SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia.
SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia.
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SUV39H1 调节 MLL-AF9 诱导的急性髓系白血病的进展
DOI：
10.1038/s41388-020-01495-6
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发表时间：
2020-12
期刊：
影响因子：
8
通讯作者：
Yuan W
中科院分区：
文献类型：
--
作者：
Chu Y;Chen Y;Guo H;Li M;Wang B;Shi D;Cheng X;Guan J;Wang X;Xue C;Cheng T;Shi J;Yuan W
表观遗传调控在白血病的发生和发展中起重要作用。SUV 39 H1是造血系统中占主导地位的H3 K9甲基转移酶，其表达随着年龄的增长而下降。然而，SUV 39 H1通过其介导的抑制性修饰H3 K9 me 3在白血病发生/白血病进展中的作用仍有待探索。我们发现，与正常个体相比，SUV 39 H1在多种白血病中下调，包括MLL-r AML。与造血干/祖细胞相比，在MLL-r诱导的AML小鼠模型的LSC中观察到Suv 39 h1表达水平和基因组H3 K9 me 3占有率降低。在MLL-r AML小鼠模型中，Suv 39 h1过表达增加了白血病潜伏期并降低了LSC的频率，而Suv 39 h1敲低则加速了疾病进展并增加了LSC的数量。Suv 39 h1表达的增加导致Hoxb 13和Six 1的失活，以及Hoxa 9/Meis 1下游靶基因的逆转，这反过来又减缓了白血病的进展。有趣的是，Hoxb 13表达在MLL-AF 9诱导的AML细胞中上调，而在MLL-AF 9白血病细胞中敲低Hoxb 13显著延长了白血病小鼠的生存期，LSC频率降低。我们的数据显示，SUV 39 H1在MLL-AF 9诱导的AML进展中起肿瘤抑制剂的作用。这些发现提供了SUV 39 H1与AML发展和进展的直接联系。
Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression remains to be explored. We found that SUV39H1 was down-regulated in a variety of leukemias, including MLL-r AML, as compared with normal individuals. Decreased levels of Suv39h1 expression and genomic H3K9me3 occupancy were observed in LSCs from MLL-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. Suv39h1 overexpression increased leukemia latency and decreased the frequency of LSCs in MLL-r AML mouse models, while Suv39h1 knockdown accelerated disease progression with increased number of LSCs. Increased Suv39h1 expression led to the inactivation of Hoxb13 and Six1, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, Hoxb13 expression is up-regulated in MLL-AF9-induced AML cells, while knockdown of Hoxb13 in MLL-AF9 leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies. Our data revealed that SUV39H1 functions as a tumor suppressor in MLL-AF9-induced AML progression. These findings provide the direct link of SUV39H1 to AML development and progression.
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影响因子：
7.3
作者：
Cherblanc, Fanny L.;Chapman, Kathryn L.;Fuchter, Matthew J.
通讯作者：
Fuchter, Matthew J.
DOI：
10.1158/1055-9965.epi-15-0247
发表时间：
2015-09
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Beebe-Dimmer JL;Hathcock M;Yee C;Okoth LA;Ewing CM;Isaacs WB;Cooney KA;Thibodeau SN
通讯作者：
Thibodeau SN
影响因子：
5.9
作者：
Djeghloul D;Kuranda K;Kuzniak I;Barbieri D;Naguibneva I;Choisy C;Bories JC;Dosquet C;Pla M;Vanneaux V;Socié G;Porteu F;Garrick D;Goodhardt M
通讯作者：
Goodhardt M
影响因子：
82.9
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.
通讯作者：
Armstrong, Scott A.
Six1 调节急性髓性白血病中白血病干细胞的维持
影响因子：
5.7
作者：
Chu, Yajing;Chen, Yangpeng;Yuan, Weiping
通讯作者：
Yuan, Weiping