Shen Chen, Ipsaro Jonathan J, Shi Junwei, Milazzo Joseph P, Wang Eric, Roe Jae-Seok, Suzuki Yutaka, Pappin Darryl J, Joshua-Tor Leemor, Vakoc Christopher R
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Howard Hughes Medical Institute, Cold Spring Harbor, NY 11724, USA.
Mol Cell. 2015 Dec 17;60(6):847-59. doi: 10.1016/j.molcel.2015.10.033. Epub 2015 Nov 25.
The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription.
含溴结构域和额外末端（BET）蛋白BRD4是急性髓系白血病（AML）的一个治疗靶点。在此，我们证明BRD4在AML中的维持功能需要其与NSD3相互作用，NSD3属于H3K36甲基转移酶亚家族。出乎意料的是，发现AML细胞仅需要缺乏甲基转移酶结构域的NSD3短异构体。我们表明，NSD3-短异构体是一种衔接蛋白，通过使用PWWP染色质读取模块并利用酸性反式激活结构域，将BRD4与CHD8染色质重塑因子连接起来，从而维持白血病状态。对NSD3或CHD8进行基因靶向模拟了BRD4抑制的表型和转录效应。此外，BRD4、NSD3和CHD8在AML基因组中共同定位，并且在化学抑制BET含溴结构域后，它们各自从超级增强子区域释放出来。这些发现表明，BET抑制剂通过从染色质上驱逐BRD4-NSD3-CHD8复合物以抑制转录，从而在白血病中发挥治疗作用。
