HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m⁶A-dependent stabilization of KDM4B mRNA

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.