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Stem Cells Dev：YAP处理有助于恢复白血病细胞对TKI的化学敏感性

2018-02-07 MedSci MedSci原创

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尽管在慢性骨髓性白血病（CML）的治疗中酪氨酸激酶抑制剂（TKI）治疗成功，但即使是在分子层面的缓解，白血病干/祖细胞仍然可检测到。尽管持续的激酶抑制，使白血病干/祖细胞持续存在的机制尚不清楚。我们以前已经表明，长时间接触甲磺酸伊马替尼（IM）导致Akt/Erk1/2信号传导失调，miR-181a的表达上调，粘附性增强以及对高水平的IM持续抵抗。为了表征这些效应的分子基础和可逆性，我们应用基因和蛋

尽管在慢性骨髓性白血病（CML）的治疗中酪氨酸激酶抑制剂（TKI）治疗成功，但即使是在分子层面的缓解，白血病干/祖细胞仍然可检测到。尽管持续的激酶抑制，使白血病干/祖细胞持续存在的机制尚不清楚。我们以前已经表明，长时间接触甲磺酸伊马替尼（IM）导致Akt/Erk1/2信号传导失调，miR-181a的表达上调，粘附性增强以及对高水平的IM持续抵抗。为了表征这些效应的分子基础和可逆性，我们应用基因和蛋白质表达分析，定量磷酸化蛋白质组学，以及直接miR-181a抑制作用于长期暴露于IM的CML细胞。

结果显示，多能性标志物（SOX2，SALL4）和粘附受体（CD44，VLA-4，CXCR4）的表达上调，以及Hippo信号传导的下调和转录共激活因子YAP的上调。此外，使用microRNA海绵抑制剂抑制miR-181a导致SOX2和SALL4的转录减少，YAP的激活减少，并且对IM的敏感性增加。

综上所述，该研究结果表明，长期接触IM导致干细胞更新调节Hippo/YAP信号通路失调，干细胞生成，YAP活性干扰可能有助于恢复对TKI的化学敏感性。

原始出处：

Chorzalska A, Kim JF, et al., Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia. Stem Cells Dev. 2017 May 1;26(9):656-677. doi: 10.1089/scd.2016.0262. Epub 2017 Feb 27.

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    2018-11-02 维他命

    #CEL#

    0

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    2018-08-14 fzwish20000

    #Dev#

    0

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    2018-10-16 gujh

    #YAP#

    0

  4. 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encryptionId=82b416e79f5, topicName=stem cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Sun May 20 19:56:00 CST 2018, time=2018-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1794902, encodeId=2c971e9490285, content=<a href='/topic/show?id=46e716e82a6' target=_blank style='color:#2F92EE;'>#stem cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16782, encryptionId=46e716e82a6, topicName=stem cells)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3883266, createdName=yykkxiaodou, createdTime=Wed Feb 21 16:56:00 CST 2018, time=2018-02-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1870438, encodeId=446a18e043878, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, 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attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1614974, encodeId=fc4016149e416, content=<a href='/topic/show?id=d74a44e2e7' target=_blank style='color:#2F92EE;'>#cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4472, encryptionId=d74a44e2e7, topicName=cells)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=659819575782, createdName=124988c7m101暂无昵称, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=)]
    2018-05-20 hb2008ye

    #stem cell#

    0

  5. 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content=<a href='/topic/show?id=7ef25e5346b' target=_blank style='color:#2F92EE;'>#敏感性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57534, encryptionId=7ef25e5346b, topicName=敏感性)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJnkE6UvGFfMS41qV0RicWvVTTeLMicqibeZH5GqO4YhNicyl1Y9jFhylIUBn9ntPYy9jhk5hrfic5cRYw/132, createdBy=5f822500020, createdName=ms5236388012055669, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1482080, encodeId=a7921482080b0, content=<a href='/topic/show?id=8cc416e78f3' target=_blank style='color:#2F92EE;'>#STEM#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16778, encryptionId=8cc416e78f3, topicName=STEM)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1614974, encodeId=fc4016149e416, content=<a href='/topic/show?id=d74a44e2e7' target=_blank style='color:#2F92EE;'>#cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4472, encryptionId=d74a44e2e7, topicName=cells)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=659819575782, createdName=124988c7m101暂无昵称, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=)]
    2018-02-21 yykkxiaodou

    #stem cells#

    0

  6. 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content=<a href='/topic/show?id=7ef25e5346b' target=_blank style='color:#2F92EE;'>#敏感性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57534, encryptionId=7ef25e5346b, topicName=敏感性)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJnkE6UvGFfMS41qV0RicWvVTTeLMicqibeZH5GqO4YhNicyl1Y9jFhylIUBn9ntPYy9jhk5hrfic5cRYw/132, createdBy=5f822500020, createdName=ms5236388012055669, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1482080, encodeId=a7921482080b0, content=<a href='/topic/show?id=8cc416e78f3' target=_blank style='color:#2F92EE;'>#STEM#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16778, encryptionId=8cc416e78f3, topicName=STEM)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1614974, encodeId=fc4016149e416, content=<a href='/topic/show?id=d74a44e2e7' target=_blank style='color:#2F92EE;'>#cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4472, encryptionId=d74a44e2e7, topicName=cells)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=659819575782, createdName=124988c7m101暂无昵称, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=)]
    2018-04-27 zhaozhouchifen

    #Cell#

    0

  7. 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content=<a href='/topic/show?id=7ef25e5346b' target=_blank style='color:#2F92EE;'>#敏感性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57534, encryptionId=7ef25e5346b, topicName=敏感性)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJnkE6UvGFfMS41qV0RicWvVTTeLMicqibeZH5GqO4YhNicyl1Y9jFhylIUBn9ntPYy9jhk5hrfic5cRYw/132, createdBy=5f822500020, createdName=ms5236388012055669, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1482080, encodeId=a7921482080b0, content=<a href='/topic/show?id=8cc416e78f3' target=_blank style='color:#2F92EE;'>#STEM#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16778, encryptionId=8cc416e78f3, topicName=STEM)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1614974, encodeId=fc4016149e416, content=<a href='/topic/show?id=d74a44e2e7' target=_blank style='color:#2F92EE;'>#cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4472, encryptionId=d74a44e2e7, topicName=cells)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=659819575782, createdName=124988c7m101暂无昵称, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=)]
    2018-02-09 lsj628

    #TKI#

    0

  8. 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content=<a href='/topic/show?id=7ef25e5346b' target=_blank style='color:#2F92EE;'>#敏感性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57534, encryptionId=7ef25e5346b, topicName=敏感性)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJnkE6UvGFfMS41qV0RicWvVTTeLMicqibeZH5GqO4YhNicyl1Y9jFhylIUBn9ntPYy9jhk5hrfic5cRYw/132, createdBy=5f822500020, createdName=ms5236388012055669, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1482080, encodeId=a7921482080b0, content=<a href='/topic/show?id=8cc416e78f3' target=_blank style='color:#2F92EE;'>#STEM#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16778, encryptionId=8cc416e78f3, topicName=STEM)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1614974, encodeId=fc4016149e416, content=<a href='/topic/show?id=d74a44e2e7' target=_blank style='color:#2F92EE;'>#cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4472, encryptionId=d74a44e2e7, topicName=cells)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=659819575782, createdName=124988c7m101暂无昵称, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=)]
    2018-02-09 ms5236388012055669

    #敏感性#

    0

  9. [GetPortalCommentsPageByObjectIdResponse(id=1960705, encodeId=55e51960e05e3, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Fri Nov 02 14:56:00 CST 2018, time=2018-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1982272, encodeId=b03719822e21a, content=<a href='/topic/show?id=13b658e849' target=_blank style='color:#2F92EE;'>#Dev#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5878, encryptionId=13b658e849, topicName=Dev)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bcaa382, 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content=<a href='/topic/show?id=7ef25e5346b' target=_blank style='color:#2F92EE;'>#敏感性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57534, encryptionId=7ef25e5346b, topicName=敏感性)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJnkE6UvGFfMS41qV0RicWvVTTeLMicqibeZH5GqO4YhNicyl1Y9jFhylIUBn9ntPYy9jhk5hrfic5cRYw/132, createdBy=5f822500020, createdName=ms5236388012055669, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1482080, encodeId=a7921482080b0, content=<a href='/topic/show?id=8cc416e78f3' target=_blank style='color:#2F92EE;'>#STEM#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16778, encryptionId=8cc416e78f3, topicName=STEM)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1614974, encodeId=fc4016149e416, content=<a href='/topic/show?id=d74a44e2e7' target=_blank style='color:#2F92EE;'>#cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4472, encryptionId=d74a44e2e7, topicName=cells)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=659819575782, createdName=124988c7m101暂无昵称, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=)]
    2018-02-09 12498bb3m92(暂无昵称)

    #STEM#

    0

  10. 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content=<a href='/topic/show?id=7ef25e5346b' target=_blank style='color:#2F92EE;'>#敏感性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57534, encryptionId=7ef25e5346b, topicName=敏感性)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJnkE6UvGFfMS41qV0RicWvVTTeLMicqibeZH5GqO4YhNicyl1Y9jFhylIUBn9ntPYy9jhk5hrfic5cRYw/132, createdBy=5f822500020, createdName=ms5236388012055669, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1482080, encodeId=a7921482080b0, content=<a href='/topic/show?id=8cc416e78f3' target=_blank style='color:#2F92EE;'>#STEM#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16778, encryptionId=8cc416e78f3, topicName=STEM)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1614974, encodeId=fc4016149e416, content=<a href='/topic/show?id=d74a44e2e7' target=_blank style='color:#2F92EE;'>#cells#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4472, encryptionId=d74a44e2e7, topicName=cells)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=659819575782, createdName=124988c7m101暂无昵称, createdTime=Fri Feb 09 08:56:00 CST 2018, time=2018-02-09, status=1, ipAttribution=)]
    2018-02-09 124988c7m101暂无昵称

    #cells#

    0

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