低氧诱导因子1α（HIF1α）在t（8;21）急性髓系白血病（AML）中异常过度表达，并通过转录激活DNA甲基转移酶3α导致DNA高甲基化，起着癌基因的功能。然而，HIF1α是否影响RNA N6-甲基腺嘌呤（m6A）甲基转移酶仍不清楚。我们发现HIF1α促进肾母细胞瘤1相关蛋白（WTAP）的表达，该蛋白是m6A甲基转移酶复合物的主要成分， 显著改变了全转录组m6A分布，并增强了t（8;21）AML的细胞增殖。与此一致，WTAP在t（8;21）AML患者中高表达，并预示着不良预后。此外，WTAP敲低抑制了白血病细胞的生长，诱导了凋亡和分化。在机理上，HIF1α通过直接结合其启动子区域的缺氧应答元件，转录激活WTAP基因表达。对HIF1α-WTAP轴的药物或基因干预导致赖氨酸去甲基化酶4B（KDM4B）转录本的m6A水平降低，其降解增加，与KDM4B的较低表达和在赖氨酸9上组蛋白H3的三甲基化水平更高相关。 KDM4B敲低抑制了体外和小鼠中的白血病细胞生长。因此，HIF1α介导WTAP的高表达增强了白血病细胞的恶性行为，并通过监控m6A依赖KDM4B翻译推动了m6A RNA甲基化和组蛋白甲基化之间的相互作用。 © 2023年作者，在Springer Nature Limited的独家许可下。

Hypoxia inducible factor 1α (HIF1α) is abnormally overexpressed in t(8;21) acute myeloid leukemia (AML) and functions as an oncogene through transactivating DNA methyltransferase 3 alpha leading to DNA hypermethylation. However, it remains unclear whether HIF1α influences RNA N6-methyladenosine (m6A) methyltransferases. Here, we show that HIF1α promotes the expression of Wilms tumor 1-associated protein (WTAP), a main component of the m6A methyltransferase complex, markedly alters the transcriptome-wide m6A distribution and enhances cell proliferation in t(8;21) AML. In agreement with this, WTAP is overexpressed and predicts poor prognosis in t(8;21) AML patients. Moreover, WTAP knockdown inhibits growth, and induces apoptosis and differentiation of leukemia cells. Mechanistically, HIF1α transactivates WTAP gene expression by directly binding to the hypoxia-response element of its promoter region. Pharmacological or genetic intervention in the HIF1α-WTAP axis results in the reduction of m6A level on lysine demethylase 4B (KDM4B) transcripts and increased its degradation, correlated with lower expression of KDM4B and higher trimethylation levels of histone H3 on lysine 9. KDM4B knockdown inhibits leukemia cell growth in vitro and in mice. Thus, HIF1α-mediated WTAP high expression enhances the malignant behavior of leukemia cells and drives a crosstalk between m6A RNA methylation and histone methylation through monitoring m6A-dependant KDM4B translation.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.