AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells
AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells
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DOI：
10.1182/blood-2002-05-1589
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发表时间：
2003-04-15
期刊：
影响因子：
20.3
通讯作者：
Nordheim, A
中科院分区：
文献类型：
--
作者：
Heidenreich, O;Krauter, J;Nordheim, A
易位t（8;21）产生白血病融合基因AML 1/MTG 8，并且与10%-15%的急性髓性白血病新发病例相关。我们证明了小干扰RNA（siRNA）在人白血病细胞系Kasumi-1和SKNO-1中对AML 1/MTG 8的有效和特异性抑制。靶向AML 1/MTG 8 mRN 4融合位点的siRNA降低了AML 1/MTG 8的水平，而不影响野生型AML 1的量。这些数据反对在这种白血病细胞中可能由siRNA诱导的传递性RNA干扰机制。AML 1/MTG 8的消耗与Kasumi-1和SKNO-1细胞对肿瘤生长因子β（1）（TGF β（1））/vltamln D-3诱导的分化的敏感性增加相关，导致CD 11b、巨噬细胞集落刺激因子（M-CSF）受体和C/EBPalpha（CAAT/增强子结合蛋白）表达增加。此外，siRNA介导的AML 1/MTG 8抑制导致细胞形状的改变，并且与TGF β 1/维生素D-3组合，严重降低Kasumi-1细胞的克隆形成。这些结果表明AML 1/MTG 8在阻止分化，从而繁殖白血病母细胞中的重要作用。因此，siRNA是用于AML 1/MTG 8的功能分析的有希望的工具，并且可用于t（8;21）阳性白血病的分子定义的治疗方法。(C)2003年，美国血液学会。
The translocation t(8;21) yields the leukemic fusion gene AML1/MTG8 and is associated with 10%-15% of all de novo cases of acute myelold leukemia. We demonstrate the efficient and specific suppression of AML1/MTG8 by small interfering RNAs (siRNAs) in the human leukemic cell lines Kasumi-1 and SKNO-1. siRNAs targeted against the fusion site of the AML1/MTG8 mRN4 reduce the levels of AML1/MTG8 without affecting the amount of wild-type AML1. These data argue against a transitive RNA interference mechanism potentially induced by siRNAs in such leukemic cells. Depletion of AML1/MTG8 correlates with an increased susceptibility of both Kasumi-1 and SKNO-1 cells to tumor growth factor beta(1) (TGFbeta(1))/vltamln D-3-induced differentiation, leading to increased expression of CD11b, macrophage colony-stimulating factor (M-CSF) receptor, and C/EBPalpha (CAAT/enhancer binding protein). Moreover, siRNA-mediated AML1/MTG8 suppression results in changes in cell shape and, in combination with TGFbeta(1)/vitamin D-3, severely reduces clonogenicity of Kasumi-1 cells. These results suggest an important role for AML1/MTG8 in preventing differentiation, thereby propagating leukemic blast cells. Therefore, siRNAs are promising tools for a functional analysis of AML1/MTG8 and may be used in a molecularly defined therapeutic approach for t(8;21)-positive leukemia. (C) 2003 by The American society of Hematology.