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靶向 MCL-1 可使 FLT3-ITD 阳性白血病对细胞毒疗法敏感。

Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies.

出版信息

Blood Cancer J. 2012 Mar;2(3):e60. doi: 10.1038/bcj.2012.5. Epub 2012 Mar 9.

DOI:10.1038/bcj.2012.5
PMID:22829255
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3317524/
Abstract

Patients suffering from acute myeloid leukemias (AML) bearing FMS-like tyrosine kinase-3-internal tandem duplications (FLT3-ITD) have poor outcomes following cytarabine- and anthracyclin-based induction therapy. To a major part this is attributed to drug resistance of FLT3-ITD-positive leukemic cells. Against this background, we have devised an antibody array approach to identify proteins, which are differentially expressed by hematopoietic cells in relation to activated FLT3 signaling. Selective upregulation of antiapoptotic myeloid cell leukemia-1 (MCL-1) was found in FLT3-ITD-positive cell lines and primary mononuclear cells from AML patients as compared with FLT3-wild-type controls. Upregulation of MCL-1 was dependent on FLT3 signaling as confirmed by its reversion upon pharmacological inhibition of FLT3 activity by the kinase inhibitor PKC412 as well as siRNA-mediated suppression of FLT3. Heterologously expressed MCL-1 substituted for FLT3 signaling by conferring resistance of hematopoietic cells to antileukemia drugs such as cytarabine and daunorubicin, and to the proapoptotic BH3 mimetic ABT-737. Conversely, suppression of endogenous MCL-1 by siRNA or by flavopiridol treatment sensitized FLT3-ITD-expressing hematopoietic cells to cytotoxic and targeted therapeutics. In conclusion, MCL-1 is an essential effector of FLT3-ITD-mediated drug resistance. Therapeutic targeting of MCL-1 is a promising strategy to overcome drug resistance in FLT3-ITD-positive AML.

摘要

患有 FMS 样酪氨酸激酶-3 内部串联重复（FLT3-ITD）的急性髓系白血病（AML）患者在接受基于阿糖胞苷和蒽环类药物的诱导治疗后，预后较差。在很大程度上，这归因于 FLT3-ITD 阳性白血病细胞的耐药性。在此背景下，我们设计了一种抗体阵列方法来鉴定与激活的 FLT3 信号相关的造血细胞差异表达的蛋白质。与 FLT3 野生型对照相比，在 FLT3-ITD 阳性细胞系和 AML 患者的单核细胞中发现抗凋亡髓细胞白血病 1（MCL-1）的选择性上调。MCL-1 的上调依赖于 FLT3 信号，这通过 FLT3 活性的药理学抑制（PKC412 激酶抑制剂）以及通过 siRNA 介导的 FLT3 抑制来逆转其证实。异源表达的 MCL-1 通过赋予造血细胞对阿糖胞苷和柔红霉素等抗白血病药物以及促凋亡 BH3 模拟物 ABT-737 的耐药性，替代 FLT3 信号。相反，通过 siRNA 或 flavopiridol 处理抑制内源性 MCL-1 可使表达 FLT3-ITD 的造血细胞对细胞毒性和靶向治疗敏感。总之，MCL-1 是 FLT3-ITD 介导的耐药性的重要效应物。靶向 MCL-1 的治疗是克服 FLT3-ITD 阳性 AML 耐药性的有前途的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/c890aa1ec853/bcj20125f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/e7fc91866d56/bcj20125f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/20f911b95491/bcj20125f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/c890aa1ec853/bcj20125f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/894f6f980438/bcj20125f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/d47d9f08436e/bcj20125f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/e6c3d93f8693/bcj20125f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/60e80a179aca/bcj20125f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/e7fc91866d56/bcj20125f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/20f911b95491/bcj20125f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a00/3317524/c890aa1ec853/bcj20125f7.jpg

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