SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia

被引：31

作者：

Bu, J. ^{[1
,2
,3
]}

Chen, A. ^{[1
,2
]}

Yan, X. ^{[2
]}

He, F. ^{[1
]}

Dong, Y. ^{[2
]}

Zhou, Y. ^{[2
]}

He, J. ^{[1
]}

Zhan, D. ^{[1
,2
,3
]}

Lin, P. ^{[2
]}

Hayashi, Y. ^{[2
]}

Sun, Y. ^{[1
,3
]}

Zhang, Y. ^{[2
,4
,5
,6
]}

Xiao, Z. ^{[4
,5
,6
]}

Grimes, H. L. ^{[7
]}

Wang, Q. F. ^{[1
,3
]}

Huang, G. ^{[2
]}

机构：

[1] Chinese Acad Sci, Beijing Inst Genom, Collaborat Innovat Ctr Genet & Dev, Key Lab Genom & Precis Med, Beijing, Peoples R China

[2] Cincinnati Childrens Hosp Med Ctr, Div Pathol & Expt Hematol & Canc Biol, 3333 Burnet Ave,Room S7-607, Cincinnati, OH 45229 USA

[3] Univ Chinese Acad Sci, Beijing, Peoples R China

[4] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China

[5] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China

[6] Peking Union Med Coll, Tianjin, Peoples R China

[7] Cincinnati Childrens Hosp Med Ctr, Div Immunol, Cincinnati, OH 45229 USA

来源：

LEUKEMIA | 2018年 / 32卷 / 04期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

ACUTE MYELOID-LEUKEMIA; RNA-POLYMERASE-II; TRANSCRIPTION FACTOR ERG; MYELODYSPLASTIC SYNDROMES; LYMPHOBLASTIC-LEUKEMIA; LYMPHOCYTIC-LEUKEMIA; SOMATIC MUTATIONS; HISTONE H3; METHYLATION; CELLS;

D O I：

10.1038/leu.2017.339

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：890 / 899

页数：10

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