METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m⁶A Modification

Area of Science:

• Molecular Biology
• Epigenetics
• Hematology

Background:

• N⁶-methyladenosine (m⁶A) is a prevalent mRNA modification crucial for various biological processes.
• The specific roles of m⁶A and its associated enzymes in normal and malignant hematopoiesis are not fully understood.

Purpose of the Study:

• To investigate the function of METTL14, a key m⁶A methyltransferase component, in normal and malignant hematopoiesis.
• To elucidate the underlying mechanisms of METTL14's involvement in acute myeloid leukemia (AML).

Main Methods:

• Analysis of METTL14 expression in hematopoietic stem/progenitor cells (HSPCs) and AML cells.
• Functional studies involving METTL14 silencing in normal HSPCs and AML models.
• Investigation of METTL14's regulatory targets and pathways, including MYB, MYC, and SPI1.

Main Results:

• METTL14 is highly expressed in normal HSPCs and specific AML subtypes, and downregulated during myeloid differentiation.
• METTL14 silencing promotes myeloid differentiation, inhibits AML cell survival and proliferation, and impairs leukemia stem/initiation cell self-renewal.
• METTL14 regulates oncogenic targets MYB and MYC via m⁶A modification, and its expression is negatively controlled by SPI1.

Conclusions:

• The SPI1-METTL14-MYB/MYC signaling axis is critical for myelopoiesis and leukemogenesis.
• METTL14 plays a vital role in both normal hematopoiesis and the development and maintenance of AML.
• Targeting METTL14 and m⁶A modification presents a potential therapeutic strategy for AML.