BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells.
BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells.
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DOI：
10.1158/0008-5472.can-14-1849
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发表时间：
2015-04-01
期刊：
影响因子：
11.2
通讯作者：
Chambers TC
中科院分区：
文献类型：
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作者：
Alford SE;Kothari A;Loeff FC;Eichhorn JM;Sakurikar N;Goselink HM;Saylors RL;Jedema I;Falkenburg JH;Chambers TC
BH3模拟药物可能对治疗急性淋巴细胞白血病（ALL）有用，但原代肿瘤细胞的敏感性尚未得到充分评估。在此，对一组源自原发性肿瘤的B系ALL细胞培养物进行了研究，考察其对BH3模拟物ABT - 263和ABT - 199的敏感性以及对Bcl - 2的依赖性和功能。这些ALL细胞均高水平表达Bcl - 2，并对ABT - 263和ABT - 199表现出高度敏感性，这两种药物可诱导细胞快速凋亡。BH3谱分析表明，ALL细胞培养物依赖于Bcl - 2。免疫共沉淀研究揭示了Bcl - 2在结合促凋亡蛋白伴侣（包括Bax、Bak、Bik和Bim）方面具有多方面的作用。ABT - 263破坏了细胞中Bcl - 2与Bim的相互作用。Mcl - 1的过表达使ALL细胞对ABT - 263和ABT - 199产生抗性，此时Mcl - 1承担了Bcl - 2结合Bim的作用。新分离的儿童ALL原始细胞也高水平表达Bcl - 2，并对BH3模拟化合物抑制Bcl - 2表现出高度敏感性。总体而言，我们的结果表明，原代ALL细胞培养物对BH3模拟物比先前已评估的已建立的ALL细胞系更敏感，且反应更一致。此外，此处所描述的原代细胞模型为治疗ALL的新药和药物组合的临床前测试提供了一个强大的系统。
BH3 mimetic drugs may be useful to treat acute lymphoblastic leukemia (ALL) but the sensitivity of primary tumor cells has not been fully evaluated. Here B-lineage ALL cell cultures derived from a set of primary tumors were studied with respect to sensitivity to the BH3 mimetics ABT-263 and ABT-199 and to Bcl-2 dependence and function. These ALL cells each expressed high levels of Bcl-2 and exhibited great sensitivity to ABT-263 and ABT-199, which induced rapid apoptotic cell death. BH3 profiling indicated that the ALL cultures were Bcl-2 dependent. Co-immunoprecipitation studies revealed a multi-faceted role for Bcl-2 in binding pro-apoptotic partners including Bax, Bak, Bik and Bim. ABT-263 disrupted Bcl-2:Bim interaction in cells. Mcl-1 overexpression rendered ALL cells resistant to ABT-263 and ABT-199 with Mcl-1 assuming the role of Bcl-2 in binding Bim. Freshly isolated pediatric ALL blasts also expressed high levels of Bcl-2 and exhibited high sensitivity to Bcl-2 inhibition by the BH3 mimetic compounds. Overall our results showed that primary ALL cultures were both more sensitive to BH3 mimetics and more uniform in their response than established ALL cell lines which have been evaluated previously. Further, the primary cell model characterized here offers a powerful system for preclinical testing of novel drugs and drug combinations to treat ALL.