AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3α transactivation
AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3α transactivation
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AML1/ETO 与 HIF1α 合作通过 DNMT3a 反式激活促进白血病发生
DOI：
10.1038/leu.2015.56
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发表时间：
2015-08-01
期刊：
影响因子：
11.4
通讯作者：
Yu, L.
中科院分区：
文献类型：
--
作者：
Gao, X. N.;Yan, F.;Yu, L.
AML1/ETO(A/E)融合蛋白在无突变事件的急性髓系白血病(AML)中诱导白血病发生的机制仍不清楚。在这里，我们证明A/E和缺氧诱导因子1α(HIF1α)之间的相互作用足以启动白血病细胞随后的侵袭性生长。与此一致的是，HIF1α在A/E阳性的AML患者中高度表达，并强烈预测不良预后，而不考虑基因突变。A/E和HIF1α在白血病细胞中的共表达导致体外细胞增殖率较高，使小鼠的白血病状态更加严重。机制上，A/E和HIF1α形成正向调控回路，协同反式激活DNMT3α基因，导致DNA高甲基化。药物或遗传干预A/E-HIF1α环导致DNA低甲基化，肿瘤抑制基因p15(INK4b)高甲基化重新表达，抑制白血病生长。因此，HIF1α的高表达是一个可靠的标记物，可以在预后良好的AML组中识别预后较差的患者，并代表着高危A/E驱动的白血病的创新治疗靶点。
The mechanisms by which AML1/ETO (A/E) fusion protein induces leukemogenesis in acute myeloid leukemia (AML) without mutagenic events remain elusive. Here we show that interactions between A/E and hypoxia-inducible factor 1 alpha ( HIF1 alpha) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1 alpha is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1 alpha in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1 alpha form a positive regulatory circuit and cooperate to transactivate DNMT3 alpha gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1 alpha loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15(INK4b) and the blockage of leukemia growth. Thus high HIF1 alpha expression serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group and represents an innovative therapeutic target in high-risk A/E-driven leukemia.