A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival.
A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival.
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DOI：
10.1038/s41419-021-03738-0
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发表时间：
2021-06-03
影响因子：
9
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Massett ME;Monaghan L;Patterson S;Mannion N;Bunschoten RP;Hoose A;Marmiroli S;Liskamp RMJ;Jørgensen HG;Vetrie D;Michie AM;Huang X
表观基因组失调是人类恶性血液病的常见病理特征。H3 K9 me 3是急性髓系白血病（AML）的重要表观基因组标志物。其相关的甲基转移酶，如SETDB 1，抑制AML白血病发生，而H3 K9 me 3脱甲基酶KDM 4C是混合谱系白血病重排AML所必需的。然而，KDM 4家族的另一个成员KDM 4A的具体作用和分子作用机制以前尚未明确定义。在这项研究中，我们描绘并功能验证了KDM 4A调控的表观基因组网络。我们表明，KDM 4A的选择性丢失足以在广谱的人AML细胞中诱导凋亡。这种有害的表型是由于H3 K9 me 3和H3 K27 me 3在KDM 4A靶向基因组基因座处的整体积累，从而导致与KDM 4C不同的白血病发生所必需的KDM 4A-PAF 1控制的转录程序的下调。从这个调控网络中，我们进一步提取了富含白血病干细胞活性的KDM 4A-9基因特征; KDM 4A-9评分单独或与已知的LSC 17评分组合，有效地对高风险AML患者进行了分层。总之，这些结果确立了KDM 4A对AML自我更新和生存的重要和独特作用，支持进一步研究KDM 4A及其靶点作为AML的潜在治疗弱点。
Epigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
H3K9ME3依赖性异染色质：细胞命运变化的屏障。
DOI：
10.1016/j.tig.2015.11.001
发表时间：
2016-01
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Becker JS;Nicetto D;Zaret KS
通讯作者：
Zaret KS
影响因子：
50.3
作者：
Muntean AG;Tan J;Sitwala K;Huang Y;Bronstein J;Connelly JA;Basrur V;Elenitoba-Johnson KS;Hess JL
通讯作者：
Hess JL
影响因子：
64.5
作者：
Kim J;Guermah M;Roeder RG
通讯作者：
Roeder RG
影响因子：
11.4
作者：
通讯作者：
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