Ricerc@Sapienza

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.