SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation.
SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation.
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DOI：
10.3324/haematol.2019.223883
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发表时间：
2020-09-01
期刊：
影响因子：
10.1
通讯作者：
Muntean AG
中科院分区：
文献类型：
--
作者：
Ropa J;Saha N;Hu H;Peterson LF;Talpaz M;Muntean AG
表观遗传调节因子在正常和恶性造血中起关键作用。HOXA基因簇的失调控，包括表观遗传失调控，驱动约50%的急性髓性白血病（AML）的转化。我们最近发现组蛋白3赖氨酸9甲基转移酶SETDB1通过MLL-AF9白血病细胞启动子H3K9三甲基化沉积负性调节白血病前基因Hoxa9及其辅助因子Meis1的表达。在这里，我们研究了SETDB1表达改变和H3K9甲基化变化对AML的生物学影响。我们证明SETDB1表达与AML患者的疾病状态和总体生存相关。我们在小鼠中总结了这些发现，其中SETDB1的高表达通过促进白血病细胞分化来延迟MLL-AF9介导的疾病进展。我们还探讨了用H3K9甲基转移酶抑制剂UNC0638治疗正常和恶性造血细胞的生物学影响。骨髓白血病细胞对UNC0638表现出细胞毒性，而正常骨髓细胞则表现出cKit+造血干细胞和祖细胞的扩增。与这些数据一致，我们发现用UNC0638处理的骨髓更容易被MLL-AF9转化。下一代白血病细胞测序显示，SETDB1的高表达诱导启动子表观基因组的抑制性变化和AML相关基因的下调，包括Dock1和MLL-AF9靶基因Hoxa9、Six1等。这些数据揭示了SETDB1在白血病中的新靶点，指出SETDB1在负调控白血病前靶基因和抑制AML中的作用。
Epigenetic regulators play a critical role in normal and malignant hematopoiesis. Deregulation, including epigenetic deregulation, of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia (AML). We recently showed that the histone 3 lysine 9 methyltransferase SETDB1 negatively regulates the expression of the proleukemic genes Hoxa9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation in MLL-AF9 leukemia cells. Here, we investigated the biological impact of altered SETDB1 expression and changes in H3K9 methylation on AML. We demonstrate that SETDB1 expression is correlated to disease status and overall survival in AML patients. We recapitulated these findings in mice, where high expression of SETDB1 delayed MLL-AF9 mediated disease progression by promoting differentiation of leukemia cells. We also explored the biological impact of treating normal and malignant hematopoietic cells with an H3K9 methyltransferase inhibitor, UNC0638. While myeloid leukemia cells demonstrate cytotoxicity to UNC0638 treatment, normal bone marrow cells exhibit an expansion of cKit+ hematopoietic stem and progenitor cells. Consistent with these data, we show that bone marrow treated with UNC0638 is more amenable to transformation by MLL-AF9. Next generation sequencing of leukemia cells shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with AML, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in leukemia that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing AML.