Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML.
Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML.
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小分子对BRD4的抑制作用是消除急性髓样白血病AML中白血病干细胞和祖细胞的一种新方法。
DOI：
10.18632/oncotarget.733
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Valent P
中科院分区：
文献类型：
--
作者：
Herrmann H;Blatt K;Shi J;Gleixner KV;Cerny-Reiterer S;Müllauer L;Vakoc CR;Sperr WR;Horny HP;Bradner JE;Zuber J;Valent P
急性髓性白血病（AML）是一种危及生命的干细胞疾病，其特征是成髓细胞的不受控制的增殖和积聚。在AML小鼠模型中使用先进的RNAi筛选方法，我们最近将表观遗传“阅读器”BRD 4鉴定为AML中有希望的靶点。在目前的研究中，我们询问了小分子抑制剂JQ 1对BRD 4的抑制是否会导致原代人AML干细胞和祖细胞的生长抑制和凋亡。原代细胞样品获自37名患有新鲜诊断的AML（n=23）或难治性AML（n=14）的患者。在所有受检患者中，BRD 4在未分级AML细胞以及高度富集的CD 34 +/CD 38 −和CD 34 +/CD 38+干细胞和祖细胞中均以mRNA和蛋白质水平表达。在未分级白血病细胞中，亚微摩尔浓度的JQ 1在大多数样品中诱导了主要的生长抑制作用（IC 50 0.05-0.5 μM），包括来自复发或难治性患者的细胞。此外，JQ 1被发现诱导CD 34 +/CD 38 −和CD 34 +/CD 38+干细胞和祖细胞在所有供体检查的细胞凋亡，如联合表面/Annexin-V染色证明。此外，我们能够证明JQ 1与ARA-C协同诱导AML细胞的生长抑制。总之，BRD 4靶向药物JQ 1在广泛的人类AML亚型中发挥主要的抗白血病作用，包括复发性和难治性患者以及所有相关的干细胞和祖细胞区室，包括CD 34 +/CD 38 −和CD 34 +/CD 38 + AML细胞。这些结果将BRD 4抑制表征为AML中有希望的新治疗方法，其应在临床试验中进一步研究。
Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic ‘reader’ BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar concentrations of JQ1 induced major growth-inhibitory effects (IC50 0.05-0.5 μM) in most samples, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all donors examined as evidenced by combined surface/Annexin-V staining. Moreover, we were able to show that JQ1 synergizes with ARA-C in inducing growth inhibition in AML cells. Together, the BRD4-targeting drug JQ1 exerts major anti-leukemic effects in a broad range of human AML subtypes, including relapsed and refractory patients and all relevant stem- and progenitor cell compartments, including CD34+/CD38− and CD34+/CD38+ AML cells. These results characterize BRD4-inhibition as a promising new therapeutic approach in AML which should be further investigated in clinical trials.
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影响因子：
--
作者：
Martelli AM;Evangelisti C;Chiarini F;McCubrey JA
通讯作者：
McCubrey JA
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
DOI：
10.1111/j.1365-2362.2007.01746.x
发表时间：
2007-01-01
影响因子：
5.5
作者：
Hauswirth, A. W.;Florian, S.;Valent, P.
通讯作者：
Valent, P.
影响因子：
20.3
作者：
Elrick, LJ;Jorgensen, HG;Holyoake, TL
通讯作者：
Holyoake, TL
DOI：
10.1182/asheducation-2008.1.400
发表时间：
2008-01-01
期刊：
Hematology. American Society of Hematology. Education Program
影响因子：
--
作者：
Haferlach, Torsten
通讯作者：
Haferlach, Torsten