Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.
Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.
复制标题
靶向UHRF 1-SAP 30-MXD 4轴用于白血病启动骨髓性白血病的细胞根除。
DOI：
10.1038/s41422-022-00735-6
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发表时间：
2022-12
期刊：
影响因子：
44.1
通讯作者：
Wang, Lan
中科院分区：
文献类型：
--
作者：
Hu, Cheng-Long;Chen, Bing-Yi;Li, Zijuan;Yang, Tianbiao;Xu, Chun-Hui;Yang, Ruirui;Yu, Peng-Cheng;Zhao, Jingyao;Liu, Ting;Liu, Na;Shan, Bin;Zhang, Qunling;Song, Junhong;Fei, Ming-Yue;Zong, Li-Juan;Zhang, Jia-Ying;Wu, Ji-Chuan;Chen, Shu-Bei;Wang, Yong;Chang, Binhe;Hou, Dan;Liu, Ping;Jiang, Yilun;Li, Xiya;Chen, Xinchi;Deng, Chu-Han;Ren, Yi-Yi;Wang, Roujia;Jin, Jiacheng;Xue, Kai;Zhang, Ying;Du, Meirong;Shi, Jun;Wu, Ling-Yun;Chang, Chun-Kang;Shen, Shuhong;Chen, Zhu;Chen, Sai-Juan;Liu, Xiaolong;Sun, Xiao-Jian;Zheng, Mingyue;Wang, Lan
白血病起始细胞（LIC）的异常自我更新驱动侵袭性急性髓细胞白血病（AML）。在这里，我们报告了UHRF 1，一种招募DNMT 1使DNA甲基化的表观遗传调节因子，在AML中高度表达，并预测预后不良。UHRF 1通过维持LIC的自我更新而为髓性白血病发生所需。从机制上讲，UHRF 1通过SRA结构域中的两个关键氨基酸G572和F573与Sin3A相关蛋白30（SAP 30）直接相互作用，以抑制基因表达。UHRF 1或SAP 30的缺失使编码MYC拮抗剂的重要靶基因MXD 4去抑制，并导致白血病发生的抑制。进一步敲低MXD 4可以通过激活MYC通路来挽救白血病发生。最后，我们鉴定了一种UHRF 1抑制剂UF 146，并证明了其在髓系白血病PDX模型中的显著治疗效果。总之，我们的研究揭示了AML中改变表观遗传程序的机制，并提供了一种有希望的针对AML的靶向治疗策略。
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
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DOI：
10.1056/nejmoa1609324
发表时间：
2017-03-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hochhaus A;Larson RA;Guilhot F;Radich JP;Branford S;Hughes TP;Baccarani M;Deininger MW;Cervantes F;Fujihara S;Ortmann CE;Menssen HD;Kantarjian H;O'Brien SG;Druker BJ;IRIS Investigators
通讯作者：
IRIS Investigators
影响因子：
8.1
作者：
Hatlen, Megan A;Wang, Lan;Nimer, Stephen D
通讯作者：
Nimer, Stephen D
DOI：
10.1074/jbc.m117.799700
发表时间：
2017-12-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Houliston RS;Lemak A;Iqbal A;Ivanochko D;Duan S;Kaustov L;Ong MS;Fan L;Senisterra G;Brown PJ;Wang YX;Arrowsmith CH
通讯作者：
Arrowsmith CH
影响因子：
5.4
作者：
Conacci-Sorrell, Maralice;McFerrin, Lisa;Eisenman, Robert N.
通讯作者：
Eisenman, Robert N.
影响因子：
5.2
作者：
Ahmadmehrabi K;Haque AR;Aleem A;Griffiths EA;Roloff GW
通讯作者：
Roloff GW