A positive feed-forward regulatory loop between METTL3 and WTAP sustains the oncogenic role of the m6A methylation complex in myeloid leukemia

The Wilms tumor 1 (WT1)-associated protein (WTAP) is upregulated in many tumours, including, acute myeloid leukemia (AML), where it plays an oncogenic role by interacting with different proteins involved in RNA processing and cell proliferation. In addition, WTAP is also a regulator of the nuclear complex required for the deposition of N6-Methyladenosine (m6A) into mRNAs, containing the METTL3 methyltransferase. However, it is not clear if WTAP may have m6A-independent regulatory functions that might contribute to its oncogenic role. Here, we show that both knockdown and overexpression of METTL3 protein results in WTAP protein upregulation, indicating that METTL3 levels are critical for WTAP protein homeostasis. However, we show that WTAP upregulation is not sufficient to promote cell proliferation in the absence of a functional METTL3. Our results indicate the existence of a positive feedforward regulatory loop, where METTL3 upregulates WTAP, which is relevant to increase WTAP expression concomitantly to the METTL3/METTL14 core m6A methylation complex and sustain the oncogenic role reported for the m6A modification complex in leukemia.