Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells
Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells
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DOI：
10.1182/blood.v98.8.2301
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发表时间：
2001-10-15
期刊：
影响因子：
20.3
通讯作者：
Jordan, CT
中科院分区：
文献类型：
--
作者：
Guzman, ML;Neering, SJ;Jordan, CT
人类急性髓系白血病（AML）被认为是由一种罕见的恶性干细胞群引发的。这种性质的细胞，在此被称为白血病干细胞（LSCs），几乎在所有AML亚型中都有记载，并且似乎符合干细胞的标准，因为它们能够自我更新，并产生在许多白血病细胞群中发现的细胞。由于这些细胞可能对白血病的发生和持续存在至关重要，本研究试图描述白血病干细胞群独特的分子特性，尤其着重于转录因子核因子 - κB（NF - κB）。先前的实验表明，未受刺激的人类CD34（+）祖细胞不表达NF - κB。相比之下，通过电泳迁移率变动分析和基因表达研究评估，原发性AML CD34（+）细胞显示出容易检测到的NF - κB活性。此外，对富集的AML干细胞（CD34（+）/CD38（ - ）/CD123（+））的详细分析表明，NF - κB在白血病干细胞群中也是有活性的。鉴于NF - κB在白血病原始细胞中表达，但在正常原始细胞中不表达，通过用蛋白酶体抑制剂MG - 132（一种众所周知的NF - κB抑制剂）处理原代细胞，对抑制NF - κB可能诱导白血病特异性凋亡这一假设进行了测试。白血病CD34（+）/CD38（ - ）细胞在MG - 132作用下迅速诱导细胞死亡，而正常CD34（+）/CD38（ - ）细胞几乎没有受到影响。综上所述，这些数据表明，原始AML细胞异常表达NF - κB，并且该因子的存在可能为优先清除白血病干细胞提供独特的机会。（C）2001年美国血液学会版权所有。
Human acute myelogenous leukemia (AML) is thought to arise from a rare population of malignant stem cells. Cells of this nature, herein referred to as leukemic stem cells (LSCs), have been documented for nearly all AML subtypes and appear to fulfill the criteria for stem cells in that they are self-renewing and give rise to the cells found in many leukemic populations. Because these cells are likely to be critical for the genesis and perpetuation of leukemic disease, the present studies sought to characterize unique molecular properties of the LSC population, with particular emphasis on the transcription factor, nuclear factor-kappaB (NF-kappaB). Previous experiments have shown that unstimulated human CD34(+) progenitor cells do not express NF-kappaB. In contrast, primary AML CD34(+) cells display readily detectable NF-kappaB activity as assessed by electrophoretic mobility shift assay and gene expression studies. Furthermore, detailed analyses of enriched AML stem cells (CD34(+)/CD38(-)/CD123(+)) indicate that NF-kappaB is also active in the LSC population. Given the expression of NF-kappaB in leukemic, but not normal primitive cells, the hypothesis that inhibition of NF-kappaB might induce leukemia-specific apoptosis was tested by treating primary cells with the proteasome inhibitor MG-132, a well-known inhibitor of NF-kappaB. Leukemic CD34(+)/CD38(-) cells displayed a rapid induction of cell death in response to MG-132, whereas normal CD34(+)/CD38(-) cells showed little if any effect. Taken together, these data indicate that primitive AML cells aberrantly express NF-kappaB and that the presence of this factor may provide unique opportunities to preferentially ablate LSCs. (C) 2001 by The American Society of Hematology.