DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia.
DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia.
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DOI：
10.1038/nm.3832
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发表时间：
2015-04
期刊：
影响因子：
82.9
通讯作者：
Armstrong, Scott A.
中科院分区：
文献类型：
--
作者：
Chen, Chun-Wei;Koche, Richard P.;Sinha, Amit U.;Deshpande, Aniruddha J.;Zhu, Nan;Eng, Rowena;Doench, John G.;Xu, Haiming;Chu, Scott H.;Qi, Jun;Wang, Xi;Delaney, Christopher;Bernt, Kathrin M.;Root, David E.;Hahn, William C.;Bradner, James E.;Armstrong, Scott A.
MLL -重排产生结合DNA并驱动致白血病基因表达的MLL-融合蛋白。该基因表达程序依赖于组蛋白3赖氨酸79（H3 K79）甲基转移酶DOT 1 L，并且小分子DOT 1 L抑制剂显示出作为这些白血病的治疗剂的前景。然而，这种依赖性的机制尚不清楚。我们进行了基因组规模的RNAi筛选，发现组蛋白去乙酰化酶SIRT 1是DOT 1 L抑制后在MLL融合靶基因周围建立异染色质样状态所必需的。DOT 1 L抑制由SIRT 1和SUV 39 H1组成的抑制性复合物的染色质定位，从而保持开放的染色质状态，在ML融合靶基因处具有升高的H3 K9乙酰化和最小的H3 K9甲基化。此外，SIRT 1激活剂和DOT 1 L抑制剂的组合显示出对MLL重排的白血病细胞的增强的活性。这些结果表明，控制基因表达的激活和抑制的染色质调节剂之间的动态相互作用可以为联合治疗提供新的机会。
MLL -rearrangements generate MLL-fusion proteins that bind DNA and drive leukemogenic gene expression. This gene expression program is dependent on the histone 3 lysine 79 (H3K79) methyltransferase DOT1L, and small molecule DOT1L inhibitors show promise as therapeutics for these leukemias. However, the mechanisms underlying this dependency are unclear. We conducted a genome-scale RNAi screen and found that the histone deacetylase SIRT1 is required for the establishment of a heterochromatin-like state around MLL-fusion target genes after DOT1L inhibition. DOT1L inhibits chromatin localization of a repressive complex composed of SIRT1 and SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation and minimal H3K9 methylation at MLL-fusion target genes. Furthermore, the combination of SIRT1 activators and DOT1L inhibitors shows enhanced activity against MLL-rearranged leukemia cells. These results indicate that the dynamic interplay between chromatin regulators controlling activation and repression of gene expression could provide novel opportunities for combination therapy.
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DOI：
10.1073/pnas.0409875102
发表时间：
2005-02-08
影响因子：
11.1
作者：
Kuzmichev, A;Margueron, R;Reinberg, D
通讯作者：
Reinberg, D
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA
影响因子：
9.2
作者：
Feng, Q;Wang, HB;Zhang, Y
通讯作者：
Zhang, Y
影响因子：
20.3
作者：
Deshpande, Aniruddha J.;Chen, Liying;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
影响因子：
12.3
作者：
Langmead B;Trapnell C;Pop M;Salzberg SL
通讯作者：
Salzberg SL