Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding.
Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding.
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作者：
t（8;21）易位将造血主调节因子RUNX 1的DNA结合结构域融合到ETO蛋白。所得到的RUNX 1/ETO融合蛋白是一种白血病起始转录因子，可干扰RUNX 1的功能。这种干扰的结果是阻断分化，最终导致急性髓性白血病（AML）的发展。为了深入了解RUNX 1/ETO依赖的表观遗传学改变，我们测量了t（8;21）细胞中全基因组RUNX 1和RUNX 1/ETO结合区域，并评估了RUNX 1/ETO对表观基因组的影响在多大程度上取决于其在已建立的白血病细胞中的持续表达。为此，我们确定了组蛋白乙酰化，RNA聚合酶II结合和RUNX 1占用的存在或不存在的RUNX 1/ETO使用敲除方法的动态变化。对染色质可及性和动力学基因表达数据的综合评估表明，RUNX 1/ETO控制造血分化和自我更新的重要调节因子的表达。我们发现，选择性去除RUNX 1/ETO导致表观遗传重编程的广泛逆转和RUNX 1结合的全基因组重新分布，从而抑制白血病增殖和自我更新，并诱导分化。这表明RUNX 1/ETO代表AML的关键治疗靶点。
The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.
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影响因子：
20.3
作者：
Heidenreich, O;Krauter, J;Nordheim, A
通讯作者：
Nordheim, A
影响因子：
3.7
作者：
Debernardi, S;Lillington, DM;Young, BD
通讯作者：
Young, BD
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
DOI：
10.1073/pnas.0308531101
发表时间：
2004-03-23
影响因子：
11.1
作者：
Brunet, JP;Tamayo, P;Mesirov, JP
通讯作者：
Mesirov, JP
影响因子：
20.3
作者：
Bergmann, L;Miething, C;Hoelzer, D
通讯作者：
Hoelzer, D