SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia.
SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia.
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MLL 重排白血病中 SETD2 介导的 H3K36me3 和 H3K79me2 之间的串扰
DOI：
10.1038/leu.2017.339
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Huang G
中科院分区：
文献类型：
--
作者：
Bu J;Chen A;Yan X;He F;Dong Y;Zhou Y;He J;Zhan D;Lin P;Hayashi Y;Sun Y;Zhang Y;Xiao Z;Grimes HL;Wang QF;Huang G
以前，我们在22%的MLL重排（MLLR）急性白血病患者中发现了SETD 2功能丧失突变，这暗示了SETD 2突变和MLL融合之间的协同作用机制。然而，SETD 2-H3 K36 me 3下调如何加速MLLR白血病的详细机制仍不清楚。在这里，我们发现在MLLR白血病中，H3 K79 me 2和H3 K36 me 3都异常升高，并且在一组基因中共同富集。SETD 2失活导致H3 K36 me 3的总体减少和H3 K79 me 2的进一步升高，但不改变已知MLL融合靶基因的表达。相反，这种组蛋白变化模式与一组新基因的转录失调有关;下调肿瘤抑制因子（例如ASXL 1）和上调癌基因（例如ERG）。综上所述，我们的研究结果揭示了致癌DOT 1 L-H3 K79 me 2轴和肿瘤抑制性SETD 2-H3 K36 me 3轴之间在基因调控中的全局串扰，提供了关于SETD 2突变如何通过其他肿瘤抑制因子和癌基因的差异调节加速MLLR白血病发生的分子见解。
Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusion target genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes.
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影响因子：
16.6
作者：
Mar, Brenton G.;Bullinger, Lars B.;McLean, Kathleen M.;Grauman, Peter V.;Harris, Marian H.;Stevenson, Kristen;Neuberg, Donna S.;Sinha, Amit U.;Sallan, Stephen E.;Silverman, Lewis B.;Kung, Andrew L.;Lo Nigro, Luca;Ebert, Benjamin L.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
婴儿MLL重新培养急性淋巴细胞白血病中体细胞突变的景观。
影响因子：
30.8
作者：
Andersson AK;Ma J;Wang J;Chen X;Gedman AL;Dang J;Nakitandwe J;Holmfeldt L;Parker M;Easton J;Huether R;Kriwacki R;Rusch M;Wu G;Li Y;Mulder H;Raimondi S;Pounds S;Kang G;Shi L;Becksfort J;Gupta P;Payne-Turner D;Vadodaria B;Boggs K;Yergeau D;Manne J;Song G;Edmonson M;Nagahawatte P;Wei L;Cheng C;Pei D;Sutton R;Venn NC;Chetcuti A;Rush A;Catchpoole D;Heldrup J;Fioretos T;Lu C;Ding L;Pui CH;Shurtleff S;Mullighan CG;Mardis ER;Wilson RK;Gruber TA;Zhang J;Downing JR;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
通讯作者：
St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
20.3
作者：
Grossmann, Vera;Tiacci, Enrico;Falini, Brunangelo
通讯作者：
Falini, Brunangelo