文章：

靶向MCL-1使FLT3-ITD阳性白血病对细胞毒性治疗增敏

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

原文发布日期：2012-03-09

DOI: 10.1038/bcj.2012.5

类型: Original Article

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英文摘要：

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.

摘要翻译： 

患有携带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。这主要归因于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，以识别与FLT3信号激活相关的造血细胞差异表达的蛋白质。与FLT3野生型对照组相比，在FLT3-ITD阳性细胞系和AML患者的原代单核细胞中，发现抗凋亡髓系细胞白血病-1（MCL-1）选择性上调。MCL-1的上调依赖于FLT3信号传导，这一点通过使用激酶抑制剂PKC412药物抑制FLT3活性以及siRNA介导的FLT3抑制后MCL-1表达逆转得到证实。异源表达的MCL-1通过赋予造血细胞对阿糖胞苷、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，替代了FLT3信号传导的功能。相反，通过siRNA或flavopiridol处理抑制内源性MCL-1，使表达FLT3-ITD的造血细胞对细胞毒性和靶向治疗药物敏感。总之，MCL-1是FLT3-ITD介导的耐药性的关键效应因子。靶向MCL-1的治疗是克服FLT3-ITD阳性AML耐药性的一种有前景的策略。

原文链接：

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