Blood:巨核细胞钙网蛋白与SOCE的互作异常促进骨髓增生性肿瘤的发生发展

2019-10-27 QQY MedSci原创

约1/4的原发性血小板增多症或原发性骨髓纤维化患者携带CALR(钙网蛋白的编码基因)的体细胞突变。最常见的突变是缺失52bp(I型突变)和插入5bp(II型突变)。CALR突变导致骨髓增殖表型的机制尚未完全明确。研究人员对健康人和CALR突变型骨髓增生性肿瘤患者来源的巨核细胞中的钙网蛋白和储存操作的钙(Ca2+)进入(SOCE)机制之间的相互作用进行研究。

中心点:

在正常巨核细胞中,钙网蛋白通过与ERp57和STIM1相互作用来调节SOCE的激活。

在CALR突变型MPNs中,突变的钙网蛋白和SOCE蛋白之间的缺陷互作可促进巨核细胞的增殖。

摘要:

约1/4的原发性血小板增多症或原发性骨髓纤维化患者携带CALR(钙网蛋白的编码基因)的体细胞突变。最常见的突变是缺失52bp(I型突变)和插入5bp(II型突变)。CALR突变导致骨髓增殖表型的机制尚未完全明确。现研究人员对健康人和CALR突变型骨髓增生性肿瘤患者来源的巨核细胞中的钙网蛋白和储存操作的钙(Ca2+)进入(SOCE)机制之间的相互作用进行研究。

在健康人的的巨核细胞中,重组人血小板生成素与c-Mpl的结合诱导STAT5、AKT和ERK1/2激活,调控内质网肌醇三磷酸(IP3)依赖性Ca2+释放。进一步导致钙网蛋白和STIM1之间的ERp57介导的复合物解离(STIM1是SOCE机制中促进Ca2+动员的一种蛋白)。

在CALR突变型骨髓增生性肿瘤患者来源的巨核细胞中,突变型钙网蛋白、ERp57和STIM1之间互作缺陷激活了SOCE,并导致自发的胞浆Ca2+流,进而导致巨核细胞异常增殖;使用特定的SOCE抑制剂可逆转上述过程。

综上所述,巨核细胞中Ca2+流的异常SOCE调控会促进CALR突变型骨髓增生性肿瘤的病理进展。因此,SOCE或可成为对抗骨髓增生性肿瘤巨核细胞增殖及其临床影响的新治疗靶点。

原始出处:

Christian Andrea Di Buduo, et al.Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients withmyeloproliferative neoplasms.Blood.2019001103.https://doi.org/10.1182/blood.2019001103

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09:09:00 CST 2019, time=2019-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1490278, encodeId=6aa814902e886, content=<a href='/topic/show?id=af9f48201a9' target=_blank style='color:#2F92EE;'>#巨核细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=48201, encryptionId=af9f48201a9, topicName=巨核细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f3d78715376, createdName=liuquan, createdTime=Tue Oct 29 09:09:00 CST 2019, time=2019-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=374511, encodeId=7cd73e4511bd, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bbc11488193, createdName=thm112988, createdTime=Mon Oct 28 00:20:04 CST 2019, 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  5. 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09:09:00 CST 2019, time=2019-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1490278, encodeId=6aa814902e886, content=<a href='/topic/show?id=af9f48201a9' target=_blank style='color:#2F92EE;'>#巨核细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=48201, encryptionId=af9f48201a9, topicName=巨核细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f3d78715376, createdName=liuquan, createdTime=Tue Oct 29 09:09:00 CST 2019, time=2019-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=374511, encodeId=7cd73e4511bd, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bbc11488193, createdName=thm112988, createdTime=Mon Oct 28 00:20:04 CST 2019, time=2019-10-28, status=1, ipAttribution=)]
  6. 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  7. 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09:09:00 CST 2019, time=2019-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1490278, encodeId=6aa814902e886, content=<a href='/topic/show?id=af9f48201a9' target=_blank style='color:#2F92EE;'>#巨核细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=48201, encryptionId=af9f48201a9, topicName=巨核细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f3d78715376, createdName=liuquan, createdTime=Tue Oct 29 09:09:00 CST 2019, time=2019-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=374511, encodeId=7cd73e4511bd, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bbc11488193, createdName=thm112988, createdTime=Mon Oct 28 00:20:04 CST 2019, time=2019-10-28, status=1, ipAttribution=)]
    2019-10-29 ylz8405
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    2019-10-28 thm112988

    0

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