?id=d193900940b' target=_blank style='color:#2F92EE;'>#衍生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=90094, encryptionId=d193900940b, topicName=衍生物)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=仁心济世, createdTime=Thu Jan 10 07:45:00 CST 2019, time=2019-01-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943569, encodeId=56d319435695a, content=<a href='/topic/show?id=17f15192ab' target=_blank style='color:#2F92EE;'>#Crbn#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5192, encryptionId=17f15192ab, topicName=Crbn)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=9d17305, createdName=listen318, createdTime=Thu Apr 18 00:45:00 CST 2019, time=2019-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=336066, encodeId=09fd336066b0, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://login.medsci.cn/upload/avatar/f3d88083d8829740786bed95c22464d1/e325f3af93bb747a620d16c209094d69.jpg, createdBy=9efb2014947, createdName=小小小麦兜, createdTime=Fri Aug 03 21:02:47 CST 2018, time=2018-08-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=335779, encodeId=7d22335e7907, content=挺好的学习资料,每天都可以学到新知识,每天都有新收获,谢谢。。。, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKcmgibQ4oCrK7Z6f4CvMcs4k7QUGCkhopcGxvxaBfVciadECSIwaRVttllIOEKumpEaRrq5PoOUxow/0, createdBy=e3bb2081203, createdName=哈哈869, createdTime=Thu Aug 02 13:22:43 CST 2018, time=2018-08-02, status=1, ipAttribution=)]
  2. [GetPortalCommentsPageByObjectIdResponse(id=1812672, encodeId=e27e18126e2c1, content=<a href='/topic/show?id=d193900940b' target=_blank style='color:#2F92EE;'>#衍生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=90094, encryptionId=d193900940b, topicName=衍生物)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=仁心济世, createdTime=Thu Jan 10 07:45:00 CST 2019, time=2019-01-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943569, encodeId=56d319435695a, content=<a href='/topic/show?id=17f15192ab' target=_blank style='color:#2F92EE;'>#Crbn#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5192, encryptionId=17f15192ab, topicName=Crbn)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=9d17305, createdName=listen318, createdTime=Thu Apr 18 00:45:00 CST 2019, time=2019-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=336066, encodeId=09fd336066b0, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://login.medsci.cn/upload/avatar/f3d88083d8829740786bed95c22464d1/e325f3af93bb747a620d16c209094d69.jpg, createdBy=9efb2014947, createdName=小小小麦兜, createdTime=Fri Aug 03 21:02:47 CST 2018, time=2018-08-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=335779, encodeId=7d22335e7907, content=挺好的学习资料,每天都可以学到新知识,每天都有新收获,谢谢。。。, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKcmgibQ4oCrK7Z6f4CvMcs4k7QUGCkhopcGxvxaBfVciadECSIwaRVttllIOEKumpEaRrq5PoOUxow/0, createdBy=e3bb2081203, createdName=哈哈869, createdTime=Thu Aug 02 13:22:43 CST 2018, time=2018-08-02, status=1, ipAttribution=)]
    2019-04-18 listen318
  3. [GetPortalCommentsPageByObjectIdResponse(id=1812672, encodeId=e27e18126e2c1, content=<a href='/topic/show?id=d193900940b' target=_blank style='color:#2F92EE;'>#衍生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=90094, encryptionId=d193900940b, topicName=衍生物)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=仁心济世, createdTime=Thu Jan 10 07:45:00 CST 2019, time=2019-01-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943569, encodeId=56d319435695a, content=<a href='/topic/show?id=17f15192ab' target=_blank style='color:#2F92EE;'>#Crbn#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5192, encryptionId=17f15192ab, topicName=Crbn)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=9d17305, createdName=listen318, createdTime=Thu Apr 18 00:45:00 CST 2019, time=2019-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=336066, encodeId=09fd336066b0, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://login.medsci.cn/upload/avatar/f3d88083d8829740786bed95c22464d1/e325f3af93bb747a620d16c209094d69.jpg, createdBy=9efb2014947, createdName=小小小麦兜, createdTime=Fri Aug 03 21:02:47 CST 2018, time=2018-08-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=335779, encodeId=7d22335e7907, content=挺好的学习资料,每天都可以学到新知识,每天都有新收获,谢谢。。。, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKcmgibQ4oCrK7Z6f4CvMcs4k7QUGCkhopcGxvxaBfVciadECSIwaRVttllIOEKumpEaRrq5PoOUxow/0, createdBy=e3bb2081203, createdName=哈哈869, createdTime=Thu Aug 02 13:22:43 CST 2018, time=2018-08-02, status=1, ipAttribution=)]
    2018-08-03 小小小麦兜

    学习了

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1812672, encodeId=e27e18126e2c1, content=<a href='/topic/show?id=d193900940b' target=_blank style='color:#2F92EE;'>#衍生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=90094, encryptionId=d193900940b, topicName=衍生物)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=仁心济世, createdTime=Thu Jan 10 07:45:00 CST 2019, time=2019-01-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943569, encodeId=56d319435695a, content=<a href='/topic/show?id=17f15192ab' target=_blank style='color:#2F92EE;'>#Crbn#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5192, encryptionId=17f15192ab, topicName=Crbn)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=9d17305, createdName=listen318, createdTime=Thu Apr 18 00:45:00 CST 2019, time=2019-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=336066, encodeId=09fd336066b0, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://login.medsci.cn/upload/avatar/f3d88083d8829740786bed95c22464d1/e325f3af93bb747a620d16c209094d69.jpg, createdBy=9efb2014947, createdName=小小小麦兜, createdTime=Fri Aug 03 21:02:47 CST 2018, time=2018-08-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=335779, encodeId=7d22335e7907, content=挺好的学习资料,每天都可以学到新知识,每天都有新收获,谢谢。。。, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKcmgibQ4oCrK7Z6f4CvMcs4k7QUGCkhopcGxvxaBfVciadECSIwaRVttllIOEKumpEaRrq5PoOUxow/0, createdBy=e3bb2081203, createdName=哈哈869, createdTime=Thu Aug 02 13:22:43 CST 2018, time=2018-08-02, status=1, ipAttribution=)]
    2018-08-02 哈哈869

    挺好的学习资料,每天都可以学到新知识,每天都有新收获,谢谢。。。

    0