N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic messenger
RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in
normal and malignant hematopoiesis remain elusive. Here, we report that METTL14, a
key component of the m6A methyltransferase complex, is highly expressed in normal
hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells
carrying t(11q23), t(15;17), or t(8;21) and is downregulated during myeloid differentiation.
Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and
AML cells and inhibits AML cell survival/proliferation. METTL14 is required for development
and maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs).
Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets
(e.g., MYB and MYC) through m6A modification, while the protein itself is negatively
regulated by SPI1. Collectively, our results reveal the SPI1-METTL14-MYB/MYC signaling
axis in myelopoiesis and leukemogenesis and highlight the critical roles of METTL14
and m6A modification in normal and malignant hematopoiesis.